1303
illness. Vitamin A therapy has been shown to reduce the severity of measles; Arthur et al and another unpublished (West KP) vitamin A trial showed no impact on the frequency of infectious diseases, but found a significant impact on severity. Epidemiology and International Health, Johns Hopkins School of Hygiene and Public Health, Baltimore, Maryland 21205, USA, and Ophthalmology and International Health, Johns Hopkins Schools of Medicine and Hygiene and Public Health 1. Sommer A,
ALFRED SOMMER KEITH P. WEST, JR
Djunaedi E, Loeden AA, et al. Impact of vitamin A supplementation on a randomised controlled community trial. Lancet 1986; i:
childhood mortality:
1169-73. 2. Rahmathullah L, Underwood BA, Thulasiraj RD, et al. Reduced mortality among children in Southern India receiving a small weekly dose of vitamin A. N Engl J Med 1990; 323: 929-35. 3. West KP Jr, Pokhrel RP, Katz J, et al. Efficacy of vitamin A in reducing preschool child mortality in Nepal. Lancet 1991; 338: 67-71. 4. Daulaire NMP, Starbuck ES, Houston RM, Church MS, Stukel TA, Pandey MR. Childhood mortality after a high dose of vitamin A m a high risk population. Br Med J 1992; 304: 207-10. 5. Muhilal, Permeisih D, Idjradinata YR, Muherdiyantinigsih, Karyadi D. Vitamin A-fortified monosodium glutamate and health, growth, and survival of children: a controlled field trial. Am J Clin Nutr 1988; 48: 1271-76. 6. Sommer A, Tarwotjo I, Hussaini G, Susanto D. Increased mortality in children with mild vitamin A deficiency. Lancet 1983; ii: 585-88.
Effects of dioxins
on
thyroid function
in
newborn babies SIR,-In western Europe, concentrations of dioxins and furans in breastmilk are rather high, especially in the Netherlands, Belgium, and the UK.1 Therefore breastfeeding may expose infants to high doses of these
lipophilic compounds. Moreover, fetuses may be exposed to dioxins, since these substances can pass the placental barrier.2 Dioxins influence thyroid hormone status, as shown by animal studies.3 Since thyroid defects might have adverse effects on psychomotor development, we investigated thyroid hormone concentrations in a population of 38 healthy term breastfed infants in relation to dioxin content of breastmilk. Dioxin concentrations were measured in breastmilk three weeks after delivery. Infants were divided into two groups according to dioxin concentrations of milk fat: low-exposure group 8-7-28-0 ng TEQ/kg (mean 18-6) (TEQ/kg = toxic equivalents per kg milk fat) and high-exposure group 29-2-62-7 ng TEQ/kg (37-5). Mean gestational age and mean birthweight were much the same in both groups. Thyroxine (T4), thyroid binding globulin (TBG), and thyrotropin (TSH) were measured in cord plasma and in plasma samples taken one and eleven weeks after birth. Mean T4 concentrations at birth and at one week were higher in the high-exposure than in the low-exposure group, but the difference was only statistically significant one week after birth (table). At this time, the T4/TBG ratio was also significantly increased in the high-exposure group, indicating that dioxins affect EFFECT OF DIOXINS-ON NEONATAL THYROID FUNCTION AFTER LOW-EXPOSURE AND HIGH-EXPOSURE AT VARIOUS AGES
the thyroxine metabolism rather than concentrations of the major thyroxine-binding protein. At birth and at one week, mean TSH concentrations were similar in both groups, suggesting that the dioxin-induced T4 rise is caused by an effect on the thyroid hormone regulatory system. Dioxins, which are structurally related to thyronines, might act at the levels of T4 transport into the cell, 5’-deiodinase, or T3 binding to the nuclear receptor. At age eleven weeks mean T4 values and T4/TBG ratio were still significantly higher in the high-exposure group, as were mean TSH values by
this time. We conclude that exposure to increased concentrations of dioxins, both intrauterine and via breastmilk, seems to modulate the hypothalamic-pituitary-thyroid regulatory system in newborn babies. H. J. PLUIM J. G. KOPPE K. OLIE Department of Neonatology (H3N AMC), University of Amsterdam, 1105 AZ Amsterdam, Netherlands, Environmental Chemistry Laboratory, University of Amsterdam, and Hospital de Heel
J. W. V D SLIKKE J. H. KOK T. VULSMA D. VAN TIJN J. J. M. DE VIJLDER
1. World Health Organisation. Levels of PCBs, PCDDs, and PCDFs in breast milk: results of WHO-coordinated interlaboratory quality control studies and analytical field studies. Copenhagen: World Health Organisation, 1989. (Environmental Health Series 34). 2. van Wijnen J, van Bavel B, Lindstrom G, Koppe JG, Olie K. Placental transport of PCDD’s and PCDF’s in infants. In: Hutzinger O, Fiedler H, eds. Dioxin ’90 congress, Bayreuth: Eco Informa Press, 1990: 47-50. 3. Henry EC, Gasiewicz TA. Changes m thyroid hormones and thyroxine glucuronidation in hamsters compared with rat following treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicol Appl Pharmacol 1987; 89: 165-74.
