- Email: [email protected]
Childhood coeliac disease in Sweden
conducted an active surveillance study on the risk of HCV infection in the dialysis setting, in which the prevalence of HCV-RNA-positive infected patients is high.3 In 9 Italian dialysis centres with an overall HCV prevalence among patients of 39-4% (enzyme immunoassay and recombinant immunoblot assay-11) we followed up 61 health-care workers who sustained needlestick injury, 29 with mucous membrane contamination, and 40 with non-intact skin contact with blood from an HCV-positive patient. In 34 cases the needlestick injury was caused by a blood-filled, hollow-bore needle. None of the HCV-exposed health-care workers seroconverted to HCV after a mean follow-up of 10 months (range 1-18, median 11-5). Moreover, the HCV prevalence among dialysis health-care workers was 1-7%, which was not related to job category and was similar to that in Italian blood donors.4 Among the determinants of HCV risk of infection to health-care workers is the type of needle, the amount .of blood in the device, and the HCV-RNA status of the source patient. From a practical point of view, since polymerase chain reaction is not always available, it is of importance to know if the injury was caused by a blood-filled, hollow-bore needle. We believe that further studies are needed to better the HCV-seroconversion rate estimate following In ad hoc surveys, circumstances of occupational exposure. the accident, gauge and type of needle, amount of blood contamination of the device, and severity of the injury should always be ascertained. Knowledge of these factors is needed to counsel the exposed worker about the potential of HCV transmission. We
occupational
Members of the study group are P Allaria, C Arici, M P Beraldi, M P Corradi, M Daglio, M Della Volpe, E Duranti, A Giangrande, P Gilli, M Ktena, M Lombardi, D Marchesi, A M Savastano, S Soffritti, S Spada. The study is supported by Italian Ministry of Health ISS AIDS Research Project (grant 8201.19-9201.04).
rendered the patients substantially hypocapnic-a possible explanation for some of the adverse effects. Hypocapnia would not be rapidly detected with the infrequent 6 month follow-up examinations. The comment that ventilator adjustments were made to bring PACO, to at least 10% of recorded daytime value while breathing air does not make sense.
In the UK and elsewhere, nasal ventilation has never been used prophylactically in DMD. It is made available to patients with symptoms and documented nocturnal and diurnal hypercapnia, with the aim of relieving symptoms related to respiratory failure-if this is in accordance with the wishes of the patient and his family. No randomised controlled trial has been carried out of this application of nasal ventilation because the inevitable consequence of withholding respiratory support would be death.’ Vianello and co-workers2 examined the clinical course and pulmonary function in two comparable DMD groups with hypercapnic respiratory failure. One group received nasal ventilation and the other elected not to undergo assisted ventilation. After 24 months all patients receiving nasal ventilation were still alive and in the group treated conservatively, 4 of 5 patients had died. At 6 months the mean decrease in forced vital capacity and minute ventilation was higher in the nonventilated patients. We agree that nasal ventilation is contraindicated in symptom-free normocapnic DMD patients. Its use in patients with hypercapnic respiratory failure should continue subject to continued assessment, including quality of life measures of patients and carers. F Muntoni, M
1
Nicola Petrosillo, Vincenzo Puro, Giuseppe Ippolito, and Italian Study Group on Blood-borne Occupational Risk in Dialysis Centro di Riferimento AIDS,
1
2
3
4
Ospedale "L Spallanzani", 00149 Roma, Italy
Hird, A K Simonds
Department of Paediatrics and Neonatal Medicine, Hammersmith Hospital, London W12 OHS, UK; and Royal Brompton Hospital, London
2
Hill NS. Noninvasive positive pressure ventilation in neuromuscular disease. Enough is enough. Chest 1994; 105: 337-38. Vianello A, Bevilacqua M, Salvador V, Cardaioli C, Vincenti E. Long-term nasal intermittent positive pressure ventilation in advanced Duchenne’s muscular dystrophy. Chest 1994; 105: 445-48.
