NEUTROPHILS AND ADULT RESPIRATORY DISTRESS SYNDROME

1392

SIR,-Professor Hull and Dr Nicoll raise an important point concerning differences in guidelines about immunisation. With regard to pertussis immunisation in particular, I suggest that the guidelines should be based on acceptable scientific evidence rather than on anecdotal evidence repeated from one publication to another. For instance, after a thorough search of the literature listed in Index Medicus I was unable to determine the evidence on which it is said by some that epilepsy (in the child or a near or distant relative), developmental delay, perinatal hypoxia, cerebral irritation in the newborn, neurological disease, family history of CNS disorders, or any other condition increase the risk of "brain damage" as a result of the vaccine. The common febrile reaction to pertussis or measles vaccine may precipitate a febrile convulsion in any child, especially in an epileptic; a child with mental subnormality or cerebral palsy (especially of the spastic type) is more likely than others to have a convulsion during childhood; and one might be unlucky in any of the above conditions to precipitate the first seizure-but in none of those, except in the very small likelihood of a prolonged convulsion, would brain damage result, and nor would it in the rare case of a breath-holding convulsion or syncope immediately after an injection. It would certainly be foolhardy to give a second or subsequent dose of pertussis vaccine to a child who for any reason had had a convulsion with a previous dose-but the reason for this is not clear. One difficulty in interpreting previous work on the subject lies in the lack of evidence that children who are said to have suffered brain damage from the vaccine were in fact previously normal: every paediatrician must have seen abnormal infants who had been previously thought by the parents to be normal. Before accepting the story that the infant had been "normal" before the vaccine one would have to have a convincing developmental history from the parent, a normal head circumference in relation to weight, and evidence of normal development in the notes of a competent family doctor, clinical medical officer, or health visitor. Another difficulty is that "brain damage" said to result from the vaccine is in no way different from that which occurs in unvaccinated infants. A thorough reading of the literature on pertussis immunisation has not suggested to me that we know the risk factors for brain damage resulting from the vaccine. It is not surprising that Hull and Nicoll found such discrepancies in the guidelines. 8

Harley Road,

Sheffield S 11 9SD

R. S. ILLINGWORTH

VALPROATE AND SPINA BIFIDA

SIR,-Since the first publication suggesting an association between maternal exposure to valproic acid (VPA) during early pregnancy and the birth of children with spina bifida, confirmatorr-4 and negative5-7 studies have appeared and the statistical interpretation of the first cases has been questioned.Our first report was based on data from the monitoring registry, at 1’Institut Europeen des Genomutations, and no information was available on exposure rates to VPA among pregnant women with epilepsy. Such information is now available. We retrieved 797 hospital records of women aged 15-45 who had had an electroencephalogram at l’Hôpital de Neurologie et Neurochirurgie P. Wertheimer, Lyon, between 1976 and 1983. 646 were epileptic and these were sent a questionnaire asking for information on seizures, drug use, and pregnancies. Answers were obtained from 280, specifying 74 deliveries (52 women) between 1976 and 1983. 7 were delivered outside the Rhone-Alpes area (covered by the monitoring system), leaving 67. To this material was added a group of 74 epileptic women who delivered an infant at one of Lyon’s three maternity hospitals with computerised records (1979-83). 5 of these women had been identified via the EEG search, leaving 141 deliveries. The rate for all malformations in the monitoring registry is 1307o for the former group of infants and 23% in the latter group (=2-1, NS) and the respondents to the questionnaire seem not to have been biased by the presence of a malformation in their baby. In 40 of the 141 pregnancies the mother had used VPA alone or in combination, an exposure rate of 28%. In a previous study,9 14 epileptic women with spina bifida infants were described; 12 had

used VPA. If the 2807o estimate of VPA use is applied to these 14 cases the expected number of VPA exposures is 4. Since that report, we identified 3 epileptic women on VPA with spina bifida infants among 63 241 births. Given the spina bifida rate in the population and the 7 per 1000 estimateio of epileptic women among mothers of spina bifida infants, the expected number of epileptic women having an infant with spina bifida is only O. 17 (Poisson, p<0 0 1). 1 of these women had twins concordant for spina bifida. These new data strongly support the notion that VPA causes

spina bifida.

We thank ProfM. Berland, ProfF. Charvet, Prof D. Dargent, and ProfJ. M. Thoulon for access to maternity records at Hospices Civils de Lyon. Institut Européen des Génomutations, 69005 Lyon, France Functional Neurology and Epilepsy Service,

Hôpital Neurologique, Lyon

ELISABETH ROBERT ELISABETH LOFKVIST

FRANÇOIS MAUGUIERE

E, Guibaud P. Maternal valproic acid and congenital neural tube defects. Lancet 1982; ii: 937. 2. Jeavons PM. Sodium valproate and neural tube defects. Lancet 1982; ii. 1282-83. 3. Lindhout D, Meinardi H, Peters PWJ, Kreis IA. Teratogenicity of epileptic drug combinations. In 11th Conference of European Teratology Society (Paris) Abstr Teratol 1984; 29: 28A 4. Lindhout D, Meinardi H. Spins bifida and in-utero exposure to valproate Lancet 1984; 1. Robert

ii:

396.