Benzodiazepines and violent deaths SIR,—Dr Vuori and Dr Klaukka (March 14, p 676) report that or otherwise unexpected deaths in Finland were often associated with the presence of oxazepam than triazolam when the number of cases were adjusted for differences in consumption-ie, in sales. The adjustment was based on sales as defined daily doses (DDD) for each benzodiazepine. The DDD for each drug is a technical unit of comparison, derived from the recommended daily dose for the main indication of the drug. However, the actual mean prescribed daily dose (PDD) may sometimes differ strikingly from the DDD, as for oxazepam. Thus, although the DDD for oxazepam is 50 mg, the PDD (at least in Sweden) is less than 25 mg. On the assumption that this is also so in Finland, the number of subjects taking oxazepam as judged from sales statistics would be more than twice as many as Vuori and Klaukka presume. The number of fatal cases in which oxazepam was present would then be proportional to the number of patients on oxazepam treatment. This emphasises that calculations relating clinical outcome to drug consumption should not be based on DDD but on PDD.
violent, sudden, more
Corporation of Pharmacies, Lund; and Drug Information Unit, National
Departments of Clinical Pharmacology and Community Health Sciences, University of Lund, Sweden
i
i
T4 in nmol/l, TBG in nmolll, TSH m mU/I *Two-talled Independent Student’s (-test tNo for low-exposure and high-exposure groups, respectively
A. EKEDAHL H. LIEDHOLM A. MELANDER
***This letter has been shown to Dr Vuori and colleagues, whose reply follows.-ED. L. SIR,-We share Dr Ekedahl and colleagues’ feelings about defmed daily doses (DDD)-these are only technical units, and there are limitations to their use. For example, in Nordic countries’ DDDs include only sales to pharmacies. However, there is, so far, no better way to compare the consumption of various drugs, at least in Finland where data on prescriptions are not systematically available. The difficulty that DDD is not necessarily equal to prescribed daily dose (PDD) is also true for drugs other than oxazepam. Our results would be changed only if the DDD/PDD ratio were different for the drugs we examined. Moreover, nor are PDDs reliable, because they do not show the actual dose taken.