Kiyosawa K, Sodeyama T, Tanaka E. Hepatitis C in hospital employees with needlestick injuries. Ann Intern Med 1991; 115: 367-69. Mitsui T, Iwano K, Masuko K, et al. Hepatitis C virus infection in medical personnel after needlestick accident. Hepatology 1992; 16: 1109-14. Chan TM, Lok ASF, Cheng IKP, Chan RT. Prevalence of hepatitis C virus infection in hemodialysis patients: a longitudinal study comparing the results of RNA and antibody assays. Hepatology 1993; 17: 5-8. Chiaramonte M, Stroffolini T, Caporaso N, et al. Hepatitis-C virus infection in Italy: a multicentric sero-epidemiological study. Ital J Gastroenterol 1991; 23: 555-58.+10 pt
Preventive nasal ventilation in Duchenne muscular dystrophy concerned that the outcome of Raphael and randomised study of preventative nasal ventilation in Duchenne muscular dystrophy (DMD) (June 25, p 1600) could lead to confusion about the role and mechanism of action of nasal ventilation at various stages of this condition. The prime goal of assisted ventilation is PaCOz control. These workers have clarified that nasal ventilation offers no survival advantage or reduction in respiratory handicap in DMD patients with a forced vital capacity of between 20 and 50% of predicted. Symptoms were not documented. Benefit was unlikely, however, as this group was normocapnic on entry to the study. Indeed, the controlled pattern of ventilation and apparent absence of nocturnal PaC02 or transcutaneous monitoring might have
SiR-We
are
colleagues’
340
Childhood coeliac disease in Sweden SIR-Juto and colleagues (May 28, p 1372) discuss the unique threefold to fourfold increase of childhood coeliac disease in Sweden. They state that "an earlier more cautious exposure to a diet low in gluten, while the baby is still breastfed, might lower the incidence of coeliac disease in Swedish children". They disregard the fact that the prevalence of diagnosed coeliac disease is not equal to the prevalence of gluten enteropathy. Gluten enteropathy is the important determinant for associated ill-health such as malignant disease, osteoporosis, and deficiency diseases.,It is well known that gluten enteropathy is underdiagnosed. An Italian study of schoolchildren (Jan 22, p 200) and a Swedish study of blood donors2 have shown a prevalence of gluten enteropathy of 3-4 per 1000, which is close to the present Swedish figures for diagnosed childhood coeliac disease.
Juto and colleagues indicate that the feeding pattern in Denmark with very low gluten consumption in infancy might prevent subsequent coeliac disease. However, preliminary results from a study on Danish blood donors indicate that the prevalence of gluten enteropathy might be the same as in Sweden (E Grodzinsky, personal communication). If that is true, it means that for every diagnosed case of coeliac disease in Denmark, 30-40 remain undiagnosed.
We have shown that Swedish infants, starting with glutencontaining food at 6 months of age, have a two to three times higher intake of wheat protein than do Finnish infants.’ Allthough Swedish children with coeliac disease still have classic symptoms and a median age at diagnosis of 1-3 years, the Finnish patients have very vague symptoms and a median age at diagnosis of 8-8 years. In some parts of Finland where the search for coeliacs has been intensive, prevalence is unchanged, whereas falling figures are reported from other parts of the country. The frequency of diagnosed coeliac disease in Sweden probably indicates an early diagnosis of most cases of gluten-induced enteropathy in genetically predisposed individuals, who, with a lower intake, would otherwise remain undetected. Juto et al discuss the ethical dimension of provoking the disease in early childhood instead of decades later. However, they are looking only at the diagnosed coeliac disease. Studies have shown that a diagnostic delay over decades is common in adults. It is also ethically questionable to recommend a dietary feeding pattern that allows more individuals to run risks of subsequent ill-health, attributable disease that is amenable to treatment. These workers’ suggestion for infant feeding is one of many interesting and controversial hypotheses.s We think that the appropriate way to answer the questions posed is to undertake well-designed studies instead of issuing premature recommendations for changes in infant feeding. This opinion was put forward in consensus discussions in the Board for Gastroenterology and Nutrition within the Swedish Paediatric Association and its working group for coeliac disease, who also co-ordinate several continuing studies addressing these questons.
to a
Henry Ascher, Bengt Kristiansson
normal for
time. There is no evidence whatsoever for final assuming prevalence of gluten enteropathy of mechanisms involved in the development of independent tolerance against dietary proteins. We suspect that not every individual with a genetic predisposition will develop coeliac disease, not even silent disease. Even if that is so, it seems more appropriate to develop strategies to find those cases in late childhood or in adults, rather than to provoke early cases. The years (up to decades) of wellbeing before disease onset gained by risk reduction must also be valued by the patient. Besides, several million pounds are now spent every year in Sweden to subsidise the purchase of gluten-free food items for children with coeliac disease, and this expense could easily be more than halved by lowering the incidence of the disease to the prevailing rates in our neighbouring countries. Consider the consequences if Ascher and Kristiansson should prove to be correct in their assumptions. Would they recommend health professionals in other countries to promote the Swedish practice of a sudden massive gluten exposure at six months of age to screen out future patients, silent cases included? If parents were asked what they want for their children-the options being possible early-onset or late clinical or subclinical disease-we can guess that many would prefer the latter. The main ethical dilemma lies in the fact that Swedish parents are not asked such questions, and most start giving their 6-month-old infants gluten-containing follow-up formulas, which are recommended as safe feeding practice. We see no reason why bottle feeds should ever contain gluten; the original product for babies does not. some a
Per Juto, Gunnar Meeuwisse Department of Clinical Virology, University Hospital of Northern Sweden, 901 85 Umeå, Sweden; and Department of Paediatrics, Regional Hospital, Karlskrona, Sweden
Department of Paediatrics, University of Goteborg, 41685, Goteborg, Sweden
and colleagues discuss possible reasons for the of coeliac disease in Swedish children born incidence high since the mid 1980s. They suggest that increased amounts of gluten in "välling" (typical Swedish cereal-based follow-up formula) and an abrupt exposure to gluten in infants could explain the increased frequency of the disease. This may very well be the case. It was also discussed briefly by us in our report of the incidence of childhood coeliac disease, which was based on a study performed by the commission of the section for gastroenterology and nutrition of the Swedish Paediatric Society.’1 Juto and co-workers question the high prevalence of coeliac disease in Sweden. However, the prevalence in Swedish children born in the 1980s and fed with gluten from the age of 6 months is almost exactly the same as the prevalence in adult blood donors born decades earlier and fed gluten from the age of one month." This finding is hardly a coincidence but rather an indication of the true prevalence of gluten-induced enteropathy in Sweden. It may thus be that infant-feeding practices in Sweden encourage coeliac disease to manifest at an early age, when it is easier to diagnose, rather than to produce new cases, although this has not yet finally been proved. It is noteworthy that a further indication of the true prevalence of gluten-induced enteropathy was given in a study of Italian schoolchildren (Jan 22, p 200) reporting almost the same result as the Swedish studies.
