MALARIA AND THE TRAVELLER

1340

drug; the danger is that generalised use of chloroquine in prophylaxis, especially if indiscriminate and irregular, will encourage widespread chloroquine resistance, as in parts of south-east Asia and Latin America. I prefer maloprim,z one tive

Letters

to

the Editor

MALARIA AND THE TRAVELLER

SIR,-Dr Warwick and her colleagues (June 9, p. 1242) warn of increasing importation of malaria into Britain and plead for "medical education in the use of malaria prophylaxis". I would like to set out, for doctors practising in countries where malaria is not endemic, the limitations as well as the benefits of chemoprophylaxis. Of the 1909 cases of malaria imported into Britain in 1978, 1448 (76%) were infected in the Indian subcontinent and 452 (23..5%) in Africa.’ On the Indian subcontinent, the common malaria is vivax malaria (infection with Plasmodium vivax) which used to be known as benign tertian malaria. All the prophylactic drugs in common use can suppress an attack of vivax malaria only while they are taken regularly; once the tablets are stopped, and even if they have been taken for 4 weeks after the traveller has returned, a febrile attack is bound to occur later. These tablets are effective against parasites in the blood but not against foci of infection in the liver (the primary and secondary exoerythrocytic phases); since liver involvement continues for 2-3 years prophylaxis would have to continue throughout this time to ensure freedom from clinical malaria. The usual story is that a few weeks or months after return and after stopping the prophylactic tablets (it may be as long as 13 months), the traveller goes down with an attack of vivax malaria; chloroquine quickly terminates the attack but recurrence is likely over the next 2 years because of persistence of the secondary exoerythrocytic phase in the liver. The only drugs capable of destroying malaria parasites in the liver are the 8-aminoquinolines, of which primaquine is the best known, hence they are used when it is desired to eradicate a P. vivax infection. Largely due to their toxicity, these drugs are not used prophylactically. A similar situation holds good for two rare types of malaria-ovale (P. ovale) and quartan (P. malarice)-except that the secondary exoerythrocytic phase of P. malarice can survive in the liver for much longer and quartan malaria will recur over many years unless primaquine is given. In Africa, the common type of malaria is falciparum malaria, previously known as malignant tertian or subtertian malaria, and is unique in several ways. Firstly, it is renowned for its capacity to kill. Secondly, P. falciparum is prone to develop resistance to every antimalarial in common use, with the possible exception of quinine. Thirdly, P. falciparum does not persist in the liver beyond the primary exoerythrocytic phase. Because some antimalarials (proguanil and pyrimethamine) can destroy this phase and others can kill parasites in the erythrocytic phase which occurs about 2 weeks after infection (chloroquine, amodiaquine, mepacrine, sulphonamide, and dapsone), an attack of falciparum malaria will not occur when prophylaxis is stopped, provided that the strain of P. falciparum is not resistant to the antimalarial used and provided that tablets are taken for 4 weeks after return from Africa. If falciparum malaria does develop in a returned traveller, due to drug resistance or to neglect of chemoprophylaxis, successful treatment spells the end of the disease, but if the erythrocytic phase is not diagnosed and treated, a non-immune patient will die. Of the 452 patients infected in Africa in 1978 and treated in Britain, 9 died, and all these deaths were due to P. falciparum, whereas there were no deaths among the 1448 patients infected in the subcontinent of India. The choice of prophylactic antimalarial for travellers to Africa lies between a 4-amino-

quinoline (chloroquine

or

amodiaquine)

or a

drug combining

antimalarials which potentiate each other (one is ’Maloprim’ [pyrimethamine and dapsone] and another is ’Fansidar’ [pyrimethamine and sulphadoxine]). I prefer not to advise a 4-aminoquinoline because resistant strains of P. falciparum in Africa are very rare and chloroquine is so valuable as a curatwo

1. Malaria in the United Kingdom, 1978 Br.

med. J. 1979,i, 1496.

tablet once a week for an adult. I have observed its value among expatriates and their families on two diamond mines in West Africa; for over 5 years no case of falciparum malaria has occurred, whereas cases had been occurring previously in expatriates taking proguanil or pyrimethamine. Doctors who prescribe proguanil or pyrimethamine prophylaxis for travellers to Africa may not be aware that strains of P. falciparum resistant to proguanil and pyrimethamine are now widespread on that continent. Cross-resistance between these two drugs is the rule, as it is between mepacrine and the 4-aminoquinolines. The table summarises the doses and names for -antimalarial drugs. PHARMACEUTICAL NOTES ON ANTIMALARIAL PROPHYLAXIS

