PROSTAGLANDINS, SMOKING, AND DUODENAL ULCERS

212 SERIAL ANTIBODY TITRES AND IMMUNOGLOBULIN LEVELS

Letters to the Editor COLD-RELATED DEATHS IN SOME DEVELOPED COUNTRIES

SIR,-During the cold spell in Britain last February newspapers reported that the death rate was 1000 per week above normal. Such statistics are not recorded for other countries, even those with much colder winters, such as Canada and Sweden. Few people die of cold as such, but many die of related illnesses. Cold-related deaths amount to 12% of total deaths in England and Wales, 11 % in Scotland, but only 4-6 % in the other countries

investigated (table). COLD-RELATED DEATHS IN SOME DEVELOPED COUNTRIES

concentration and platelet count were increasing discharged, on tapering doses of prednisone and oral acyclovir (400 mg/m2 thrice daily). The patient was doing well when

haemoglobin when he

was

March 13,1986, but he was readmitted 6 weeks later with a the accelerated phase. The patient was treated with intravenous prednisone, acyclovir, and etoposide. His hospital

seen on

relapse of

was complicated by longlasting pancytopenia, staphylococcal sepsis, and gastrointestinal haemorrhages, but he slowly improved and was discharged on July 3 on oral acyclovir and prednisone. On Sept 17 the patient was readmitted for chemotherapy in preparation for a bone marrow transplant but he died of disseminated aspergillus infection. He had IgG and IgA antibodies to EA-R and, less strikingly, to VCA; titres fell in parallel with clinical improvement and rose during relapse. The terminally low titres reflect, at least in part, advancing hypogammaglobulinaemia. These data provide further evidence that EBV plays an important role in the emergence of the accelerated phase of CHS and suggest that acyclovir has some

course

Source: Umted Nations DemographIc Yearbook (1980), table 30. Total deaths in year less 12 times the monthly deaths for July to September, expressed as number of deaths (and as % of total).

Since about 500 people per million of population die of cold each year and since the population of Europe, the USSR, and North America is about 1000 million, it can be estimated that about half a million people in these regions die of cold in a year. It seems that cold is to the developed countries what malnutrition is to the developing countries. Neither kills directly-they kill by proxy. Cold-related deaths as % of total are to some extent poverty indicators but I doubt if the high figure for Britain is entirely due to poverty. Even wealthy people in that country shiver their way through winter, and I am not merely referring to unfortunates in unheatable stately homes. Cold-related death is serious numerically in developed countries and in Britain in particular; its prevention lies not only in poverty alleviation but also in education. Apt 814E, 4201 Cathedral Avenue NW, Washington DC 20016, USA

MIKAEL GRUT

ACYCLOVIR IN ACCELERATED PHASE OF CHEDIAK-HIGASHI SYNDROME

SiR,—Chediak-Higashi syndrome (CHS) is an autosomal recessive disorder characterised by giant lysosomal granules, partial albinism, and recurrent infections. An accelerated, lymphoproliferative phase of this disease, with fever, massive hepatosplenomegaly, coagulopathy, and pancytopenia, heralds death in most patients.1,2 The accelerated phase has been associated with seroconversion and an abnormal antibody reponse to EpsteinBarr virus (EBV).3,4 Antibodies to the viral capsid antigen (VCA) reach high titres that are often matched by similarly high levels of antibodies to the restricted component of the early antigen (EA-R).3,4 High antibody titres to EA-R suggest a persistent, active EBV infection with the release of infectious EBV particles. Because acyclovir has had some benefit in the acute, lytic phase of EBV infection,’’achild in the accelerated phase of CHS was treated with this drug. At age 2! years this child had varicella complicated by encephalitis. At age 3 (on Nov 4, 1985) he was admitted with fever, hepatosplenomegaly, coagulopathy, pancytopenia, and an EBVspecific antibody profile characteristic of the accelerated phase (table) of CHS. The patient was treated with prednisone 2 mg/kg daily and a 10-day course of intravenous acyclovir 500 mg/m2 three times daily. The fever and coagulopathy resolved and the

beneficial effect in this disorder. Children’s Hospital of Philadelphia,

Philadelphia, Pennsylvania 19104, USA; and Joseph Stokes, Jr Research Institute, University of Pennsylvania School of Medicine