1304
The supply of various strengths of psychotropics varies greatly, between neighbouring countries. For example, in Finland oxazepam is sold as 15, 30, and 50 mg tablets. In Sweden the corresponding strengths are 5,10,15, and 25 mg. So perhaps in our country the PDD of oxazepam is closer to DDD (50 mg) than in even
Sweden. When we reexamined our data after receiving Ekedahl and co-workers’ letter, we noticed a minor inaccuracy. Benzodiazepines have been screened since March, 1989, and our data were derived from a total of 7193 (cumulative figure), rather than 5106 cases. This mistake does not affect our findings since all drugs listed in the table were alreadv marketed in Finland in 1989 Department of Forensic Medicine, University of Helsinki, SF-00300 Helsinki, Finland, and Social Insurance Institution of Finland
Case 3 (75, M). Admitted with a history of breathlessness, recent haemoptysis, profound malaise, and occasional nosebleeds. He was taking thyroxine for hypothyroidism. On transfer to Addenbrooke’s Hospital he was found to have serum creatinine of 1237 pmol/l. His IgG ANCA titre was 100% and IgM ANCA titre was 68% (anti-myeloperoxidase). Anti-GBM was not detectable. Chest X-ray showed extensive bilateral infiltrates (P02 8 kPa). He was started on cyclophosphamide and prednisolone and received one 41 PE by cell separator followed by five exchanges with a filter. IgG and IgM ANCA values fell sharply after cell separation; further filtration resulted in a continued fall in IgG ANCA but only a slow fall in IgM ANCA. Lung haemorrhage ceased. The patient remains
dialysis. Although ANCA are sometimes seen in association with GBM antibodies2 this is the first time that development of an IgM ANCA has been reported. It should be considered in cases of anti-GBM disease with relapse or non-response to treatment. A second clinically important point is that, contrary to the manufacturer’s data, plasma filters cannot remove circulating IgM. It is not certain whether ANCAs have a pathogenic role,3 but it on
ERKKI VUORI TIMO KLAUKKA
Pulmonary-renal syndrome in association with anti-GBM and IgM ANCA SiR,—The treatment of pulmonary-renal syndromes caused by glomerular basement membrane (GBM) antibodies or associated with anti-neutrophil cytoplasmic antibodies (ANCA) consists of intense immunosuppression, which may include plasma exchange (PE). We report three such cases in which IgM ANCA may have
played an important part. Case 1 is the first report of IgM ANCA in anti-GBM disease. In two cases the IgM ANCA was not cleared by PE with a plasma filter alone and the patients died. In the third PE was with both cell separator and filtration, and the patient survived. Case 1 (48, F). Admitted with a 3-week history of breathlessness and haemoptysis. She was oliguric, cyanosed, and had some crackles at her right mid-zone. Her serum creatinine was 330 imol/1 and arterial p02 11-2 kPa on 35% 02" Urinalysis showed protein + and blood + + +. Chest radiography showed diffuse reticulonodular shadowing. The presumptive diagnosis was an immunologically mediated pulmonary/renal syndrome and she immediately received a 3 1 PE (filter only) plus pulse methylprednisolone. Renal biopsy revealed focal necrotising proliferative glomerulonephritis with crescents; immunofluorescence demonstrated characteristic linear IgG on the GBM. Tests on a blood sample before therapy began confirmed Goodpasture’s syndrome (anti-GBM + ve, titre 86%). Cyclophosphamide 2 mg/kg orally was started and oral steroids commenced after three pulses of intravenous methylprednisolone. Plasma filtration was repeated daily. Respiratory function improved rapidly and by day 3 the patient no longer required oxygen. On day 4 she had a fresh pulmonary haemorrhage and required mechanical ventilation. By day 14 she was anti-GBM negative and PE was discontinued. However, she remained dialysis dependent and on day 37 had a fresh pulmonary haemorrhage. Plasma filtration was repeated daily for 6 days, when the antibody results from the start of the relapse became available. GBM antibodies were negative but she now had an IgM ANCA, with anti-myeloperoxidase specificity. The ANCA IgM might not have been cleared by plasma filtration so the patient was transferred to the University Hospital of Wales for whole volume PE by cell separator. She received three 3 1 exchanges, and the lung bleeding resolved. She was then transferred back to Cardiff Royal Infirmary where she received daily monoclonal anti-CD3 (OKT3; Cilag). However, she became septicaemic and died. Case 2 (27, M). Admitted in November, 1989, with a history of congested sinuses with epistaxis, bilateral deafness, redness of the right eye, flitting arthralgia, haemoptysis, and rash, accompanied by night sweats and fever. He was transferred to Addenbrooke’s Hospital in acute renal failure (creatinine 418 pmol/1). The patient had an Hb of 6-6 g/l, his p0 was 6-6 kPa, and there were bilateral infiltrates on chest radiography. Renal biopsy revealed focal necrotising glomerulonephritis with crescents. He was treated with cyclophosphamide, hydrocortisone, and plasma filtration, 4daily with a filter. He deteriorated with continuing lung haemorrhage and died 72 h later. At presentation his IgG ANCA titre was 44% and IgM ANCA 58% (anti-proteinase 3). The plasma filtrate contained IgG 36% but no detectable IgM. GBM antibodies were not found.
