187
for the controls in study 1. The potential bias in the way the data were collected and the difference in eligibility for cases and controls in study 1 may have distorted the fenoterol effect; study 2 should be relatively free of this distortion. Both studies show that the fenoterol effect is greater in those presumed to have more severe disease. The fact that risk increases with severity has been proposed4 as a compelling argument that the fenoterol effect is not due to true
confounding by severity. To summarise, this multivariate analysis confirms the conclusions of the original articlesl,2 and the recommendation by the New Zealand Department of Health that fenoterol be prescribed with caution. According to analyses in the original reports the effect seems to be specific to fenoterol among the P-agonists; a comparison of fenoterol with salbutamol users would be helpful here, but this is not possible from the published data. Other plausible interpretations remain, however, outstanding issues being the reasons for and timing of prescriptions of fenoterol and other medications and the validity of the variables used to represent severity. We note the greater consistency when hospital admissions and steroids are used as markers of severity; "number of drug categories" is inevitably more difficult to interpret because this could include fenoterol and steroids, both of which are themselves of interest.
S. D. WALTER D. L. SACKETT H. S. SHANNON M. LEVINE G. P. BROWNMAN
Department of Clinical Epidemiology and Biostatistics and Department of Medicine, McMaster Univeristy, Hamilton, Ontario L8N 3ZS, Canada
for the twofold higher prevalence in women than in men.’ might be "protected" by testicular ACE, which is under androgenic controlbut to our knowledge testicular ACE has not been demonstrated in lung tissue. A more likely explanation is that women have a lower threshold for cough.8 Genetic polymorphism of the ACE gene could be related to cough in some other way but our hypothesis could readily be tested by genotyping patients with this side-effect.
account
Men
University Department of Medicine and Pharmacology, Royal Hallamshire Hospital, Sheffield S10 2JF, UK
W. W. YEO L. E. RAMSAY A. H. MORICE
Just PM The positive association of cough with angiotensin-converting enzyme inhibitors. Pharmacotherapy 1989; 9: 82-87. 2. McEwan JR, Choudry N, Street R, Fuller RW. Change in cough reflex after treatment with enalapril and ramipril. Br Med J 1989; 299: 13-16. 3. Yeo WW, Maclean D, Richardson PJ, Ramsay LE. Cough and enalapril: assessment by spontaneous reporting and visual analogue scale under double-blind conditions. BrJ Clin Pharmacol (in press). 4. Rigat B, Hubert C, Athenc-Gelas F, Cambien F, Corvol P, Soubrier F. An insertion/deletion polymorphism m the angiotensin 1-converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest 1990; 86: 1.
1343-46. 5. Monce AH, Lowry R, Brown MJ, Higenbottam T. Angiotensin-converting enzyme and the cough reflex. Lancet 1987; ii: 1116-18. 6. McEwan JR, Choudry NB, Fuller RW. The effect of sulindac on the abnormal cough reflex associated with dry cough. J Pharmacol Exp Ther 1990; 225: 161-64. 7. Ehlers MRW, Fox EA, Strydom DJ, Riordan JF. Molecular cloning of human testicular angiotensin-converting enzyme: the testis isoenzyme is identical to the C-terminal half of endothelial angiotensin-converting enzyme. Proc Natl Acad Sci USA 1989; 86: 7741-45. 8. Fujimura M, Sakamoto S, Kamio Y, Matsuda T. Sex difference m the inhaled tartaric acid cough threshold in non-atopic healthy subjects. Thorax 1990; 45: 633-34.
1. Crane J, Flatt A, Jackson R, et al. Prescribed fenoterol and death from asthma in New
Zealand 1981-83: case-control study. Lancet 1989; i: 917-22 Grainger J, Atkinson M, et al. Case-control study of prescribed fenoterol and death from asthma in New Zealand, 1977-81. Thorax 1990, 45: 170-75. 3 Mantel N, Haenszel W Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 1959, 22: 719-48. 4. Sackett DL, Shannon HS, Browman GW. Fenoterol and fatal asthma. Lancet 1990; 335: 45-46.
Medical rubber anaphylaxis
2 Pearce N,
ACE inhibitor
cough:
a
genetic link?