5. Nakane

Y, et al. Multi-institutional study on the teratogenicity and fetal toxicity of antiepileptic drugs a report ofa collaborative study group in Japan. Epilepsia (NY) 1980; 21: 663-80.

6. Hiilesman VK, et al Valproic acid during pregnancy Lancet 1980; i: 883. 7. Castilla E. Valproic acid and spina bifida. Lancet 1983, ii 683.

8. MacRae KD. Sodium valproate and neural tube defects Lancet 1982; ii: 1282. 9 Robert E, Rosa F. Valproate and birth defects. Lancet 1983; ii: 1142. 10 International Clearinghouse for Birth Defects Monitoring Systems. Annual report 1982. Stockholm.

NEUTROPHILS AND ADULT RESPIRATORY DISTRESS SYNDROME

SIR,-Your Oct

6 editorial (p 790) cited the work of Thommasen renal dialysis patients showing that neutrophils may be involved in the pathogenesis of adult respiratory distress syndrome (ARDS). Some further evidence that this is so comes from observations in patients recovering from severe myelosuppression whose respiratory function worsens as the neutrophil count rises, as the following case illustrates. A 26-year-old man with a long history of swelling of the left testis presented with hepatosplenomegaly and a serum a-fetoprotein level of 13 800 kU/1. He underwent orchidectomy, histology confirming an undifferentiated malignant teratoma, and cytotoxic chemotherapy was started. During the fourth course of chemotherapy severe renal failure and myelosuppression developed, which persisted for two weeks. On July 22, 1983, his total white cell count was 0 - 4 x 109/1. By July 29 it had risen to 1 - 6 (1-37x10/1 lymphocytes and 0-14x10/1 monocytes). No neutrophils were seen. He was febrile during this period and was treated with piperacillin and tobramycin; after the development ofa rash this was changed to cefuroxime and metronidazole. The patient had an epileptic seizure on July 29 which was shown to be due to a intraventricular haemorrhage probably caused by hypertension secondary to his renal failure. On this date crepitations were audible at the right base and on July 30 he coughed a small amount of purulent sputum, and a chest X-ray showed patchy shadowing at both bases. A coagulase-negative staphylococcus was grown from his sputum. His condition deteriorated rapidly over the next 24 h. Spontaneously breathing 60% oxygen he had a Pa02 of 57 mm Hg. He coughed up frothy bloodstained sputum and chest X-ray showed increased shadowing which was considered to be due to pulmonary oedema and his intravenous fluid input was reduced to that required for medication. His Pa02 fell to 47 mm Hg on Aug 2 and he required intubation and ventilation. Before mechanical ventilation started his mean pulmonary artery wedge pressure was 10 mm Hg. On the preceding day his peripheral white count was 16 - 8 x 109/1 and his neutrophil count was 12-6. He required 10 mm Hg positive end-expiratory pressure, on which his Pa02 became normal, being et

all

on

1393 109 mm Hg on Aug 3. Mechanical ventilation was discontinued the following day. This patient had disorder in many body systems after treatment for advanced testicular tumour. The respiratory component of his

DRUG AND METABOLITE EXCRETION AFTER

60. mg

METHOXYPHENAMINE HYDROCHLORIDE ORALLY TO FIVE HEALTHY VOLUNTEERS

illness worsened considerably at the same time as first monocytes and then neutrophils started to appear in his peripheral blood-a sequence of events consistent with the hypothesis that ARDS results from neutrophil products. A further pointer in this direction is the impression that some neutropenic patients may have radiologically severe changes in the lungs and yet be free of respiratory distress. This problem is not common, but when it does occur prospective monitoring of these patients may permit further investigation of ARDS; and recovery from cytotoxic drug induced neutropenia is a possible approach by which experimental pathologists may examine its mechanism. Cross Hospital, London W6 8RF

Charing

1. Thommasen

with adult

S. M. CRAWFORD

HV, Russell JA, Boyko WJ, Hogg JC Transient leucopenia associated respiratory distress syndrome Lancet 1984, i. 809-12.