suggested that IgM ANCA may be associated with pulmonary haemorrhage,4,s and our observations argue for an important role for IgM ANCA in pulmonary haemorrhage caused by systemic vasculitis. Despite becoming anti-GBM negative patient 1 had further pulmonary haemorrhage in association with the development of IgM ANCA. The bleeding resolved following plasma exchange on a cell separator, and IgM ANCA titres fell. Patient 2 died and his IgM ANCA was not removed by PE. In patient 3 IgG and IgM ANCA were cleared by a cell separator and his pulmonary haemorrhage resolved. In rapidly progressive glomerulonephritis PE is an integral part of treatment.6 Many renal units use a plasma filter (incorporated into a standard dialysis extracorporeal circuit) which will, according to the manufacturers, remove both IgG and IgM. In our patients, however, IgM was not adequately cleared, probably because it is pentameric in vivo, and cell separation seems to be needed. These cases emphasise the need for rapid assays for anti-GBM and ANCA-and the test for ANCA must distinguish antibody isotypes, so that the correct form of PE can be chosen.
has been
Institute of Nephrology, Cardiff Royal Infirmary, Cardiff CF2 1SZ, UK
University of Cambridge School of Clinical Medicine, Addenbrooke’s Hospital, Cambridge
DAVID M. THOMAS RICHARD MOORE KIERON DONOVAN DAVID C. WHEELER V. L. M. ESNAULT C. MARTIN LOCKWOOD
1. Mathieson PW, Cobbold SP, Hale G, et al. Monoclonal-antibody therapy in systemic vasculitis. N Engl J Med 1990; 323: 250-54. 2. Jayne DRW, Marshall PD, Jones SJ, Lockwood CM. Autoantibodies to GBM and neutrophil cytoplasm in rapidly progressive glomerulonephritis. Kidney Int 1990; 37: 965-70. 3. Falk RJ, Hogan S, Jennette JC, the Glomerular Disease Collaborative Network. Clinical course of anti-neutrophil associated glomerulonephritis and systemic vasculitis. Ann Intern Med 1990; 113: 656-63. 4. Jayne DRW, Jones SJ, Severn A, Shaunak S, Murphy J, Lockwood CM. Severe pulmonary hemorrhage and systemic vasculitis in association with circulating anti-neutrophil cytoplasm antibodies of IgM class. Clin Nephrol 1989; 32: 101-06. 5. Esnault VLM, Soleimani B, Keogan MT, Brownlee AA, Jayne DRW, Lockwood CM. Association of IgM with IgG ANCA in patients presenting with haemorrhage. Kidney Int (in press). 6. Pusey CD, Lockwood CM. Plasma exchange for glomerular disease. In: Robinson RR, ed. Proceedings of the IXth International Congress of Nephrology, New York:
Springer, 1984:
1474-85.
