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RECOMBINANT HUMAN ERYTHROPOIETIN TREATMENT IN PATIENTS ON MAINTENANCE HOME HAEMODIALYSIS
569 RECOMBINANT HUMAN ERYTHROPOIETIN TREATMENT IN PATIENTS ON MAINTENANCE HOME HAEMODIALYSIS
SIR,-Dr Pascual and colleagues (July 15, p 160) report the safe recombinant human erythropoietin (rhEPO) in home dialysis 1 patients, believing our patients to have been treated in hospital. Five of our original ten patients continued home dialysis after treatment with rhEPO (Cilag, UK) had been established in hospital as part of the clinical trial protocol. We have now treated twenty-two patients at home without significant problems (mean duration of treatment 16 months, range 2-37). Six patients reported infuenzalike symptoms after administration but these abated spontaneously or were abolished or ameliorated by taking either aspirin or paracetamol an hour before injection of rhEPO. The first dose was given in hospital to show the patient how to administer the agent at the end of dialysis. use of
Because of the reports of sudden rises in blood pressure associated rapid increases in haemoglobinl-3 we have taken several
with
precautions: (1) Blood
pressure had to be well controlled before home
instituted, and patients measured their blood pressures thrice daily and were instructed to report any sudden changes or the development of headaches. (2) A low dose of rhEPO, about 50 U/kg intravenously thrice weekly, was prescribed to avoid a rapid increase in the haemoglobin concentration. (3) The need for compliance with potassium restriction was emphasised because of the reports of hyperkalaemia in some treatment was
patients.4 (4) Follow-up (which monthly to monitor the
is
two monthly) was undertaken of response and establish the lowest
usually
rate
maintenance dose. We agree that with care home administration of rhEPO can be safe and that there is no need to switch patients needing this treatment to
costly hospital dialysis. C. G. WINEARLS E. FORMAN P. WIFFEN D. O. OLIVER
Renal Unit, Churchill Hospital, Oxford OX3 7LJ
1. Winearls CG, Oliver DO, Pippard MJ, Reid C, Downing MR, Cotes PM. Effect of human erythropoietin denved from recombinant DNA on the anaemia of patients maintained by chronic haemodialysis. Lancet 1986; ii: 1175-78. 2. Tomson CRV, Venning MC, Ward MK. Blood pressure and erythropoietin. Lancet 1988; i: 351. 3. Edmunds ME, Walls J. Blood pressure and erythropoietin. Lancet 1988; i: 352. 4. Casati S, Passerini P, Campise MR, et al. Benefits and risk of protracted treatment with recombinant human eruthropoietin in patients having haemodialysis. Br Med J
1987, 295: 1017-20.
DETECTION OF CAMPYLOBACTER PYLORI INFECTION
SIR,-Dr Loffeld and colleagues’ report (May 27, p 1182) on an
immunoassay to detect Campylobacter pylori antibodies contains conceptual errors which, if corrected, might significantly alter their conclusions. All serological
tests on
sonicates
or
crude
extracts
of whole
C pylori have suffered from frequent false positive and false negative results. Such preparations contain antigens that cross-react with antibodies directed against other bacteria (eg, Cjejuni, Cfetus, and Escherichia cola.l Adjusting the ELISA cut-off to avoid false positives increases the false negative rate.l Loffeld and colleagues found a positive predictive value of 100% at the high cut-off but with negative predictive value of only 76%. Lowering the cut-off value to 1 ’0 had the expected opposite effect-namely, a negative predictive value of 100% and a positive predictive value of only 89%. Their test is not a good discrimination between presence or absence of C pylori infection. Several groups have found a significant decrease in C pylori antibody after absorption of sera with C jejuni,2-4 and crossreactivity can also be reduced by absorbing sera first. Loffeld et al claim that there was cross-reactivity to C pylori but they did not
directly test for it.
