1090 of whooping-cough immunisation was between and 991 % in 1970-73. In the past two decades the age-distribution of whooping-cough incidence among the infants has changed. Before the introduction of compulsory whooping-cough vaccination, about 60% of cases were in children above 6 months; in the 70s about 80% of cases were under 6 months of age." From these data, we can hardly say that " the vaccine cannot protect infants ", but we can say that if we cannot immunise the infants they will not be protected. Further improvement in the quality of whooping-cough vaccine is under way. 1’, 19 But, while a better vaccine is not available, we propose to perform the complete primary immunisation at the earliest possible age and to give the complete booster immunisation to diminish the number of contacts and so achieve a further reduction of infant morbidity. ance
97-4%
is in distinguishing between ironthe anaemia of chronic disorders. However well conducted the haematological examination, they are both likely to have hypochromic, microcytic red cells on the blood film and similar red-cell indices on the Coulter print-out. But while both have low serum-irons, the iron-binding capacity is raised in iron deficiency and reduced in the anaemia of chronic disorders. Since this latter does not respond to iron therapy, it is important to make the diagnosis, and the only other certain way is to examine the bone-marrow for stainable iron, a procedure at least as expensive and time-consuming as the biochemical tests under consideration, and more painful for the patient.
minor, their real place deficiency anaemia and
Department of Pathology, Royal Victoria Hospital, Bournemouth BH1 4JG.
T.
J. HAMBLIN.
Department of Active Immunisation, HUMAN Institute for
Serobacteriological Production and Research, H-1475 Budapest, P.O.B. 4, Hungary.
Z. CSIZÉR.
IS YOUR IRON AND IRON-BINDING CAPACITY REALLY NECESSARY?
SIR,-In national control schemes’which
most clinical
laboratories in this country have joined, the average coefficient of variation for serum-iron estimations is between 10% and 15%, Therefore, 95% of results obtained on a given sample fall in the range of 75% and 125% of the true result, and results approaching the lower or upper limits of normal must be equivocal. How many clinicians carefully take blood samples for serum-iron estimations in the morning ? There is a significant normal diurnal variation, with lower values in the afternoon and evening. Overt iron-deficiency anaemia can be confirmed very rapidly by full blood-count and film examination, regardless of the associated serum-iron value. Similarly, iron-binding-capacity results in an extensively used national quality-control scheme have an average coefficient of variation of more than 15%. Therefore 95% of results obtained on a sample containing 300 tg. per 100 ml. would fall in a range of 200-400 g. per 100 ml.-i.e., from just below normal right up to the upper limit of normal. This latter estimation is probably useful in the diagnosis of haemochromatosis and hasmosiderosis, and serum-iron values are probably only clinically useful when high values are found in hxmochromatosis, haemosiderosis, iron poisoning, and sideroblastic anaemias. We will continue to receive requests for serum-iron, iron-binding capacity, vitamin-B12 levels, and serum and red-cell folate concentrations, before the clinician has had time to read the full blood-count results, because all the samples have been taken at the same time. This saves both clinical time and thought. Why should we complain in the laboratories ? The results may not be useful, but they take a great deal of time to produce, and justify the appointment of more laboratory staff and the purchase of more sophisticated (see O.E.D.) apparatus. Department of Pathology, Frenchay Hospital, Bristol BS16 1LE.
R. D. EASTHAM.
SiR,—Mr Sanderson (April 26, p. 988) asks why we request serum irons and iron-binding capacities. Although these measurements have some value in the diagnosis of haemochromatosis, sideroblastic anmmia, and thalassaemia 17. Erdös, L., Solt, K. Ann. Immunol. Hung. 1971, 15, 35. 18. Dolby, J. M. Lancet, April 5, 1975, p. 804. 19. Larsson, B., Neumüller, C., Salenstedt, C. R., Söderholm, Tiru, M. Progr. immunobiol. Standard. 1972, 5, 513.