SiR Juto
1 Holmes GKT. Long-term health risks for unrecognized coeliac patients. In: Auricchio S, Visakorpi JK, eds. Common food intolerances I: epidemiology of coeliac disease. Basel: Karger, 1992: 105-18. 2 Grodzinsky E, Franzen L, Hed J, Ström M. High prevalence of celiac disease in healthy adults revealed by antigliadin antibodies. Ann Allergy 1992; 69: 66-70. 3 Ascher H, Holm K, Kristiansson B, Mäki M. Different features of coeliac disease in two neighbouring countries. Arch Dis Child 1993; 69: 375-80. 4 Auricchio S, Visakorpi JK, eds. Common food intolerances 1: epidemiology of coeliac disease. Basel: Karger, 1992. 5 Mowat AM. Oral tolerance and regulation of immunity to dietary antigens. In: Ogra PL, Lamm ME, Strober W, McGhee JR, Bienenstock J, eds. Handbook of mucosal immunology. San Diego: Academic Press, 1994: 185-201.
Authors’
reply
SiR-Ascher and Kristiansson’s main argument for not modifying baby feeding practice in Sweden rests on the assumption that all genetically predisposed individuals will ultimately develop coeliac disease, overt or silent. Their reasoning is on the basis that low childhood cumulative incidence rates after addition of silent cases seen in screening studies in some countries are of the same magnitude as we are experiencing as clinical cases in Sweden before age two. We regard this as a weak argument for not acting now to reduce the risk of the disease in childhood. The pathogenesis of coeliac disease depends on genetic and environmental factors, of which exposure to gluten is crucial. Other hitherto-unknown risk-modifying factors can also be involved. We know, for example, from findings in identical twins discordant for coeliac disease, that several years may pass after dietary introduction of gluten before any sign of the disorder develops-ie, the mucosa remains
Juto et al speculate that current feeding practices may produce additional cases of coeliac disease later in life. Only time can show if this is so. However, we know that Swedish infant feeding as practised before 1983 led to late diagnoses of this disease in a substantial number of patients and to missed diagnoses in an additional but unknown number. This omission is serious, taking into account the fact that untreated gluten enteropathy involves a risk of many 341
complications including malignant disease.3 Juto and colleagues ask if infant-feeding practices that may provoke coeliac disease in early childhood in genetically predisposed children are ethically justifiable. We would like to rephrase the question: is it ethically justifiable to neglect the opportunity to diagnose and treat a condition that unrecognised and untreated may lead to serious complications? We lack the vital information and knowledge that could justify major changes in infant-feeding practices in Sweden. However, several studies are in progress that are examining various aspects of childhood coeliac disease. We believe that we should await the results of these studies. To produce insufficiently founded infant-feeding recommendations today would be unwise and might even confuse the situation and present new difficulties rather than solve old ones. Lars Stenhammar, for the Swedish Working Group for Childhood Coeliac Disease Department of Paediatrics, Norrköping Hospital, 601 82 Norrkoping, Sweden
1
2
3
Cavell B, Stenhammar L, Ascher H, et al. Increasing incidence of childhood coeliac disease in Sweden: results of a national study. Acta Paediatr 1992; 81: 589-92. Grodzinsky E, Franzén L, Hed J, Ström M. High prevalence of celiac disease in healthy adults revealed by antigliadin antibodies. Ann Allergy
1992; 69: 66-70. Holmes G. Long-term health risks for unrecognized coeliac patients. In: Auricchio S, Visakorpi J, eds. Common food intolerances I:
epidemiology of coeliac disease.