SIR,-Persistent dry cough is the most common side-effect of angiotensin-converting enzyme (ACE) inhibitors, with a frequency of about 15%. Why only certain individuals are affected is unclear.’=However, those with cough have a shift to the left in the cough response to challenge with capsaicin,2arelatively specific C-fibre stimulant, and this shift seems to be limited to the 15 % or so of patients in whom a cough develops. When cough frequency was measured in patients on ACE inhibitors high scores were observed in 2l %, with no change in cough score in the whole population treatedThese observations might suggest that persistent cough is an adverse reaction related to a genetic polymorphism of drug metabolism, but variation in drug metabolism is an unlikely explanation since cough is a class effect of ACE inhibitors, including those which are cleared by the kidney. Rigat et all have described a polymorphism in the gene for ACE with a frequency of 0-4 for the longer allele. About 16% of the population are homozygous for the longer allele and have significantly reduced serum ACE concentrations. The similarity in frequencies for the homozygous genotype and for persistent dry cough led us to speculate that this polymorphism may be involved in the genesis of cough. Perhaps low concentrations of perineuronal ACE’ in the larynx and lung of homo zygotes, rather than low serum ACE, predispose to cough. ACE inactivates bradykinin and substance P, both stimulants of unmyelinated C-fibres which may cause cough directly.’ Bradykinin also enhances production of prostaglandins, including PGE2, which cause cough.! PG synthetase inhibitors apparently reduce the cough threshold in patients with ACE-inhibitor-induced cough.’ Low tissue ACE might therefore be expected to promote cough by increasing bradykmm and prostaglandins. If homozygotes for the longer allele in the ACE gene have reduced tissue ACE levels, ACE inhibitor treatment may decrease tissue ACE to a critical level which causes spontaneous cough. Any explanation of ACE inhibitor cough must
Sip,—Dr Hamilton (Dec 8, p 1453) mentions studies implicating rubber accelerators, their byproducts, and preservatives in hypersensitivity reactions, including anaphylaxis. Readers should be aware that recent work strongly suggests that type-II hypersensitivity to natural rubber is triggered by protein antigens, not haptens. Patients with rubber-induced urticaria, rhinitis, and anaphylaxis were shown to have positive skin prick tests and basophil histamine release with preservative-free latex preparations as well as with extracts from the leaves of Hevea brasiliensis, the commercial rubber tree.! Western blot analysis of these and other patients has shown the presence of IgE that is specific for latex peptides of various molecular weights 23 These plant peptides are derived from Hbrasiliensis and are present in substantial amounts in natural rubber products.4 As yet, there is no evidence that changes in the accelerator, stabiliser, or preservative content of natural rubber products will lead to a reduction in the frequency of type-I reactions. However, rubber-allergic patients can tolerate products made of synthetic elastomers, such as neoprene or styrene-butadiene block-
copolymer. Department of Allergy and Immunology, Children’s National Medical Center, Washington DC 20010, USA
JAY E. SLATER
1. Slater
JE Rubber anaphylaxis. N Engl J Med 1989; 320: 1126-30. C, Basomba A, Carreira J, Sastre A. Anaphylaxis produced by rubber glove contact. case reports and immunological identification of the antigens involved. Clin Exp Allergy 1989; 19: 425-30. Slater JE Human antibody response to rubber proteins. Ann Allergy 1990; 64: 93. St Cyr DR. Rubber, natural. In: Kirk-Othmer encyclopedia of chemical technology. Vol 20 New York: John Wiley, 1982: 468-91.
2 Morales
3 4.
Adverse effect of
erythropoietin in myeloproliferative disorders
SiR,—Erythropoietin (EPO) has been used for various types of anaemia due to chronic renal failure and other such diseases.! Because EPO can reduce the need for red cell transfusion and has few side-effects, its clinical application has expanded to include autologous blood donation and surgery.’We report the aggravation
188
of splenomegaly by EPO in two patients with myeloproliferative disorders. A 65-year-old woman with primary chronic myelofibrosis was admitted in September, 1989, for palpitation and abdominal distension. Her haemoglobin concentration was 7-4 g/dl, leucocytes 15.7 x 109/1, platelets 214 x 109/1, and the spleen was palpable beneath the navel. She was being treated for splenomegaly and had had a blood transfusion. 3000 units per day intravenous (iv) recombinant human (rh) EPO was given for 5 consecutive days for anaemia. Her anorexia worsened and the spleen became larger, reaching the left ilium. Haemoglobin concentration did not change during treatment. Within a week after stopping EPO the spleen returned to its former size. A 59-year-old man with chronic myelogenous leukaemia (Philadelphia-chromosome positive) in chronic phase was admitted in August, 1990, for anaemia. He was receiving hydroxyurea 1000 mg daily. His haemoglobin concentration was 7-7 g/dl, leucocytes 28x109/1, platelets 146-2 x 109/l, and the spleen was palpable 5 cm beneath the left hypochondrium. He was given iv rhEPO 3000 units on Aug 14, and 9000 units on Aug 15 and 17. On Aug 17, he had a temperature of 39°C and the spleen was tender and palpable beneath the navel. Haemoglobin concentration did not change during EPO. After stopping the drug his temperature returned to normal; the spleen was not tender and gradually returned to its former size in 7 days. EPO administration in these two patients seems to have resulted in the stimulation of extramedullary haematopoiesis and the aggravation of splenomegaly. EPO might contraindicated for the anaemia of myeloproliferative disorders.