HYPERLIPIDÆMIA AFTER RENAL TRANSPLANTATION SiR,—HyperHpoproteinaemia, related to corticosteroid therapy, has been reported as a general feature in renaltransplant patients. 1, 2- But Dr Beaumont and his colleagues (March 15, p. 599) found that 78% of their transplant
patients,
whom
prednisone
was
given
on
alternate
days,
EFFECT OF DAILY AND ALTERNATE-DAY STEROID SCHEDULES
All data mean ± S.D.
showed normal lipid patterns. They concluded that their data are consistent with the hypothesis that glucose intolerance, reactive hyperinsulinaemia, and hyperlipidasmia are not associated with alternate-day prednisone, in contrast to a daily regimen, and that relative rarity of hyperlipidxmia may be an advantage of that treatment. We have given alternate-day or daily prednisone, in equivalent doses, to two comparable groups of patients. Our alternate-day steroid protocol consisted of a single dose of prednisone between 7 and 8 A.M., tapered every 48 hours, so that in 60th-70th day after operation, the alternate-day dose began. We can confirm that this schedule reduces steroid morbidity and has no untoward effects on graft survival or function; but we have seen no important difference in lipid patterns between patients treated daily or on alternate days. Comparing subjects 1.
J.,
to
2.
Ghosh, P., Evans, D. B., Tomlinson, S. A., Calne, R. Y. Transplantation, 1973, 15, 521. Casaretto, A., Marchioro, T. L., Goldsmith, R., Bagdade, J. D. Lancet, 1974, i, 481.
1091 a renal transplant for at least 6 months, and who had a serum-creatinine of less than 3 mg. per 100 ml., no difference was found between two groups in the percentage of hyperlipaemic patients, fasting serum-triglycerides, or pre-P-lipoproteins. Only serum-cholesterol levels were higher in patients on daily steroid, but the mean level was still in the normal range (see accompanying
who had had
table). These results do not confirm, therefore, the action of alternate-day steroids in preventing post-transplant hyperlipidaemia, even if our patients had a shorter post-transplant period than Beaumont et al. patients (mean 17 months v. 43 months). The role of steroids in this complication requires further definition; it might be best elucidated by serial determination of the lipid patterns after transplantation. But steroid therapy may not be the only cause of transplant hyperlipxmia: for instance, after successful transplant many patients, for psychological and physical reasons, tend to overheat, which on its own or in combination with prednisone can predispose to lipid disorders. The observation that a low-calorie/low-starch diet restores the lipid pattern to normal in transplanted patients3 means that other factors besides steroids might explain the
hyperlipidxmia. Sezione di Nefrologia
from the data whether there was a consistent and continued fall in T.B.K. in any of the individuals studied. If some individuals show a clinically significant fall in T.B.K., a means of identifying them would be needed, so that they could be given potassium supplements. Department of Pharmacology and Therapeutics, London Hospital Medical College, Turner Street, London E1 2AD.
**We showed this letter follows.-ED. L.
Northwick Park Hospital and Clinical Research Centre, Watford Road, Harrow, Middlesex HA1 3UJ.
awl. give to the work of Gutman et al. is not in agreement with the conclusion those authors reached. Heparin administered during hmmodialysis activates lipoprotein lipase, which splits triglycerides in free fatty acids and glycerol. 6-8 The effects of heparin wear off in a few hours and triglycerides and lipolytic activity return to predialysis values. Gutman et al. showed that these effects did not occur with regional heparinisation and peritoneal dialysis, and therefore rightly concluded that metabolic improvement occasioned by dialysis did not seem to be responsible for these triglyceride and postheparin lipolytic activity changes. et
Elisabeth Gasthuis, Haarlem.
A. P. ROODVOETS.
Academisch Ziekenhuis, Utrecht, Netherlands.
A. STRUYVENBERG.
BODY POTASSIUM DURING PROLONGED THIAZIDE THERAPY
SIR,-If Dr Wilkinson and his colleagues (April 5, p. 759) right in concluding that potassium supplements are not necessary in the treatment of essential hypertension with a thiazide, this is important. However, they say nothing about the dietary potassium intake of their patients. It seems are
relevant to know whether this was in the middle of the normal range for all of them. Secondly, although the mean total body potassium (T.B.K.) changed little, it is not clear 3. 4.