Basel:
Karger,
1992: 105-18.
follow-up. Of the 18 who did not respond to vaccination, 13 were given interferon: 3 of them had no more HBV replication at the end of follow-up. An exacerbation of hepatitis, as assessed by a striking increase in aminotransferase, preceded the disappearance of 12/17 patients and resulted in serum HBV DNA in normal transaminase activities. Vaccination was persistently otherwise uneventful; in particular, no patient had signs of immune complex-related disease. the end of
Since 6-month spontaneous clearance of HBV replication is around 2%2 we can assume that vaccination against HBV alone stopped HBV replication in around 44%, a figure at least similar to that obtained by antiviral treatments.3 The mechanisms involved in the response to HBV vaccination are unclear and should be further analysed. We postulate that vaccination is mainly efficient in patients who should benefit from a-interferon therapy but we cannot exclude that specific vaccination might enhance the efficacy of antiviral therapies. We are now conducting controlled trials to answer these points. Our study is another example of chronic viral infection for which treatment might be improved by vaccination. Stanislas Pol, Françoise Driss, Marie-Louise Michel, Bertrand Nalpas, Pierre Berthelot, Christian Brechot Unite
1 2
Specific vaccine therapy in chronic hepatitis B infection SiR-Straus and colleagues (June 11, p 1460) report a placebo-controlled trial of vaccination with recombinant glycoprotein D of herpes simplex virus type 2 for immunotherapy of genital herpes. They show that vaccination recipients had significantly fewer recurrences per month, fewer virologically confirmed recurrences per month, and a lower median number of recurrences than placebo recipients. Cohen’ has emphasised the potential use of vaccine for the treatment of other chronic recurring viral diseases. We add further support for this approach. In a pilot study, we established that specific vaccine therapy by a standard anti-hepatitis B virus (HBV) vaccination may reduce HBV replication and cancel the immune tolerance to HBsAg particles in half of patients.2 We report our experience with 32 patients (26 men, 6 women; mean age 42 years) with active chronic HBV replication (presence of HBV DNA in all) leading to chronic hepatitis. After a 3-month period during which serum HBV DNA was measured monthly, the patients were given three standard injections of the GenHevacB vaccine (PasteurMerieux, France) in the deltoid muscle at 1 month intervals. Each 0-5 mL dose contains 20 Ilg of HBsAg and pre-S2 protein, with aluminium hydroxide as adjuvant. Postvaccination follow-up was for 6 months after the first dose. Responders were defined as patients with a sustained loss of a decrease of more than 50% in or titres. 6-9 months after the first vaccine dose, prevaccination standard antiviral therapy (5 MU a2b interferon thrice weekly subcutaneously for 4 months) was proposed to all patients and was accepted by 21 of the 32. Follow-up lasted 17 months (range 6-26). Over the 3 months after completion of vaccination, serum HBV DNA became undetectable in 10 (31%) and substantially decreased in 4 other patients (13%). After interferon, 8 of the 14 patients who responded to vaccine still had no HBV replication at
HBV
342
DNA
d’Hépatologie,
INSERM U-99, U-163, and U-370, Hôpital Necker and Institut
Pasteur, 75747 Paris, France
3
Cohen J. Vaccines get a new twist. Science 1994; 264: 503-05. Pol S, Driss F, Carnot F, Michel ML, Berthelot P, Bréchot C. Efficacité d’une immunothérapie par vaccination contre le virus de l’hépatite B sur la multiplication virale B. CR Acad Sci (Paris) 1993; 316: 688-91. Perrillo R, Regenstein F, Peters M, et al. Prednisone withdrawal followed by recombinant alpha-interferon in the treatment of chronic type B hepatitis: a randomised controlled trial. Ann Intern Med 1988; 109: 95-100.