METHOXYPHENAMINE AND DEXTROMETHORPHAN AS SAFE PROBES FOR DEBRISOQUINE HYDROXYLATION POLYMORPHISM

SiR,—Dr Kupfer and others (Sept 1, p 517) suggest dextromethorphan as a safe probe for assessing debrisoquine-type drug hydroxylation polymorphism. We too have investigated interphenotype differences in the handling of a component of cough syrups-namely, methoxyphenamine (MP), a 02-adrenergic stimulant that is metabolised by three distinct metabolic pathways 1 (aromatic hydroxylation, N-demethylation, and O-demethylation).1 60’ 3 mg methoxyphenamine hydrochloride was given by mouth to healthy volunteers who were poor (three) or extensive (eight) hydroxylators of debrisoquine. Samples of the 0-12 h urine were hydrolysed with sulphatase/glucuronidase and analysed for MP and the three metabolites.2No interphenotype differences for the N-demethyl metabolite were found. However, there were significant differences in the urinary excretion of hydroxymethoxyphenamine (OHMP) and O-demethylMP and in the urinary metabolic ratios of MP to either of these two metabolites. A highly significant correlation was found between the debrisoquine metabolic ratio and either of the MP metabolic ratios, as shown (figure) for the MP/O-demethylMP ratio. Thus, both the aromatic hydroxylation and the O-demethylation of MP are likely coinherited with determined genetically debrisoquine

hydroxylation. Dextromethorphan (pKa 8’3)3 and MP (pKa 10’45)4 are basic drugs, where the excretion of drug and many non-conjugated metabolites retaining the basic centre is dependent upon the urinary pH. However, the excretion of a metabolite largely eliminated in the urine as conjugates is pH independent. Thus, a metabolic ratio expressed in terms of a parent drug and this latter type of metabolite will be affected by urine pH. This has an important implication in

that an individual phenotyped by such a metabolic ratio on two different occasions may give widely different results. MP was orally administered to five healthy volunteers on two separate occasions under controlled acidic and alkaline conditions. The renal excretions of MP, O-demethylMP, and N-demethylMP were pH dependent, while OHMP excretion was independent of pH (table). Thus, metabolic ratios based on OHMP, a metabolite largely (>70%) excreted as glucuronide and/or sulphate conjugates, are affected by urine pH. On the other hand, O-demethylMP is and the MP/0largely excreted non-conjugated (>90%), demethylMP metabolic ratio is not appreciably affected by changes in urine pH. Thus, the relatively innocuous agent methoxyphenamine can be used reliably to assess genetic drug hydroxylation

phenotype. Since the 0-demethyl and N,O-didemethyl metabolites of dextromethorphan are largely excreted as conjugates,5 it is likely that metabolic ratios based on parent drug to either of these metabolites will be affected by changes in renal pH. Therefore, it is necessary to ensure that renal pH will not affect phenotype status before recommending dextromethorphan as a safe probe of debrisoquinetype drug hydroxylation polymorphism.

Supported by Medical

Research Council of Canada, MA-8673.

College of Pharmacy, University of Saskatchewan, Saskatoon, Saskatchewan, Canada S7N

0W0

S. D. ROY E. M. HAWES J. W. HUBBARD G. MCKAY K. K. MIDHA

1. Midha

KK, Cooper JK, McGilveray IJ, Coutts RT, Dawe R. Metabolism ofmethoxyphenamine in man and in monkey. Drug Metab Dispos 1976; 4: 568-76 2. Roy SD, Hawes EM, McKay G, Hubbard JW, Midha KK Methoxyphenamine metabolism in rat models of human debrisoquine phenotypes. Can J Physiol Pharmacol (in press) 3. Newton DW, Kluza RB. pKa values of medicinal compounds in pharmacy practice. Drug Intell Clin Pharm 1978; 12: 546-54. 4 Warren RJ, Begosh PP, Zarembo JE Identification of amphetamines and related sympathomimetic amines. J Assoc Off Analyt Chem 1971; 54: 1179-91. 5 Barnhart JW The urinary excretion of dextromethorphan and three metabolites in dogs and humans Toxicol Appl Pharmacol 1980, 55: 43-48.

AFLATOXIN, HEPATOCELLULAR CARCINOMA, AND SCHISTOSOMIASIS

SIR,-In his hypothesis linking aflatoxin with hepatocellular

Debrisoquine/4-hydroxydebrisoquine

(MRDEB) and methoxyphenamine/0-demethylmethoxyphenamine metabolic ratios (MRMP) in three poor (8) and eight extensive metaboliser phenotypes (0) of debrisoquine hydroxylation (p
carcinoma (HCC) Dr Enwonwu (Oct 27, p 957) invokes parasitic infection with schistosomes as a co-factor in hepatic carcinogenesis. However, he is incorrect in suggesting that schistosomiasis "acts by stimulating a hyperplastic response of the liver, thus rendering it more vulnerable to malignant transformation by ingested chemicalcarcinogens". Liver injury in Schistosoma mansonz and S japonicum infections is confined to fibrosis of portal tracts: so-called Symmers’ pipestem fibrosis.’ The hepatic parenchyma is unaffected, apart from some increase in collagen in the space ofDisse. The result is an alteration of hepatic haemodynamics without a change in hepatocellular function, which is well preserved until the very late stages of the disease. There is no "hyperplastic response". In murine schistosomiasis mixed function oxidase (MFO) enzyme activity is depressed2 and in compensated human schistosomiasis,3 drug-metabolising activity is decreased, at least in Brazilians.3 Therefore schistosomiasis per se is unlikely to render the liver