5. 6.
7. 8.
Ponticelli, C., Barbi, G., Annoni, G., Cantaluppi, A., Mauri, F. Br. med. J. (in the press). Cramp, D. G., Moorhead, J. F., Wills, M. R. Lancet, March 22, 1975, p. 672. Gutman, R. A., Uy, A., Shalhoub, R. J., Wade, A. D., O’Connell, J. M. B., Recant, L. Am. J. clin. Nutr. 1973, 26, 165. Roodvoets, A. P., Neerbos, B. R. van, Hooghwinkel, G. J. M., Hulsmans, H. A. M., Beukers, H. Proc. Eur. Dial. Transplant. Ass. 1967, 4, 257. Tsaltas, T. T., Friedman, E. A. Am. J. clin. Nutr. 1968, 21, 430. Roodvoets, A. P. Hyperlipemie bij nierinsufficientie. Thesis, Leyden University, 1974.
reply
PETER WILKINSON.
NEUROBLASTOMA, IMMUNODEFICIENCY,
BLOOD-LIPIDS IN RENAL DISEASE
SiR,—The interpretation that Cramp
Dr Wilkinson, whose
SIR,-All our patients had potassium intakes around the middle of the normal range, with the usual seasonal variation. Only one patient showed a persistent fall in T.B.K. to 80-7% of his pre-treatment value after 12 months; however, at 15 months his T.B.K. was 85-2% and at 18 months 92-5%, without potassium supplements. We noted this stabilisation of T.B.K. in all the other patients, but it usually occurred after 6 months of therapy. We would like to emphasise that routine potassium supplements are not necessary in the treatment of essential hypertension with a thiazide..
C. PONTICELLI G. BARBI A. CANTALUPPI E. CEGLIA.
Dialisi, Ospedale Policlinico, Milan, and Istituto di Clinica Medica III, Università, Milan, Italy. e
to
A. HERXHEIMER.
AND CATECHOLAMINES
SIR,-Your editorial on neuroblastoma (Feb. 15, p. 379) commented on the high urinary level of vanillylmandelic acid (V.M.A.) in up to 90% of children with .
neuroblastoma. This may be related to the poor prognosis in this disease. The immune system may be very important in the prevention and in the response to treatment of malignancy. Patients with congenital immunodeficiency of various types have a markedly increased incidence of neoplasia.1 Many human neoplasms, including neuroblastoma, have tumour-specific antigens which elicit an immune response from patients’ tissue in vitro, despite the fact that the tumour grows in vivo. Cancer patients with immunological deficiency have a poor prognosis even if little or no detectable disease is present. No matter how exuberant the immune response, it has been shown repeatedly that immunotherapy is of no avail if the tumour mass is as small as 1 c.cm. In patients freed of gross neuroblastoma by surgery, radiation, or chemotherapy, microscopic foci of disease may remain and immunocompetence may be important under these conditions. It is at this point that the excretory products of the neuroblastoma may be
damaging. Adrenaline can modify (generally by inhibition) a wide variety of immune processes by increasing leucocyte CyCliC-A.M.P. levels.3 The most familiar example is its use in the treatment of asthma. Adrenaline and other drugs that increase leucocyte cyclic-A.M.P. levels reduce the production or secretion of antibody,’ suppress T-cellmediated cytolysis,5 and reduce D.N.A. synthesis in both T and B lymphocytes after mitogen stimulation.s Waldmann, T. A., Strober, M. D., Blacse, R. M. Ann. intern. Med. 1972, 77, 605. 2. Eilber, F. R., Morton, D. L. Cancer, 1970, 25, 362. 3. Bourne, H. R., Lichtenstein, L. M., Melmon, K. L., Henny, C. S., Weinstein, Y. Science, 1974, 184, 19. 4. Melmon, K. L., Bourne, H. R., Weinstein, Y., Shearer, G. M., Bauminger, S., Kram, J. J. clin. Invest. 1974, 53, 13. 5. Henney, C. S., Lichtenstein, L. M. J. Immun. 1971, 107, 610. 6. Diamantstein, T., Ulmer, A. Immunology, 1975, 28, 113. 1.