Warm heart surgery SiR,—Your April 4 editorial sounds a note of caution about warm heart surgery. Hypothermia has been an integral part of open heart surgery on the basis of lessons learned at centres throughout the world in the late 1950s. Protection of the brain has been the foremost concern of cardiac surgeons from the beginning of this surgery in which the circulation is interrupted, and it remains so. The pump oxygenator can alleviate this by providing an adequate systemic circulation for the duration of the procedure. However, researchers have demonstrated lasting cerebral dysfunction is some 30% of patients. 12 In these studies, systemic hypothermia has been used.
illness. Vitamin A therapy has been shown to reduce the severity of measles; Arthur et al and another unpublished (West KP) vitamin A trial showed no impact on the frequency of infectious diseases, but found a significant impact on severity. Epidemiology and International Health, Johns Hopkins School of Hygiene and Public Health, Baltimore, Maryland 21205, USA, and Ophthalmology and International Health, Johns Hopkins Schools of Medicine and Hygiene and Public Health 1. Sommer A,
ALFRED SOMMER KEITH P. WEST, JR
Djunaedi E, Loeden AA, et al. Impact of vitamin A supplementation on a randomised controlled community trial. Lancet 1986; i:
childhood mortality:
1169-73. 2. Rahmathullah L, Underwood BA, Thulasiraj RD, et al. Reduced mortality among children in Southern India receiving a small weekly dose of vitamin A. N Engl J Med 1990; 323: 929-35. 3. West KP Jr, Pokhrel RP, Katz J, et al. Efficacy of vitamin A in reducing preschool child mortality in Nepal. Lancet 1991; 338: 67-71. 4. Daulaire NMP, Starbuck ES, Houston RM, Church MS, Stukel TA, Pandey MR. Childhood mortality after a high dose of vitamin A m a high risk population. Br Med J 1992; 304: 207-10. 5. Muhilal, Permeisih D, Idjradinata YR, Muherdiyantinigsih, Karyadi D. Vitamin A-fortified monosodium glutamate and health, growth, and survival of children: a controlled field trial. Am J Clin Nutr 1988; 48: 1271-76. 6. Sommer A, Tarwotjo I, Hussaini G, Susanto D. Increased mortality in children with mild vitamin A deficiency. Lancet 1983; ii: 585-88.
Effects of dioxins
on
thyroid function
in
newborn babies SIR,-In western Europe, concentrations of dioxins and furans in breastmilk are rather high, especially in the Netherlands, Belgium, and the UK.1 Therefore breastfeeding may expose infants to high doses of these
lipophilic compounds. Moreover, fetuses may be exposed to dioxins, since these substances can pass the placental barrier.2 Dioxins influence thyroid hormone status, as shown by animal studies.3 Since thyroid defects might have adverse effects on psychomotor development, we investigated thyroid hormone concentrations in a population of 38 healthy term breastfed infants in relation to dioxin content of breastmilk. Dioxin concentrations were measured in breastmilk three weeks after delivery. Infants were divided into two groups according to dioxin concentrations of milk fat: low-exposure group 8-7-28-0 ng TEQ/kg (mean 18-6) (TEQ/kg = toxic equivalents per kg milk fat) and high-exposure group 29-2-62-7 ng TEQ/kg (37-5). Mean gestational age and mean birthweight were much the same in both groups. Thyroxine (T4), thyroid binding globulin (TBG), and thyrotropin (TSH) were measured in cord plasma and in plasma samples taken one and eleven weeks after birth. Mean T4 concentrations at birth and at one week were higher in the high-exposure than in the low-exposure group, but the difference was only statistically significant one week after birth (table). At this time, the T4/TBG ratio was also significantly increased in the high-exposure group, indicating that dioxins affect EFFECT OF DIOXINS-ON NEONATAL THYROID FUNCTION AFTER LOW-EXPOSURE AND HIGH-EXPOSURE AT VARIOUS AGES
the thyroxine metabolism rather than concentrations of the major thyroxine-binding protein. At birth and at one week, mean TSH concentrations were similar in both groups, suggesting that the dioxin-induced T4 rise is caused by an effect on the thyroid hormone regulatory system. Dioxins, which are structurally related to thyronines, might act at the levels of T4 transport into the cell, 5’-deiodinase, or T3 binding to the nuclear receptor. At age eleven weeks mean T4 values and T4/TBG ratio were still significantly higher in the high-exposure group, as were mean TSH values by
this time. We conclude that exposure to increased concentrations of dioxins, both intrauterine and via breastmilk, seems to modulate the hypothalamic-pituitary-thyroid regulatory system in newborn babies. H. J. PLUIM J. G. KOPPE K. OLIE Department of Neonatology (H3N AMC), University of Amsterdam, 1105 AZ Amsterdam, Netherlands, Environmental Chemistry Laboratory, University of Amsterdam, and Hospital de Heel
J. W. V D SLIKKE J. H. KOK T. VULSMA D. VAN TIJN J. J. M. DE VIJLDER
1. World Health Organisation. Levels of PCBs, PCDDs, and PCDFs in breast milk: results of WHO-coordinated interlaboratory quality control studies and analytical field studies. Copenhagen: World Health Organisation, 1989. (Environmental Health Series 34). 2. van Wijnen J, van Bavel B, Lindstrom G, Koppe JG, Olie K. Placental transport of PCDD’s and PCDF’s in infants. In: Hutzinger O, Fiedler H, eds. Dioxin ’90 congress, Bayreuth: Eco Informa Press, 1990: 47-50. 3. Henry EC, Gasiewicz TA. Changes m thyroid hormones and thyroxine glucuronidation in hamsters compared with rat following treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicol Appl Pharmacol 1987; 89: 165-74.