Equivocal serological diagnosis of sporadic fulminant hepatitis E in pregnant Indians SiR-Hepatitis E virus (HEV) is implicated in causing excess mortality during epidemics in India, particularly in pregnancy. We wish to contest the view that hepatitis E virus is almost automatically implicated in the diagnosis of pregnant women presenting with liver failure in India. IgM and IgG HEV antibodies (enzyme immunoassay, Abbott Labs, USA) were sought in 5 unrelated patients presenting with hepatic encephalopathy, renal dysfunction, and grossly raised bilirubin (204-1292 umol/L). 4 women from Madras presented in the third trimester. The male (M, aged 57 years [M57]) developed acute liver failure in the UK after travelling through India. Only a 19-year-old woman (F19) and her baby survived. M57 died from a myocardial infarction 1 month after transplantation without obvious reinfection. Serum was taken 11 months later from his symptom-free wife (F60) who accompanied him and 2 siblings (M58, M56) in the UK. Admission sera were negative for IgM hepatitis A virus antibodies, IgM HBc, and HBeAg (Abbott Labs, USA); and hepatitis C virus antibodies (United Biomedical Inc, USA). F22 and F19 were positive for HBsAg and F23 for anti-HBs (Abbott Labs, USA). Supplemental testing for HEV on coded sera used synthetic peptides spB4-2 and spB3-2, corresponding to the 33 and 42 carboxyl terminal residues of HEV ORF3 and ORF2, respectively.’ Western blots used CMP-KDO synthetase-HEV recombinant fusion proteins and CPM-KDO synthetase alone. All proteins and peptides were derived from the Burmese strain of HEV.’ HEV RNA was sought by reverse transcriptase polymerase chain
occupational
Members of the study group are P Allaria, C Arici, M P Beraldi, M P Corradi, M Daglio, M Della Volpe, E Duranti, A Giangrande, P Gilli, M Ktena, M Lombardi, D Marchesi, A M Savastano, S Soffritti, S Spada. The study is supported by Italian Ministry of Health ISS AIDS Research Project (grant 8201.19-9201.04).
rendered the patients substantially hypocapnic-a possible explanation for some of the adverse effects. Hypocapnia would not be rapidly detected with the infrequent 6 month follow-up examinations. The comment that ventilator adjustments were made to bring PACO, to at least 10% of recorded daytime value while breathing air does not make sense.
In the UK and elsewhere, nasal ventilation has never been used prophylactically in DMD. It is made available to patients with symptoms and documented nocturnal and diurnal hypercapnia, with the aim of relieving symptoms related to respiratory failure-if this is in accordance with the wishes of the patient and his family. No randomised controlled trial has been carried out of this application of nasal ventilation because the inevitable consequence of withholding respiratory support would be death.’ Vianello and co-workers2 examined the clinical course and pulmonary function in two comparable DMD groups with hypercapnic respiratory failure. One group received nasal ventilation and the other elected not to undergo assisted ventilation. After 24 months all patients receiving nasal ventilation were still alive and in the group treated conservatively, 4 of 5 patients had died. At 6 months the mean decrease in forced vital capacity and minute ventilation was higher in the nonventilated patients. We agree that nasal ventilation is contraindicated in symptom-free normocapnic DMD patients. Its use in patients with hypercapnic respiratory failure should continue subject to continued assessment, including quality of life measures of patients and carers. F Muntoni, M
1
Nicola Petrosillo, Vincenzo Puro, Giuseppe Ippolito, and Italian Study Group on Blood-borne Occupational Risk in Dialysis Centro di Riferimento AIDS,
1
2
3
4
Ospedale "L Spallanzani", 00149 Roma, Italy
Hird, A K Simonds
Department of Paediatrics and Neonatal Medicine, Hammersmith Hospital, London W12 OHS, UK; and Royal Brompton Hospital, London
2
Hill NS. Noninvasive positive pressure ventilation in neuromuscular disease. Enough is enough. Chest 1994; 105: 337-38. Vianello A, Bevilacqua M, Salvador V, Cardaioli C, Vincenti E. Long-term nasal intermittent positive pressure ventilation in advanced Duchenne’s muscular dystrophy. Chest 1994; 105: 445-48.
Kiyosawa K, Sodeyama T, Tanaka E. Hepatitis C in hospital employees with needlestick injuries. Ann Intern Med 1991; 115: 367-69. Mitsui T, Iwano K, Masuko K, et al. Hepatitis C virus infection in medical personnel after needlestick accident. Hepatology 1992; 16: 1109-14. Chan TM, Lok ASF, Cheng IKP, Chan RT. Prevalence of hepatitis C virus infection in hemodialysis patients: a longitudinal study comparing the results of RNA and antibody assays. Hepatology 1993; 17: 5-8. Chiaramonte M, Stroffolini T, Caporaso N, et al. Hepatitis-C virus infection in Italy: a multicentric sero-epidemiological study. Ital J Gastroenterol 1991; 23: 555-58.+10 pt
Preventive nasal ventilation in Duchenne muscular dystrophy concerned that the outcome of Raphael and randomised study of preventative nasal ventilation in Duchenne muscular dystrophy (DMD) (June 25, p 1600) could lead to confusion about the role and mechanism of action of nasal ventilation at various stages of this condition. The prime goal of assisted ventilation is PaCOz control. These workers have clarified that nasal ventilation offers no survival advantage or reduction in respiratory handicap in DMD patients with a forced vital capacity of between 20 and 50% of predicted. Symptoms were not documented. Benefit was unlikely, however, as this group was normocapnic on entry to the study. Indeed, the controlled pattern of ventilation and apparent absence of nocturnal PaC02 or transcutaneous monitoring might have
SiR-We
are
colleagues’
340
Childhood coeliac disease in Sweden SIR-Juto and colleagues (May 28, p 1372) discuss the unique threefold to fourfold increase of childhood coeliac disease in Sweden. They state that "an earlier more cautious exposure to a diet low in gluten, while the baby is still breastfed, might lower the incidence of coeliac disease in Swedish children". They disregard the fact that the prevalence of diagnosed coeliac disease is not equal to the prevalence of gluten enteropathy. Gluten enteropathy is the important determinant for associated ill-health such as malignant disease, osteoporosis, and deficiency diseases.,It is well known that gluten enteropathy is underdiagnosed. An Italian study of schoolchildren (Jan 22, p 200) and a Swedish study of blood donors2 have shown a prevalence of gluten enteropathy of 3-4 per 1000, which is close to the present Swedish figures for diagnosed childhood coeliac disease.