97-4%
is in distinguishing between ironthe anaemia of chronic disorders. However well conducted the haematological examination, they are both likely to have hypochromic, microcytic red cells on the blood film and similar red-cell indices on the Coulter print-out. But while both have low serum-irons, the iron-binding capacity is raised in iron deficiency and reduced in the anaemia of chronic disorders. Since this latter does not respond to iron therapy, it is important to make the diagnosis, and the only other certain way is to examine the bone-marrow for stainable iron, a procedure at least as expensive and time-consuming as the biochemical tests under consideration, and more painful for the patient.
minor, their real place deficiency anaemia and
Department of Pathology, Royal Victoria Hospital, Bournemouth BH1 4JG.
T.
J. HAMBLIN.
Department of Active Immunisation, HUMAN Institute for
Serobacteriological Production and Research, H-1475 Budapest, P.O.B. 4, Hungary.
Z. CSIZÉR.
IS YOUR IRON AND IRON-BINDING CAPACITY REALLY NECESSARY?
SIR,-In national control schemes’which
most clinical
laboratories in this country have joined, the average coefficient of variation for serum-iron estimations is between 10% and 15%, Therefore, 95% of results obtained on a given sample fall in the range of 75% and 125% of the true result, and results approaching the lower or upper limits of normal must be equivocal. How many clinicians carefully take blood samples for serum-iron estimations in the morning ? There is a significant normal diurnal variation, with lower values in the afternoon and evening. Overt iron-deficiency anaemia can be confirmed very rapidly by full blood-count and film examination, regardless of the associated serum-iron value. Similarly, iron-binding-capacity results in an extensively used national quality-control scheme have an average coefficient of variation of more than 15%. Therefore 95% of results obtained on a sample containing 300 tg. per 100 ml. would fall in a range of 200-400 g. per 100 ml.-i.e., from just below normal right up to the upper limit of normal. This latter estimation is probably useful in the diagnosis of haemochromatosis and hasmosiderosis, and serum-iron values are probably only clinically useful when high values are found in hxmochromatosis, haemosiderosis, iron poisoning, and sideroblastic anaemias. We will continue to receive requests for serum-iron, iron-binding capacity, vitamin-B12 levels, and serum and red-cell folate concentrations, before the clinician has had time to read the full blood-count results, because all the samples have been taken at the same time. This saves both clinical time and thought. Why should we complain in the laboratories ? The results may not be useful, but they take a great deal of time to produce, and justify the appointment of more laboratory staff and the purchase of more sophisticated (see O.E.D.) apparatus. Department of Pathology, Frenchay Hospital, Bristol BS16 1LE.
R. D. EASTHAM.
SiR,—Mr Sanderson (April 26, p. 988) asks why we request serum irons and iron-binding capacities. Although these measurements have some value in the diagnosis of haemochromatosis, sideroblastic anmmia, and thalassaemia 17. Erdös, L., Solt, K. Ann. Immunol. Hung. 1971, 15, 35. 18. Dolby, J. M. Lancet, April 5, 1975, p. 804. 19. Larsson, B., Neumüller, C., Salenstedt, C. R., Söderholm, Tiru, M. Progr. immunobiol. Standard. 1972, 5, 513.