Benzodiazepines and violent deaths SIR,—Dr Vuori and Dr Klaukka (March 14, p 676) report that or otherwise unexpected deaths in Finland were often associated with the presence of oxazepam than triazolam when the number of cases were adjusted for differences in consumption-ie, in sales. The adjustment was based on sales as defined daily doses (DDD) for each benzodiazepine. The DDD for each drug is a technical unit of comparison, derived from the recommended daily dose for the main indication of the drug. However, the actual mean prescribed daily dose (PDD) may sometimes differ strikingly from the DDD, as for oxazepam. Thus, although the DDD for oxazepam is 50 mg, the PDD (at least in Sweden) is less than 25 mg. On the assumption that this is also so in Finland, the number of subjects taking oxazepam as judged from sales statistics would be more than twice as many as Vuori and Klaukka presume. The number of fatal cases in which oxazepam was present would then be proportional to the number of patients on oxazepam treatment. This emphasises that calculations relating clinical outcome to drug consumption should not be based on DDD but on PDD.
violent, sudden, more
Corporation of Pharmacies, Lund; and Drug Information Unit, National
Departments of Clinical Pharmacology and Community Health Sciences, University of Lund, Sweden
i
i
T4 in nmol/l, TBG in nmolll, TSH m mU/I *Two-talled Independent Student’s (-test tNo for low-exposure and high-exposure groups, respectively
A. EKEDAHL H. LIEDHOLM A. MELANDER
***This letter has been shown to Dr Vuori and colleagues, whose reply follows.-ED. L. SIR,-We share Dr Ekedahl and colleagues’ feelings about defmed daily doses (DDD)-these are only technical units, and there are limitations to their use. For example, in Nordic countries’ DDDs include only sales to pharmacies. However, there is, so far, no better way to compare the consumption of various drugs, at least in Finland where data on prescriptions are not systematically available. The difficulty that DDD is not necessarily equal to prescribed daily dose (PDD) is also true for drugs other than oxazepam. Our results would be changed only if the DDD/PDD ratio were different for the drugs we examined. Moreover, nor are PDDs reliable, because they do not show the actual dose taken.