I hope that my earlier remarks about vivax malaria have not given the impression that travellers to the Indian subcontinent do not. need malarial prophylaxis. On the contrary, it is necessary because of the scattered foci of falciparum, and maloprim would be my choice for prophylaxis. - blood films should be done on every recently returned traveller who has .afebrile illness, irrespective of whether the clinical diagnosis is dysentery, influenza, infectious hepatitis, or encephalitis, and at least one thick film and two thin films should be made. To make a thick film, place a generous drop of blood on the centre of a glass slide, and, using the stabbing needle held parallel to the slide, the drop is evenly spread to

the size of a postage stamp, after which the smear is allowed to dry with the slide horizontal. The best way to ensure a good thin smear is first to clean the slide with soap and hot water to remove grease and dust, and then to rinse well and dry with a clean smooth towel. 33 Crown Lane Gardens, London SW16 3HZ

W. H. JOPLING

RECURRENT ANAPHYLAXIS DUE TO PLASMODIUM VIVAX INFECTION can present in unusual forms. We describe where Plasmodium vivax antigen was eventually pinpointed as the likely cause of recurrent anaphylaxis. A 40-year-old male was first seen in August, 1977, with complaints of generalised urticaria and mild puffiness of the face which responded to antihistamines. He had attacks on alternate days. During the third episode he had swelling of lips, a choking sensation, and prostration with hypotension and was admitted as an emergency. He was treated for acute anaphylaxis with adrenaline, intravenous fluids, hydrocortisone, and antihistamines. P. vivax infection was also found and antimalarial therapy was prescribed. The anaphylaxis was

SIR,-Malaria

here

2.

a case

Jopling,

W. H. Good Health Abroad:

a

traveller’s handbook. Bristol, 1975.

1341 to one of the drugs he had been taking before admission. In December, 1977, he was again admitted in an attack of anaphylaxis. Investigations revealed no clue to the cause of anaphylaxis: there was no eosinophilia, stools were negative for parasites, there was no history of drug intake before this episode, and there was no history of atopy. A blood-film revealed P. vivax for which he was given antimalarial treatment. When he again presented in April, 1978, with symptoms of anaphylactic shock and fever, the previous episodes were reviewed, and the fever, P. vivax infection, and periodicity suggested that the infection might have been responsible for the anaphylaxis. Prophylactic chemotherapy with weekly chloroquine was advised, and he remained well until July, 1978, when he stopped chloroquine because of his suspicion of eye toxicity. After 2 weeks fever, angioneurotic oedema, and hypotension returned and a blood smear was once more positive P. vivax. He has since been on prophylactic chloroquine and is

ascribed

symptom-free. Immunological tests with P. vivax antigen were done to elucidate presentation of malaria. A skin test (scratch method) was positive, being 3 mm with diluent and 8 mm with P. vivax antigen; and rat mast-cell degranulation’ was 80% with the patient’s serum (10-15% with control serum). Histamine assays3 were done with human chopped lung sensitised with patient’s serum, normal control sera, and serum of another patient with malaria and then challenging with P. vivax antigen. The baseline for histamine release was set with fifteen normal sera with no antibody against malaria, and results were this unusual

recorded as percentage increases over this baseline. Values were 28.7% for the patient’s serum but only 6.8% for controls and 9.3% for the other malaria patient. Serum IgG, IgA, and IgM3 levels were 210, 129, and 260 i.u./ml, respectively; IgEwas 8000 i.u./ml (normal 594±378); and the complement profiles was normal.

The repeated episodes of anaphylaxis, urticaria, and angioredema occurring every other day with positive bloodfilm for P. vivax leave no doubt that these were related to malaria infection. Although erythematous rash and uricarial or even purpuric eruption may appear during the febrile paroxysm of malaria,6presentation as anaphylaxis has not been described. One possibility, supported by the immunological tests, is that antigens released when infected red blood-cells ruptured were responsible for these attacks. An IgE-mediated hypersensitivity reaction is supported by the raised serum-IgE. Complement activation does not seem to be responsible. Man’s ability to acquire protective immunity following exposure to malaria is well known.’ This case suggests that the immunological response may not always be protective.