HYPERLIPIDÆMIA AFTER RENAL TRANSPLANTATION SiR,—HyperHpoproteinaemia, related to corticosteroid therapy, has been reported as a general feature in renaltransplant patients. 1, 2- But Dr Beaumont and his colleagues (March 15, p. 599) found that 78% of their transplant
patients,
whom
prednisone
was
given
on
alternate
days,
EFFECT OF DAILY AND ALTERNATE-DAY STEROID SCHEDULES
All data mean ± S.D.
showed normal lipid patterns. They concluded that their data are consistent with the hypothesis that glucose intolerance, reactive hyperinsulinaemia, and hyperlipidasmia are not associated with alternate-day prednisone, in contrast to a daily regimen, and that relative rarity of hyperlipidxmia may be an advantage of that treatment. We have given alternate-day or daily prednisone, in equivalent doses, to two comparable groups of patients. Our alternate-day steroid protocol consisted of a single dose of prednisone between 7 and 8 A.M., tapered every 48 hours, so that in 60th-70th day after operation, the alternate-day dose began. We can confirm that this schedule reduces steroid morbidity and has no untoward effects on graft survival or function; but we have seen no important difference in lipid patterns between patients treated daily or on alternate days. Comparing subjects 1.
J.,
to
2.
Ghosh, P., Evans, D. B., Tomlinson, S. A., Calne, R. Y. Transplantation, 1973, 15, 521. Casaretto, A., Marchioro, T. L., Goldsmith, R., Bagdade, J. D. Lancet, 1974, i, 481.
1091 a renal transplant for at least 6 months, and who had a serum-creatinine of less than 3 mg. per 100 ml., no difference was found between two groups in the percentage of hyperlipaemic patients, fasting serum-triglycerides, or pre-P-lipoproteins. Only serum-cholesterol levels were higher in patients on daily steroid, but the mean level was still in the normal range (see accompanying
who had had
table). These results do not confirm, therefore, the action of alternate-day steroids in preventing post-transplant hyperlipidaemia, even if our patients had a shorter post-transplant period than Beaumont et al. patients (mean 17 months v. 43 months). The role of steroids in this complication requires further definition; it might be best elucidated by serial determination of the lipid patterns after transplantation. But steroid therapy may not be the only cause of transplant hyperlipxmia: for instance, after successful transplant many patients, for psychological and physical reasons, tend to overheat, which on its own or in combination with prednisone can predispose to lipid disorders. The observation that a low-calorie/low-starch diet restores the lipid pattern to normal in transplanted patients3 means that other factors besides steroids might explain the
hyperlipidxmia. Sezione di Nefrologia
from the data whether there was a consistent and continued fall in T.B.K. in any of the individuals studied. If some individuals show a clinically significant fall in T.B.K., a means of identifying them would be needed, so that they could be given potassium supplements. Department of Pharmacology and Therapeutics, London Hospital Medical College, Turner Street, London E1 2AD.
**We showed this letter follows.-ED. L.
Northwick Park Hospital and Clinical Research Centre, Watford Road, Harrow, Middlesex HA1 3UJ.
awl. give to the work of Gutman et al. is not in agreement with the conclusion those authors reached. Heparin administered during hmmodialysis activates lipoprotein lipase, which splits triglycerides in free fatty acids and glycerol. 6-8 The effects of heparin wear off in a few hours and triglycerides and lipolytic activity return to predialysis values. Gutman et al. showed that these effects did not occur with regional heparinisation and peritoneal dialysis, and therefore rightly concluded that metabolic improvement occasioned by dialysis did not seem to be responsible for these triglyceride and postheparin lipolytic activity changes. et
Elisabeth Gasthuis, Haarlem.
A. P. ROODVOETS.
Academisch Ziekenhuis, Utrecht, Netherlands.
A. STRUYVENBERG.
BODY POTASSIUM DURING PROLONGED THIAZIDE THERAPY
SIR,-If Dr Wilkinson and his colleagues (April 5, p. 759) right in concluding that potassium supplements are not necessary in the treatment of essential hypertension with a thiazide, this is important. However, they say nothing about the dietary potassium intake of their patients. It seems are
relevant to know whether this was in the middle of the normal range for all of them. Secondly, although the mean total body potassium (T.B.K.) changed little, it is not clear 3. 4.
5. 6.
7. 8.