MARY ELLEN CONLEY WERNER HENLE

1. Blume RS, Wolff SM. The

Chediak-Higashi syndrome. Studies in four patients and a of the literature. Medicine 1972; 51: 247-80. 2. Rubin CM, Burke BA, McKenna RW, et al. The accelerated phase of ChediakHigashi syndrome. An expression of the virus-associated hemophagocytic syndrome? Cancer 1985; 56: 524-30. 3. Merino F, Klein GO, Henle W, Ramirez-Duque P, Forsgren M, Amesty C. Elevated antibody titers to Epstein-Barr virus and low natural killer cell activity m patients with Chediak-Higashi syndrome Clin Immunol Immunopathol 1983; 27: 326-39 4. Merino F, Henle W, Ramirez-Duque P. Chronic active Epstein-Barr virus infection in patients with Chediak-Higashi syndrome J Clin Immunol 1986; 6: 299-305 5. Sullivan JL, Medveczky P, Forman SJ, Vaker SM, Monrow NS, Mulder C. Epstein-Barr virus induced lymphoproliferation: Implications for antiviral chemotherapy. N Engl J Med 1984; 311: 1163-67. 6 Andersson J, Britton S, Ernberg I, et al. Effect of acyclovir on infectious mononucleosis. a double-blind, placebo-controlled study. J Infect Dis 1986, 153: 283-89 review

PROSTAGLANDINS, SMOKING, AND DUODENAL ULCERS

SIR,-Dr Hawkey and Dr Walt (Nov 8, p 1084) state that our reportl that the ill-effects of cigarette smoking on duodenal ulcer healing were nullified by E-type prostaglandins could be a chance finding, and they cite studies2-6 that they think are negative in this respect. This seems a sweeping statement that could bury an important scientific advance. One of the studies cited by Hawkey and Walt as evidence that prostaglandins do not help to overcome the adverse effects of smoking on duodenal ulcer healing is that by Brand et al.2 These workers showed that, among the 100 patients on placebo, 44% of the 63 smokers and 65% of the 37 non-smokers had their duodenal ulcer healed in 4 weeks (p 0-038), whereas among the 107 patients treated with misoprostol 200 pg four times daily for 4 weeks, 73 % of 60 smokers and 79 % of the non-smokers had their ulcers healed. These findings confirmed ours:1 in a 12-week study with repeat =

213

endoscopies in 229 patients the smokers

on

placebo consistently

healed significantly less well compared with non-smokers on placebo (p< 0-0005), whereas the healing curves of smokers and non-smokers on misoprostol 300 pg four times daily completely overlapped each other with indistinguishable healing rates. Yet these results were regarded by Hawkey and Walt as chance findings. Of two other studies cited by Hawkey and Walt as nonsupportive, one’ showed that smokers and non-smokers treated with misoprostol 400 ug twice daily did not differ significantly in 4-week healing rates (60% and 73%, respectively), whereas the other,’ with a dose of misoprostol (100 gg four times daily), which is half the recommended dose for 4 weeks, showed that smokers significantly healed less well (57%) than non-smokers (80%). These fmdings should not be taken to negate the conclusion that prostaglandin analogues can counter the ill-effects of smoking on ulcer healing. In another study5 misoprostol (200 p.g four times daily) was compared with cimetidine (300 mg four times daily). Smokers did not heal as well as non-smokers in either group but the differences were not significant statistically. In a study’ comparing enprostil 35 g twice daily and cimetidine 400 mg twice daily for 6 weeks with endoscopy control, a difference of about 20 % in favour of the non-smokers was observed between cimetidine smokers and cimetidine non-smokers; no difference between smokers and non-smokers was seen in those treated with enprostil. This study appeared in abstract only, and the data are insufficient for statistical

analysis.