Loffeld et al assume that optical density (OD) is proportional to antibody titre or concentration; it is not.5-7 Nor is OD (absorbance) on a linear scale such that an OD of 2 equals I % light transmission and OD 3 equals 0’ 1 % light transmission; their positive test is in an absorbance range that is inaccurate and should be avoided. We do need accurate reliable methods to detect C pylori infection and its eradication. Several candidates are available, including the urea breath test8 and second-generation serological tests based on purified antigens. For example, a test based on the purified, high-molecular-weight cell-associated proteins of C pylori has a positive predictive value of 100% and a sensitivity and negative predictive value of 987%.9 Loffeld and colleagues’ discussion is based on the premise that there is a safe and effective therapy for C pylori infection and that patients with this infection should be treated. Both premises are currently controversial. One of us (D. Y. G.) has predicted that the management of dyspepsia would change remarkably "If C pylori is conclusively proven to be the most important factor in chronic duodenal or gastric ulcer disease and also as responsible for a reasonable percentage of cases of non-ulcer dyspepsia." Endoscopy and barium series might be used much less often. A more cost-effective approach might be to screen the dyspeptic patient by, for example, a latex agglutinination test for antibody to C pylori urease and treat positive cases with agents active against C pylori. Only non-responders or those at high risk of gastric cancer or with complications such as anaemia would undergo other diagnostic tests. The elimination of ulcer relapse by eradicating C pylori, the availability of safe and effective therapy for C pylori, and the development of simple tests to screen for C pylori and to monitor the efficacy of therapy are reasonable predictions.lo Department of Medicine, Baylor College of Medicine and Medical Center, Houston, Texas 77030, USA
DAVID Y. GRAHAM DOYLE J. EVANS, JR DOLORES G. EVANS
BJ, Ali MH, Reed PI. An enzyme-linked immunosorbent assay for the serodiagnosis of Campylobacter pylori-associated gastritis. Scand J Gastroenterol 1988; 23 (suppl 142): 53-57. 2 Perez-Perez GI, Dworkm BM, Chodos JE, Blaser MJ. Campylobacter pylori antibodies in humans. Ann Intern Med 1988; 109: 11-17. 3. Gnarpe H, Unge P, Blomqvist C, Makitalo S. Campylobacter pylori in Swedish patients referred for gastroscopy. APMIS 1988; 96: 128-32. 4. Mitchell HM, Lee A, Berkowicz J, Barody T. The use of serology to diagnose active Campylobacter pylori infection. Med JAust 1988; 149: 604-09. 5. de Savigny D, Voller A. The communication of ELISA data from laboratory to clinician. J Immunoassay 1980; 1: 105-28. 6. Lehtonen O-P, Eerola E. The effect of different antibody affinities on ELISA absorbance and titer. J Immunol Meth 1982; 54: 233-40 7. Newell DG, Rathbone BJ. The serodiagnosis of Campylobacter pylori infection. Serodiagn Immunother Infect Dis 1989; 3: 6. 8. Klein PD, Graham DY. Campylobacter pylori detection by the 13C-urea breath test. In: Rathbone B, Heatley V, eds. Campylobacter pylori and gastroduodenal disease. Oxford: Blackwell Scientific Publications, 1989: 94-106. 9. Evans DJ Jr, Evans DG, Graham DY, Klein PD. A sensitive and specific serologic test for detection of Campylobacter pylori infection. Gastroenterology 1989, 96: 1004-08. 10. Graham DY. Campylobacter pylon and peptic ulcer disease. Gastroenterology 1989; 96 1. Newell DG, Johnston
(suppl): 615-25.