Juto and colleagues indicate that the feeding pattern in Denmark with very low gluten consumption in infancy might prevent subsequent coeliac disease. However, preliminary results from a study on Danish blood donors indicate that the prevalence of gluten enteropathy might be the same as in Sweden (E Grodzinsky, personal communication). If that is true, it means that for every diagnosed case of coeliac disease in Denmark, 30-40 remain undiagnosed.
We have shown that Swedish infants, starting with glutencontaining food at 6 months of age, have a two to three times higher intake of wheat protein than do Finnish infants.’ Allthough Swedish children with coeliac disease still have classic symptoms and a median age at diagnosis of 1-3 years, the Finnish patients have very vague symptoms and a median age at diagnosis of 8-8 years. In some parts of Finland where the search for coeliacs has been intensive, prevalence is unchanged, whereas falling figures are reported from other parts of the country. The frequency of diagnosed coeliac disease in Sweden probably indicates an early diagnosis of most cases of gluten-induced enteropathy in genetically predisposed individuals, who, with a lower intake, would otherwise remain undetected. Juto et al discuss the ethical dimension of provoking the disease in early childhood instead of decades later. However, they are looking only at the diagnosed coeliac disease. Studies have shown that a diagnostic delay over decades is common in adults. It is also ethically questionable to recommend a dietary feeding pattern that allows more individuals to run risks of subsequent ill-health, attributable disease that is amenable to treatment. These workers’ suggestion for infant feeding is one of many interesting and controversial hypotheses.s We think that the appropriate way to answer the questions posed is to undertake well-designed studies instead of issuing premature recommendations for changes in infant feeding. This opinion was put forward in consensus discussions in the Board for Gastroenterology and Nutrition within the Swedish Paediatric Association and its working group for coeliac disease, who also co-ordinate several continuing studies addressing these questons.
to a
Henry Ascher, Bengt Kristiansson
normal for
time. There is no evidence whatsoever for final assuming prevalence of gluten enteropathy of mechanisms involved in the development of independent tolerance against dietary proteins. We suspect that not every individual with a genetic predisposition will develop coeliac disease, not even silent disease. Even if that is so, it seems more appropriate to develop strategies to find those cases in late childhood or in adults, rather than to provoke early cases. The years (up to decades) of wellbeing before disease onset gained by risk reduction must also be valued by the patient. Besides, several million pounds are now spent every year in Sweden to subsidise the purchase of gluten-free food items for children with coeliac disease, and this expense could easily be more than halved by lowering the incidence of the disease to the prevailing rates in our neighbouring countries. Consider the consequences if Ascher and Kristiansson should prove to be correct in their assumptions. Would they recommend health professionals in other countries to promote the Swedish practice of a sudden massive gluten exposure at six months of age to screen out future patients, silent cases included? If parents were asked what they want for their children-the options being possible early-onset or late clinical or subclinical disease-we can guess that many would prefer the latter. The main ethical dilemma lies in the fact that Swedish parents are not asked such questions, and most start giving their 6-month-old infants gluten-containing follow-up formulas, which are recommended as safe feeding practice. We see no reason why bottle feeds should ever contain gluten; the original product for babies does not. some a
Per Juto, Gunnar Meeuwisse Department of Clinical Virology, University Hospital of Northern Sweden, 901 85 Umeå, Sweden; and Department of Paediatrics, Regional Hospital, Karlskrona, Sweden
Department of Paediatrics, University of Goteborg, 41685, Goteborg, Sweden
and colleagues discuss possible reasons for the of coeliac disease in Swedish children born incidence high since the mid 1980s. They suggest that increased amounts of gluten in "välling" (typical Swedish cereal-based follow-up formula) and an abrupt exposure to gluten in infants could explain the increased frequency of the disease. This may very well be the case. It was also discussed briefly by us in our report of the incidence of childhood coeliac disease, which was based on a study performed by the commission of the section for gastroenterology and nutrition of the Swedish Paediatric Society.’1 Juto and co-workers question the high prevalence of coeliac disease in Sweden. However, the prevalence in Swedish children born in the 1980s and fed with gluten from the age of 6 months is almost exactly the same as the prevalence in adult blood donors born decades earlier and fed gluten from the age of one month." This finding is hardly a coincidence but rather an indication of the true prevalence of gluten-induced enteropathy in Sweden. It may thus be that infant-feeding practices in Sweden encourage coeliac disease to manifest at an early age, when it is easier to diagnose, rather than to produce new cases, although this has not yet finally been proved. It is noteworthy that a further indication of the true prevalence of gluten-induced enteropathy was given in a study of Italian schoolchildren (Jan 22, p 200) reporting almost the same result as the Swedish studies.