1986; 31: 68S-74S. 2. Brand DL, Roufail WM, Thomson ABR, Tapper EJ. Misoprostol, synthetic PGE, analog, in the treatment of duodenal ulcers: a multicenter double-blind study. Dig Dis Sci 1985, 30: 147S-58S. 3 Sontag SJ, Mazure PA, Pontes JF, Beker SG, Dajani EZ. Misoprostol in the treatment of duodenal ulcer a multicenter double-blind placebo-controlled study Dig Dis Sci 1985; 30: 159S-63S. 4. Bright-Asare P, Sontag SJ, Gould RJ, et al. Efficacy of misoprostol (twice daily dosage) in acute healing of duodenal ulcer. a multicenter double-blind controlled trial. Dig Dis Sci 1986; 31: 63S-67S. 5. Nicholson PA. A multicenter international controlled comparison of two dosage regimes of misoprostol and cimetidine in the treatment of duodenal ulcer in out-patients. Dig Dis Sci 1985; 30: 171S-77S. 6. Rachmilewitz D, Chapman JW, Nicholson PA. A multicenter international controlled comparison of two dosage regimens of misoprostol with cimetidine in treatment of gastric ulcer in outpatients. Dig Dis Sci 1985; 31: 75S-80S. 7. Carlin L, Unge P, Hagg S, Almstrom C, Cronstedt J A comparison of enprostil and cimetidine in the treatment of duodenal ulcer Symposium on Protective and Therapeutic Effects of Gastrointestinal Prostaglandms (Toronto, 1985), abstr 54. 8 Lam SK. The stomach. In: Gitnick GL, ed. Current gastroenterology. Chicago: Year Book Medical Publishers, 1986: 33-62. 9. Classen M, Dammann HG, Domschke W, et al. Short-duration treatment of duodenal ulcer with omeprazole and ranitidine. Results of a multi-centre trial in Germany. Dtsch Med Wochenschr 1985; 110: 210-15. 10. McCready DR, Clark L, Cohen MM. Cigarette smoking reduces human gastric luminal prostaglandin E2. Gut 1985; 26: 1192-96. 1 1. Quimby GF, Bonnice CA, Burstem SH, et al. Active smoking depresses prostaglandin synthesis in human gastric mucosa. Ann Intern Med 1986; 104: 616-19. 12. Lam SK Prostaglandms for duodenal ulcer and gastric ulcer. J Gastroenterol Hepatol

(in press). 13 14

The last study6 cited by Hawkey and Walt was of gastric ulcers: smoking does not seem to affect the healing of gastric ulcers as consistently as it does in duodenal ulcer.8 Among patients with duodenal ulcer treated with placebo or with potent acid-reducing agents such as cimetidine, ranitidine, and large doses of antacids, smokers consistently do not heal as well as non-smokers.8This was seen even with omeprazole,9 a very potent acid-reducing agent. Our study (unpublished) comparing cimetidine (200 mg three times daily and 400 mg at night) and sucralfate, a site-protective and cytoprotective agent (1 g four times daily), showed that while smokers treated with cimetidine for 4 weeks healed their duodenal ulcer significantly less well (63%) than non-smokers (82%), the healing rates of smokers and non-smokers treated with sucralfate were practically identical. Sucralfate-treated smokers healed significantly better (82 %) than cimetidine-treated smokers (63%).). These results indicate that a site-protective and cytoprotective agent could overcome the ill-effect of smoking on duodenal ulcer healing that was seen with the use of acid-reducing agents. Cytoprotective mechanisms may help to overcome the adverse effects of smoking on duodenal ulcer healing. Two studieslo.’1 show that acute cigarette smoking was associated with decreased secretion of natural prostaglandins into the gastric juice and decreased synthesis of gastric mucosal prostaglandins in healthy subjects. Studies with more accurate radioimmunoassay techniques favour a functional or absolute deficiency of prostaglandins in peptic ulcer as a group. 12I Hawkey and Walt also claim that the use of a "cytoprotective dose" of misoprostol did not accelerate ulcer healing and they conclude that cytoprotective mechanisms may not be important for ulcer healing. Cytoprotective actions are dose-dependent.13,14 Unfortunately, when the dose of prostaglandins is increased, the antisecretory action will become obvious, so that it is impossible to tell whether the ulcer healing is related to the cytoprotective actions. One prostaglandin E (Upjohn) has been reported15 to have negligible antisecretory action, and a placebo-controlled study showed that the healing rate was significantly better with this agent, suggesting that the cytoprotective mechanisms per se may be able to heal duodenal ulcer. The effect of cytoprotection on duodenal ulcer healing should not be ignored, particularly in relation to cigarette smoking; and scientific investigators should not conclude at this early stage that prostaglandins do not contribute any advance to ulcer healing. Department of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong

1. Lam SK, Lau WY, Choi TK, et al. Prostaglandin E1 (misoprostol) overcomes the adverse effect of chronic cigarette smoking on duodenal ulcer healing. Dig Dis Sci

S. K. LAM

15.

Isenberg JI, Hogan DL, Selling JA, Koss MA. Duodenal bicarbonate secretion in humans: role of prostaglandins. Dig Dis Sci 1986; 31 (suppl): 91S-95S. Lyndia A, Sellers LA, Carroll NJH, Allen A. Misoprostol-induced increases in adherent gastric mucus thickness and luminal mucus output. Dig Dis Sci 1986, 31 (suppl). 91S-95S. Kollberg B, Slezak P. The effect of prostaglandin E2 on duodenal ulcer healing. Prostaglandins 1982; 24: 527-36.

PRENATAL DIAGNOSIS OF CHOROID PLEXUS CYSTS

SiR,—The prenatal diagnosis of choroid plexus cysts in the lateral ventricle was first reported by Chudleigh et all who described five cases seen during the second trimester. Choroid plexus cysts with diameters of 4-10 mm were first seen at gestations ranging from 17 to 19 weeks and had disappeared by 20-23 weeks. All five babies were normal at delivery. Two cases were found at routine screening and three were referred for high-resolution scanning because of family history of structural anomaly (chondroplasia punctata, a previous child with numerous anomalies, and encephalocele). Bundy et aP reviewed the prenatal sonographic findings of twelve

of trisomy 18. Only two of these were scanned between 17 and 23 weeks and one had large choroid plexus cysts. Bundy et al felt that this was most probably a normal variant. Nicolaides et aP described a further four fetuses with choroid plexus cysts in the lateral ventricle. One had exomphalos and another obstructive uropathy. In these two cases the choroid plexus cysts appear to have been present up to 24 weeks’ gestation. Both these fetuses had trisomy 18. The other two cases had no other abnormalities seen with ultrasound but one had trisomy 18 on karyotyping. All the trisomy pregnancies were terminated. In the fetus with the normal karyotype the cysts resolved spontaneously by 23 weeks and a normal infant was delivered. We have seen choroid plexus cysts as incidental findings at routine ultrasound screening in four cases. Three of these were found at 19 weeks and one at 23 weeks. Two of those seen at 19 weeks had regressed by 21 weeks. One was not scanned again until 36 weeks, at which time the cyst could not be seen. The fourth case, which was scanned only at 23 weeks and found to have choroid plexus cysts, delivered a baby with trisomy 21 and an cases

atrioventricular septal defect. that of the workers from King’s College of thirteen fetuses with choroid plexus nine Hospital, London,l3 cysts have been normal and four have had chromosomal abnormalities. In three out of these four, the choroid plexus cysts were still present at 23 weeks (the fourth pregnancy was terminated before this gestation). This supports the suggestion of Nicolaides et al that choroid plexus cysts may be associated with chromosomal abnormalities In

our

experience and