**Thisletter has been shown to Dr Loffeld and colleagues, whose reply follows.-ED. L. SIR,-We agree that serological tests with sonicates or crude extracts of Campylobacter pylori suffer from cross-reaction with other microorganisms, notably Cjejuni. Our assay, however, did not show such cross-reaction when tested by indirect methods. We see no reason why direct tests should have been done. Dr Graham and his colleagues do not seem to understand how our cut-off values were established. We compared two well-defined groups of patients with non-ulcer dyspepsia with and without campylobacter-associated gastritis, and found clear cut-offs indicating 100% positive and negative predictive values, respectively, leaving circumvention of the problem of crossreactivity totally aside. We are not aware of having stumbled into the trap of assuming that optical density is proportional to antibody titre. Extinction values do reflect the amount of antibody in serum. Measurements on test sera were divided by control values to calculate the P/N ratio
SIR,-Dr Pascual and colleagues (July 15, p 160) report the safe recombinant human erythropoietin (rhEPO) in home dialysis 1 patients, believing our patients to have been treated in hospital. Five of our original ten patients continued home dialysis after treatment with rhEPO (Cilag, UK) had been established in hospital as part of the clinical trial protocol. We have now treated twenty-two patients at home without significant problems (mean duration of treatment 16 months, range 2-37). Six patients reported infuenzalike symptoms after administration but these abated spontaneously or were abolished or ameliorated by taking either aspirin or paracetamol an hour before injection of rhEPO. The first dose was given in hospital to show the patient how to administer the agent at the end of dialysis. use of
Because of the reports of sudden rises in blood pressure associated rapid increases in haemoglobinl-3 we have taken several
with
precautions: (1) Blood
pressure had to be well controlled before home
instituted, and patients measured their blood pressures thrice daily and were instructed to report any sudden changes or the development of headaches. (2) A low dose of rhEPO, about 50 U/kg intravenously thrice weekly, was prescribed to avoid a rapid increase in the haemoglobin concentration. (3) The need for compliance with potassium restriction was emphasised because of the reports of hyperkalaemia in some treatment was
patients.4 (4) Follow-up (which monthly to monitor the
is
two monthly) was undertaken of response and establish the lowest
usually
rate
maintenance dose. We agree that with care home administration of rhEPO can be safe and that there is no need to switch patients needing this treatment to
costly hospital dialysis. C. G. WINEARLS E. FORMAN P. WIFFEN D. O. OLIVER
Renal Unit, Churchill Hospital, Oxford OX3 7LJ
1. Winearls CG, Oliver DO, Pippard MJ, Reid C, Downing MR, Cotes PM. Effect of human erythropoietin denved from recombinant DNA on the anaemia of patients maintained by chronic haemodialysis. Lancet 1986; ii: 1175-78. 2. Tomson CRV, Venning MC, Ward MK. Blood pressure and erythropoietin. Lancet 1988; i: 351. 3. Edmunds ME, Walls J. Blood pressure and erythropoietin. Lancet 1988; i: 352. 4. Casati S, Passerini P, Campise MR, et al. Benefits and risk of protracted treatment with recombinant human eruthropoietin in patients having haemodialysis. Br Med J
1987, 295: 1017-20.
DETECTION OF CAMPYLOBACTER PYLORI INFECTION
SIR,-Dr Loffeld and colleagues’ report (May 27, p 1182) on an
immunoassay to detect Campylobacter pylori antibodies contains conceptual errors which, if corrected, might significantly alter their conclusions. All serological
tests on
sonicates
or
crude
extracts
of whole
C pylori have suffered from frequent false positive and false negative results. Such preparations contain antigens that cross-react with antibodies directed against other bacteria (eg, Cjejuni, Cfetus, and Escherichia cola.l Adjusting the ELISA cut-off to avoid false positives increases the false negative rate.l Loffeld and colleagues found a positive predictive value of 100% at the high cut-off but with negative predictive value of only 76%. Lowering the cut-off value to 1 ’0 had the expected opposite effect-namely, a negative predictive value of 100% and a positive predictive value of only 89%. Their test is not a good discrimination between presence or absence of C pylori infection. Several groups have found a significant decrease in C pylori antibody after absorption of sera with C jejuni,2-4 and crossreactivity can also be reduced by absorbing sera first. Loffeld et al claim that there was cross-reactivity to C pylori but they did not
directly test for it.