Ponticelli, C., Barbi, G., Annoni, G., Cantaluppi, A., Mauri, F. Br. med. J. (in the press). Cramp, D. G., Moorhead, J. F., Wills, M. R. Lancet, March 22, 1975, p. 672. Gutman, R. A., Uy, A., Shalhoub, R. J., Wade, A. D., O’Connell, J. M. B., Recant, L. Am. J. clin. Nutr. 1973, 26, 165. Roodvoets, A. P., Neerbos, B. R. van, Hooghwinkel, G. J. M., Hulsmans, H. A. M., Beukers, H. Proc. Eur. Dial. Transplant. Ass. 1967, 4, 257. Tsaltas, T. T., Friedman, E. A. Am. J. clin. Nutr. 1968, 21, 430. Roodvoets, A. P. Hyperlipemie bij nierinsufficientie. Thesis, Leyden University, 1974.
reply
PETER WILKINSON.
NEUROBLASTOMA, IMMUNODEFICIENCY,
BLOOD-LIPIDS IN RENAL DISEASE
SiR,—The interpretation that Cramp
Dr Wilkinson, whose
SIR,-All our patients had potassium intakes around the middle of the normal range, with the usual seasonal variation. Only one patient showed a persistent fall in T.B.K. to 80-7% of his pre-treatment value after 12 months; however, at 15 months his T.B.K. was 85-2% and at 18 months 92-5%, without potassium supplements. We noted this stabilisation of T.B.K. in all the other patients, but it usually occurred after 6 months of therapy. We would like to emphasise that routine potassium supplements are not necessary in the treatment of essential hypertension with a thiazide..
C. PONTICELLI G. BARBI A. CANTALUPPI E. CEGLIA.
Dialisi, Ospedale Policlinico, Milan, and Istituto di Clinica Medica III, Università, Milan, Italy. e
to
A. HERXHEIMER.
AND CATECHOLAMINES
SIR,-Your editorial on neuroblastoma (Feb. 15, p. 379) commented on the high urinary level of vanillylmandelic acid (V.M.A.) in up to 90% of children with .
neuroblastoma. This may be related to the poor prognosis in this disease. The immune system may be very important in the prevention and in the response to treatment of malignancy. Patients with congenital immunodeficiency of various types have a markedly increased incidence of neoplasia.1 Many human neoplasms, including neuroblastoma, have tumour-specific antigens which elicit an immune response from patients’ tissue in vitro, despite the fact that the tumour grows in vivo. Cancer patients with immunological deficiency have a poor prognosis even if little or no detectable disease is present. No matter how exuberant the immune response, it has been shown repeatedly that immunotherapy is of no avail if the tumour mass is as small as 1 c.cm. In patients freed of gross neuroblastoma by surgery, radiation, or chemotherapy, microscopic foci of disease may remain and immunocompetence may be important under these conditions. It is at this point that the excretory products of the neuroblastoma may be
damaging. Adrenaline can modify (generally by inhibition) a wide variety of immune processes by increasing leucocyte CyCliC-A.M.P. levels.3 The most familiar example is its use in the treatment of asthma. Adrenaline and other drugs that increase leucocyte cyclic-A.M.P. levels reduce the production or secretion of antibody,’ suppress T-cellmediated cytolysis,5 and reduce D.N.A. synthesis in both T and B lymphocytes after mitogen stimulation.s Waldmann, T. A., Strober, M. D., Blacse, R. M. Ann. intern. Med. 1972, 77, 605. 2. Eilber, F. R., Morton, D. L. Cancer, 1970, 25, 362. 3. Bourne, H. R., Lichtenstein, L. M., Melmon, K. L., Henny, C. S., Weinstein, Y. Science, 1974, 184, 19. 4. Melmon, K. L., Bourne, H. R., Weinstein, Y., Shearer, G. M., Bauminger, S., Kram, J. J. clin. Invest. 1974, 53, 13. 5. Henney, C. S., Lichtenstein, L. M. J. Immun. 1971, 107, 610. 6. Diamantstein, T., Ulmer, A. Immunology, 1975, 28, 113. 1.