1304
The supply of various strengths of psychotropics varies greatly, between neighbouring countries. For example, in Finland oxazepam is sold as 15, 30, and 50 mg tablets. In Sweden the corresponding strengths are 5,10,15, and 25 mg. So perhaps in our country the PDD of oxazepam is closer to DDD (50 mg) than in even
Sweden. When we reexamined our data after receiving Ekedahl and co-workers’ letter, we noticed a minor inaccuracy. Benzodiazepines have been screened since March, 1989, and our data were derived from a total of 7193 (cumulative figure), rather than 5106 cases. This mistake does not affect our findings since all drugs listed in the table were alreadv marketed in Finland in 1989 Department of Forensic Medicine, University of Helsinki, SF-00300 Helsinki, Finland, and Social Insurance Institution of Finland
Case 3 (75, M). Admitted with a history of breathlessness, recent haemoptysis, profound malaise, and occasional nosebleeds. He was taking thyroxine for hypothyroidism. On transfer to Addenbrooke’s Hospital he was found to have serum creatinine of 1237 pmol/l. His IgG ANCA titre was 100% and IgM ANCA titre was 68% (anti-myeloperoxidase). Anti-GBM was not detectable. Chest X-ray showed extensive bilateral infiltrates (P02 8 kPa). He was started on cyclophosphamide and prednisolone and received one 41 PE by cell separator followed by five exchanges with a filter. IgG and IgM ANCA values fell sharply after cell separation; further filtration resulted in a continued fall in IgG ANCA but only a slow fall in IgM ANCA. Lung haemorrhage ceased. The patient remains
dialysis. Although ANCA are sometimes seen in association with GBM antibodies2 this is the first time that development of an IgM ANCA has been reported. It should be considered in cases of anti-GBM disease with relapse or non-response to treatment. A second clinically important point is that, contrary to the manufacturer’s data, plasma filters cannot remove circulating IgM. It is not certain whether ANCAs have a pathogenic role,3 but it on
ERKKI VUORI TIMO KLAUKKA
Pulmonary-renal syndrome in association with anti-GBM and IgM ANCA SiR,—The treatment of pulmonary-renal syndromes caused by glomerular basement membrane (GBM) antibodies or associated with anti-neutrophil cytoplasmic antibodies (ANCA) consists of intense immunosuppression, which may include plasma exchange (PE). We report three such cases in which IgM ANCA may have
played an important part. Case 1 is the first report of IgM ANCA in anti-GBM disease. In two cases the IgM ANCA was not cleared by PE with a plasma filter alone and the patients died. In the third PE was with both cell separator and filtration, and the patient survived. Case 1 (48, F). Admitted with a 3-week history of breathlessness and haemoptysis. She was oliguric, cyanosed, and had some crackles at her right mid-zone. Her serum creatinine was 330 imol/1 and arterial p02 11-2 kPa on 35% 02" Urinalysis showed protein + and blood + + +. Chest radiography showed diffuse reticulonodular shadowing. The presumptive diagnosis was an immunologically mediated pulmonary/renal syndrome and she immediately received a 3 1 PE (filter only) plus pulse methylprednisolone. Renal biopsy revealed focal necrotising proliferative glomerulonephritis with crescents; immunofluorescence demonstrated characteristic linear IgG on the GBM. Tests on a blood sample before therapy began confirmed Goodpasture’s syndrome (anti-GBM + ve, titre 86%). Cyclophosphamide 2 mg/kg orally was started and oral steroids commenced after three pulses of intravenous methylprednisolone. Plasma filtration was repeated daily. Respiratory function improved rapidly and by day 3 the patient no longer required oxygen. On day 4 she had a fresh pulmonary haemorrhage and required mechanical ventilation. By day 14 she was anti-GBM negative and PE was discontinued. However, she remained dialysis dependent and on day 37 had a fresh pulmonary haemorrhage. Plasma filtration was repeated daily for 6 days, when the antibody results from the start of the relapse became available. GBM antibodies were negative but she now had an IgM ANCA, with anti-myeloperoxidase specificity. The ANCA IgM might not have been cleared by plasma filtration so the patient was transferred to the University Hospital of Wales for whole volume PE by cell separator. She received three 3 1 exchanges, and the lung bleeding resolved. She was then transferred back to Cardiff Royal Infirmary where she received daily monoclonal anti-CD3 (OKT3; Cilag). However, she became septicaemic and died. Case 2 (27, M). Admitted in November, 1989, with a history of congested sinuses with epistaxis, bilateral deafness, redness of the right eye, flitting arthralgia, haemoptysis, and rash, accompanied by night sweats and fever. He was transferred to Addenbrooke’s Hospital in acute renal failure (creatinine 418 pmol/1). The patient had an Hb of 6-6 g/l, his p0 was 6-6 kPa, and there were bilateral infiltrates on chest radiography. Renal biopsy revealed focal necrotising glomerulonephritis with crescents. He was treated with cyclophosphamide, hydrocortisone, and plasma filtration, 4daily with a filter. He deteriorated with continuing lung haemorrhage and died 72 h later. At presentation his IgG ANCA titre was 44% and IgM ANCA 58% (anti-proteinase 3). The plasma filtrate contained IgG 36% but no detectable IgM. GBM antibodies were not found.