Loffeld et al assume that optical density (OD) is proportional to antibody titre or concentration; it is not.5-7 Nor is OD (absorbance) on a linear scale such that an OD of 2 equals I % light transmission and OD 3 equals 0’ 1 % light transmission; their positive test is in an absorbance range that is inaccurate and should be avoided. We do need accurate reliable methods to detect C pylori infection and its eradication. Several candidates are available, including the urea breath test8 and second-generation serological tests based on purified antigens. For example, a test based on the purified, high-molecular-weight cell-associated proteins of C pylori has a positive predictive value of 100% and a sensitivity and negative predictive value of 987%.9 Loffeld and colleagues’ discussion is based on the premise that there is a safe and effective therapy for C pylori infection and that patients with this infection should be treated. Both premises are currently controversial. One of us (D. Y. G.) has predicted that the management of dyspepsia would change remarkably "If C pylori is conclusively proven to be the most important factor in chronic duodenal or gastric ulcer disease and also as responsible for a reasonable percentage of cases of non-ulcer dyspepsia." Endoscopy and barium series might be used much less often. A more cost-effective approach might be to screen the dyspeptic patient by, for example, a latex agglutinination test for antibody to C pylori urease and treat positive cases with agents active against C pylori. Only non-responders or those at high risk of gastric cancer or with complications such as anaemia would undergo other diagnostic tests. The elimination of ulcer relapse by eradicating C pylori, the availability of safe and effective therapy for C pylori, and the development of simple tests to screen for C pylori and to monitor the efficacy of therapy are reasonable predictions.lo Department of Medicine, Baylor College of Medicine and Medical Center, Houston, Texas 77030, USA
DAVID Y. GRAHAM DOYLE J. EVANS, JR DOLORES G. EVANS
BJ, Ali MH, Reed PI. An enzyme-linked immunosorbent assay for the serodiagnosis of Campylobacter pylori-associated gastritis. Scand J Gastroenterol 1988; 23 (suppl 142): 53-57. 2 Perez-Perez GI, Dworkm BM, Chodos JE, Blaser MJ. Campylobacter pylori antibodies in humans. Ann Intern Med 1988; 109: 11-17. 3. Gnarpe H, Unge P, Blomqvist C, Makitalo S. Campylobacter pylori in Swedish patients referred for gastroscopy. APMIS 1988; 96: 128-32. 4. Mitchell HM, Lee A, Berkowicz J, Barody T. The use of serology to diagnose active Campylobacter pylori infection. Med JAust 1988; 149: 604-09. 5. de Savigny D, Voller A. The communication of ELISA data from laboratory to clinician. J Immunoassay 1980; 1: 105-28. 6. Lehtonen O-P, Eerola E. The effect of different antibody affinities on ELISA absorbance and titer. J Immunol Meth 1982; 54: 233-40 7. Newell DG, Rathbone BJ. The serodiagnosis of Campylobacter pylori infection. Serodiagn Immunother Infect Dis 1989; 3: 6. 8. Klein PD, Graham DY. Campylobacter pylori detection by the 13C-urea breath test. In: Rathbone B, Heatley V, eds. Campylobacter pylori and gastroduodenal disease. Oxford: Blackwell Scientific Publications, 1989: 94-106. 9. Evans DJ Jr, Evans DG, Graham DY, Klein PD. A sensitive and specific serologic test for detection of Campylobacter pylori infection. Gastroenterology 1989, 96: 1004-08. 10. Graham DY. Campylobacter pylon and peptic ulcer disease. Gastroenterology 1989; 96 1. Newell DG, Johnston
(suppl): 615-25.
**Thisletter has been shown to Dr Loffeld and colleagues, whose reply follows.-ED. L. SIR,-We agree that serological tests with sonicates or crude extracts of Campylobacter pylori suffer from cross-reaction with other microorganisms, notably Cjejuni. Our assay, however, did not show such cross-reaction when tested by indirect methods. We see no reason why direct tests should have been done. Dr Graham and his colleagues do not seem to understand how our cut-off values were established. We compared two well-defined groups of patients with non-ulcer dyspepsia with and without campylobacter-associated gastritis, and found clear cut-offs indicating 100% positive and negative predictive values, respectively, leaving circumvention of the problem of crossreactivity totally aside. We are not aware of having stumbled into the trap of assuming that optical density is proportional to antibody titre. Extinction values do reflect the amount of antibody in serum. Measurements on test sera were divided by control values to calculate the P/N ratio