SiR Juto
1 Holmes GKT. Long-term health risks for unrecognized coeliac patients. In: Auricchio S, Visakorpi JK, eds. Common food intolerances I: epidemiology of coeliac disease. Basel: Karger, 1992: 105-18. 2 Grodzinsky E, Franzen L, Hed J, Ström M. High prevalence of celiac disease in healthy adults revealed by antigliadin antibodies. Ann Allergy 1992; 69: 66-70. 3 Ascher H, Holm K, Kristiansson B, Mäki M. Different features of coeliac disease in two neighbouring countries. Arch Dis Child 1993; 69: 375-80. 4 Auricchio S, Visakorpi JK, eds. Common food intolerances 1: epidemiology of coeliac disease. Basel: Karger, 1992. 5 Mowat AM. Oral tolerance and regulation of immunity to dietary antigens. In: Ogra PL, Lamm ME, Strober W, McGhee JR, Bienenstock J, eds. Handbook of mucosal immunology. San Diego: Academic Press, 1994: 185-201.
Authors’
reply
SiR-Ascher and Kristiansson’s main argument for not modifying baby feeding practice in Sweden rests on the assumption that all genetically predisposed individuals will ultimately develop coeliac disease, overt or silent. Their reasoning is on the basis that low childhood cumulative incidence rates after addition of silent cases seen in screening studies in some countries are of the same magnitude as we are experiencing as clinical cases in Sweden before age two. We regard this as a weak argument for not acting now to reduce the risk of the disease in childhood. The pathogenesis of coeliac disease depends on genetic and environmental factors, of which exposure to gluten is crucial. Other hitherto-unknown risk-modifying factors can also be involved. We know, for example, from findings in identical twins discordant for coeliac disease, that several years may pass after dietary introduction of gluten before any sign of the disorder develops-ie, the mucosa remains
Juto et al speculate that current feeding practices may produce additional cases of coeliac disease later in life. Only time can show if this is so. However, we know that Swedish infant feeding as practised before 1983 led to late diagnoses of this disease in a substantial number of patients and to missed diagnoses in an additional but unknown number. This omission is serious, taking into account the fact that untreated gluten enteropathy involves a risk of many 341
complications including malignant disease.3 Juto and colleagues ask if infant-feeding practices that may provoke coeliac disease in early childhood in genetically predisposed children are ethically justifiable. We would like to rephrase the question: is it ethically justifiable to neglect the opportunity to diagnose and treat a condition that unrecognised and untreated may lead to serious complications? We lack the vital information and knowledge that could justify major changes in infant-feeding practices in Sweden. However, several studies are in progress that are examining various aspects of childhood coeliac disease. We believe that we should await the results of these studies. To produce insufficiently founded infant-feeding recommendations today would be unwise and might even confuse the situation and present new difficulties rather than solve old ones. Lars Stenhammar, for the Swedish Working Group for Childhood Coeliac Disease Department of Paediatrics, Norrköping Hospital, 601 82 Norrkoping, Sweden
1
2
3
Cavell B, Stenhammar L, Ascher H, et al. Increasing incidence of childhood coeliac disease in Sweden: results of a national study. Acta Paediatr 1992; 81: 589-92. Grodzinsky E, Franzén L, Hed J, Ström M. High prevalence of celiac disease in healthy adults revealed by antigliadin antibodies. Ann Allergy
1992; 69: 66-70. Holmes G. Long-term health risks for unrecognized coeliac patients. In: Auricchio S, Visakorpi J, eds. Common food intolerances I:
epidemiology of coeliac disease.