Departments of Internal Medicine, Pædiatrics, and Parasitology, Postgraduate Institute of Medical Education and Research,

Chandigarh 160012, India

B. K. SHARMA K. K. TALWAR V. BHATNAGAR

LATA KUMAR N. K. GANGULY R. C. MAHAJAN

LONG-TERM FOLLOW-UP OF CHILDREN BORN TO WOMEN WHO HAD AMNIOCENTESIS

SiR,-The immediate risk of injury to the fetus and the risk of abortion in a pregnancy investigated by amniocentesis are negligible89 but there have as yet been no systematic follow-up studies of children born to women who have had this proced1. Kortzer, J. L., Haddad, Z. H., Lopapa, A. F. Immunology, 1971, 20, 545. 2. Sheard, P., Killingbalk, P. G., Blair, A. M. J. N. Nature, 1967, 216, 283. 3. Mancini, G., and others Immunochemistry, 1965, 2, 235. 4. Rowe, D. D. Bull. Wld Hlth Org. 1969, 40, 613. 5. Lachman, P. S., Wales, H. T. in Handbook of Experimental Immunology (edited by D.M. Weir); p. 51. Oxford, 1978. 6. Banerjea, J. G. in A Handbook of Tropical Diseases (edited by J. C. Banerjea, and P. B. Bhattacharya); p. 53. Calcutta, 1960. 7. McGregor, I. A. Br. med. Bull. 1972, 28, 22. 8. N.I.C.H.D. Nauonal Registry for Amniocentesis Study Group J. Am. med.

Ass. 1976, 236, 1471. N. E., Dallaire, L., Miller, J. R., Siminovich, L., Hamerton, J. L., Miller, J., McKeen, C. Can. med. Ass. J. 1976, 115, 739.

9. Simpson,

We have examined 80 children aged between 4 years 8 months and 7 years who were born to the first women to be investigated by amniocentesis in Goteborg. In 90% of cases the indication for amniocentesis was maternal age (35 years or more); 1 mother had had a child with Down syndrome, and the remaining 7 had indications of a psychological nature. The mean age of the mothers at the time of birth of the children was 37.4 years (s.D. 4-4). The socioeconomic status of the families was average for Sweden. All the children in the study (47 boys and 33 girls) had a thorough medical examination, including a neuropsychiatric evaluation. Their medical histories were collected by interviewing the mother at the time of the examination. A specially designed questionnaire was used. Data were also collected from medical records. We found no children with signs of chromosome abnormality. 1 girl had a small (diameter 5 mm) circular depigmentated nasvus in the skin to the right immediately above the umbilicus. According to her mother the nxvus had been present from birth but it was not noted in the medical records. Another girl had a 3 cm long scar on the outside of the left shin. This too had been apparent at birth, according to the mother, but was not mentioned in the neonatal records. These two girls with clinically insignificant scars were the only children to show any signs or symptoms that might be connected with the amniocentesis. Injury to the fetus in connection with amniocentesis has been recorded before, with skin scars, 10 corneal scars," or more widespread damage. 12 Of the remaining children 1 girl had a serious heart condition (persistent ductus arteriosus). Of the boys, 1 had postmeningitic hydrocephalus, 1 had an undescended testis, and 2 were very overweight. A high proportion of the children in the study showed signs of minimal brain dysfunction. This finding we attributed to the high maternal age,"; comments on this aspect will be published elsewhere and we are now doing a controlled study of this relationship. We conclude that amniocentesis for chromosome analysis is a safe procedure with negligible or no long-term ill-effects on the child. ure.

Department of Pædiatrics, East Hospital, University of Göteborg, and Department of Psychiatry III, Lillhagen Hospital, University of Göteborg, Göteborg, Sweden

CHRISTOPHER GILLBERG PEDER RASMUSSE

JAN WAHL STROM

HERBICIDE USE AND INCIDENCE OF NEURAL-TUBE DEFECTS

SIR,-The herbicide 2, 4, 5-trichlorophenoxyacetic acid (2, 4, 5-T) containing 2, 3, 7, 8-tetrachloribenzo-paradioxin

(T.C.D.D. or dioxin) has induced teratogenic and fetotoxic effects under experimental conditions in animals.’ To detect any association between 2, 4, 5-T usage and neural-tube defects in man, we investigated the only Australian data accessible to us-relatively complete epidemiological information on neural-tube defects in New South Wales2 and annual usage rates of 2, 4, 5-T for the whole of Australia (usage rates for each State were not available). Methods were those used previously to test Renwick’s theory that 3potato blight was causally associated with neural-tube defects. Data for ten years yielded a linear correlation between the previous year’s Australian usage of 2, 4, 5-T and the annual Weiss, B., Kellog, B. Am. J. Obstet. Gynec. 1976, 126, 247. 11. Cross, H. E., Maumenee, A. E. Ophthalmologica, 1973, 90, 303. 12. Rehder, H., Weitzel, H. Lancet, 1978, i, 382. 13. Gillberg, C., Rasmussen, P., Wahlström, J. Acta pedopsychiat. (in the press). i. U.S. Environmental Protection Agency, Pesticide programs, Federal Register, Washington, 21 April, 1978. 2. Field, B. J. med. Genet. 1978, 15, 329. 3. Field, B., Kerr, C. Lancet, 1973, ii, 507. 10. Broome, D. L., Wilson, M. G.,