suggested that IgM ANCA may be associated with pulmonary haemorrhage,4,s and our observations argue for an important role for IgM ANCA in pulmonary haemorrhage caused by systemic vasculitis. Despite becoming anti-GBM negative patient 1 had further pulmonary haemorrhage in association with the development of IgM ANCA. The bleeding resolved following plasma exchange on a cell separator, and IgM ANCA titres fell. Patient 2 died and his IgM ANCA was not removed by PE. In patient 3 IgG and IgM ANCA were cleared by a cell separator and his pulmonary haemorrhage resolved. In rapidly progressive glomerulonephritis PE is an integral part of treatment.6 Many renal units use a plasma filter (incorporated into a standard dialysis extracorporeal circuit) which will, according to the manufacturers, remove both IgG and IgM. In our patients, however, IgM was not adequately cleared, probably because it is pentameric in vivo, and cell separation seems to be needed. These cases emphasise the need for rapid assays for anti-GBM and ANCA-and the test for ANCA must distinguish antibody isotypes, so that the correct form of PE can be chosen.
has been
Institute of Nephrology, Cardiff Royal Infirmary, Cardiff CF2 1SZ, UK
University of Cambridge School of Clinical Medicine, Addenbrooke’s Hospital, Cambridge
DAVID M. THOMAS RICHARD MOORE KIERON DONOVAN DAVID C. WHEELER V. L. M. ESNAULT C. MARTIN LOCKWOOD
1. Mathieson PW, Cobbold SP, Hale G, et al. Monoclonal-antibody therapy in systemic vasculitis. N Engl J Med 1990; 323: 250-54. 2. Jayne DRW, Marshall PD, Jones SJ, Lockwood CM. Autoantibodies to GBM and neutrophil cytoplasm in rapidly progressive glomerulonephritis. Kidney Int 1990; 37: 965-70. 3. Falk RJ, Hogan S, Jennette JC, the Glomerular Disease Collaborative Network. Clinical course of anti-neutrophil associated glomerulonephritis and systemic vasculitis. Ann Intern Med 1990; 113: 656-63. 4. Jayne DRW, Jones SJ, Severn A, Shaunak S, Murphy J, Lockwood CM. Severe pulmonary hemorrhage and systemic vasculitis in association with circulating anti-neutrophil cytoplasm antibodies of IgM class. Clin Nephrol 1989; 32: 101-06. 5. Esnault VLM, Soleimani B, Keogan MT, Brownlee AA, Jayne DRW, Lockwood CM. Association of IgM with IgG ANCA in patients presenting with haemorrhage. Kidney Int (in press). 6. Pusey CD, Lockwood CM. Plasma exchange for glomerular disease. In: Robinson RR, ed. Proceedings of the IXth International Congress of Nephrology, New York:
Springer, 1984:
1474-85.
Warm heart surgery SiR,—Your April 4 editorial sounds a note of caution about warm heart surgery. Hypothermia has been an integral part of open heart surgery on the basis of lessons learned at centres throughout the world in the late 1950s. Protection of the brain has been the foremost concern of cardiac surgeons from the beginning of this surgery in which the circulation is interrupted, and it remains so. The pump oxygenator can alleviate this by providing an adequate systemic circulation for the duration of the procedure. However, researchers have demonstrated lasting cerebral dysfunction is some 30% of patients. 12 In these studies, systemic hypothermia has been used.