Basel:
Karger,
1992: 105-18.
follow-up. Of the 18 who did not respond to vaccination, 13 were given interferon: 3 of them had no more HBV replication at the end of follow-up. An exacerbation of hepatitis, as assessed by a striking increase in aminotransferase, preceded the disappearance of 12/17 patients and resulted in serum HBV DNA in normal transaminase activities. Vaccination was persistently otherwise uneventful; in particular, no patient had signs of immune complex-related disease. the end of
Since 6-month spontaneous clearance of HBV replication is around 2%2 we can assume that vaccination against HBV alone stopped HBV replication in around 44%, a figure at least similar to that obtained by antiviral treatments.3 The mechanisms involved in the response to HBV vaccination are unclear and should be further analysed. We postulate that vaccination is mainly efficient in patients who should benefit from a-interferon therapy but we cannot exclude that specific vaccination might enhance the efficacy of antiviral therapies. We are now conducting controlled trials to answer these points. Our study is another example of chronic viral infection for which treatment might be improved by vaccination. Stanislas Pol, Françoise Driss, Marie-Louise Michel, Bertrand Nalpas, Pierre Berthelot, Christian Brechot Unite
1 2
Specific vaccine therapy in chronic hepatitis B infection SiR-Straus and colleagues (June 11, p 1460) report a placebo-controlled trial of vaccination with recombinant glycoprotein D of herpes simplex virus type 2 for immunotherapy of genital herpes. They show that vaccination recipients had significantly fewer recurrences per month, fewer virologically confirmed recurrences per month, and a lower median number of recurrences than placebo recipients. Cohen’ has emphasised the potential use of vaccine for the treatment of other chronic recurring viral diseases. We add further support for this approach. In a pilot study, we established that specific vaccine therapy by a standard anti-hepatitis B virus (HBV) vaccination may reduce HBV replication and cancel the immune tolerance to HBsAg particles in half of patients.2 We report our experience with 32 patients (26 men, 6 women; mean age 42 years) with active chronic HBV replication (presence of HBV DNA in all) leading to chronic hepatitis. After a 3-month period during which serum HBV DNA was measured monthly, the patients were given three standard injections of the GenHevacB vaccine (PasteurMerieux, France) in the deltoid muscle at 1 month intervals. Each 0-5 mL dose contains 20 Ilg of HBsAg and pre-S2 protein, with aluminium hydroxide as adjuvant. Postvaccination follow-up was for 6 months after the first dose. Responders were defined as patients with a sustained loss of a decrease of more than 50% in or titres. 6-9 months after the first vaccine dose, prevaccination standard antiviral therapy (5 MU a2b interferon thrice weekly subcutaneously for 4 months) was proposed to all patients and was accepted by 21 of the 32. Follow-up lasted 17 months (range 6-26). Over the 3 months after completion of vaccination, serum HBV DNA became undetectable in 10 (31%) and substantially decreased in 4 other patients (13%). After interferon, 8 of the 14 patients who responded to vaccine still had no HBV replication at
HBV
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DNA
d’Hépatologie,
INSERM U-99, U-163, and U-370, Hôpital Necker and Institut
Pasteur, 75747 Paris, France
3
Cohen J. Vaccines get a new twist. Science 1994; 264: 503-05. Pol S, Driss F, Carnot F, Michel ML, Berthelot P, Bréchot C. Efficacité d’une immunothérapie par vaccination contre le virus de l’hépatite B sur la multiplication virale B. CR Acad Sci (Paris) 1993; 316: 688-91. Perrillo R, Regenstein F, Peters M, et al. Prednisone withdrawal followed by recombinant alpha-interferon in the treatment of chronic type B hepatitis: a randomised controlled trial. Ann Intern Med 1988; 109: 95-100.
Equivocal serological diagnosis of sporadic fulminant hepatitis E in pregnant Indians SiR-Hepatitis E virus (HEV) is implicated in causing excess mortality during epidemics in India, particularly in pregnancy. We wish to contest the view that hepatitis E virus is almost automatically implicated in the diagnosis of pregnant women presenting with liver failure in India. IgM and IgG HEV antibodies (enzyme immunoassay, Abbott Labs, USA) were sought in 5 unrelated patients presenting with hepatic encephalopathy, renal dysfunction, and grossly raised bilirubin (204-1292 umol/L). 4 women from Madras presented in the third trimester. The male (M, aged 57 years [M57]) developed acute liver failure in the UK after travelling through India. Only a 19-year-old woman (F19) and her baby survived. M57 died from a myocardial infarction 1 month after transplantation without obvious reinfection. Serum was taken 11 months later from his symptom-free wife (F60) who accompanied him and 2 siblings (M58, M56) in the UK. Admission sera were negative for IgM hepatitis A virus antibodies, IgM HBc, and HBeAg (Abbott Labs, USA); and hepatitis C virus antibodies (United Biomedical Inc, USA). F22 and F19 were positive for HBsAg and F23 for anti-HBs (Abbott Labs, USA). Supplemental testing for HEV on coded sera used synthetic peptides spB4-2 and spB3-2, corresponding to the 33 and 42 carboxyl terminal residues of HEV ORF3 and ORF2, respectively.’ Western blots used CMP-KDO synthetase-HEV recombinant fusion proteins and CPM-KDO synthetase alone. All proteins and peptides were derived from the Burmese strain of HEV.’ HEV RNA was sought by reverse transcriptase polymerase chain