S. IKI Division of Haematology, Kanto Teishin Hospital,
Tokyo 141, Japan
M. YAGISAWA Y. OHBAYASHI H. SATO A. URABE
1. Graber SE, Krantz SB. Erythropoietin: biology and clinical use Hematol Oncol Clin N Am 1989, 3: 369-400. 2. Maeda H, Hitomi Y, Hirata R, et al Erythropoietin and autologous blood donation. Lancet 1989; ii: 284
and immobilisation of the affected limbs, associated with severe localised pruritus that could be controlled only by intravenous corticosteroids (’Celestone’, 4 mg four times a day x 3 days). Each patient presented with fever and tender regional lymphadenopathy which was controlled with analgesics and anti-inflammatory agents. Within 3 days the reactions had subsided and no further medication was needed. 6 months after treatment, all clinical manifestations of sowda had resolved, and follow-up ocular examination and skin
biopsies were negative. Patients with sowda have enhanced cell mediated5 and humoral6 immune responses to Onchocerca volvulus. Severe side-effects should be expected with any microfilaricidal agent that enhances natural killing of microfilariae. This has been well documented for diethylcarbamazineIvermectin seems to produce a similar reaction. Patients with sowda should be identified before ivermectin is used in community-based treatment programmes: they should receive treatment, since it is curative, but only under close medical
supervision. Onchocerciasis Control Project, Ministry of Public Health and Hospital Vozandes, Quito, Ecuador 1.
be very effective in the treatment of onchocerciasis and to have few side-effects.!,2 Dr Davidson and colleagues (Oct 20, p 1005) report moderate adverse reactions to ivermectin in expatriates with limited exposure to the disease. Such reactions included fever, rash, pruritus, local swelling, and tender regional lymphadenopathy. In Ecuador in 1990 all onchocercal positive communities on the Rio Santiago, in the province of Esmeraldas,3were treated with ivermectin. Only 4% had moderate adverse reactions (eg, pruritus, localised rash, and fever). However, among those treated were 2 patients with reactive onchodermatitis (sowda),4 and they had severe reactions to ivermectin. Both patients were black (of African origin) and were permanent residents in the hyperendemic focus of onchocerciasis on the Rio Santiago. One was a 45-year-old man who for the previous 10 years had had a severe hyperpigmented pruritic maculopapular dermatitis on the right arm, forearm, and right shoulder, radiating to the upper chest and back. The other was a 27-year-old woman who for the previous 4 years had had similar dermatological changes on her left leg. Both had low average dermal microfilarial densities (3 and 1 mg, respectively) on biopsy samples from both iliac crests. Histological study of skin from the affected areas showed focal hyperkeratosis, parakeratosis, and acanthosis with some follicular plugging. The dermal fibroblasts were large and numerous, while elastic fibres were reduced in number. Lymphocytes, plasma cells, histiocytes, eosinophils, and occasional mast cells were concentrated around blood vessels. Neither patient had eye lesions or palpable onchocercal nodules. Both were given ivermectin 150 mg/kg in a community-based treatment programme. Within 6 hours there was severe swelling
Pacque MC, Munoz B, Greene BM, White AT, Dukuly Z, Taylor HR. Safety of and compliance with community-based ivermectin therapy Lancet 1990; 335: 1377-80
2. Rothova A, Van der Lelij A, Stilma JS, Wilson WR, Barbe RF. Side effects of ivermectin in treatment of onchocerciasis Lancet 1989; i: 1439-42. 3. Guderian RH, Beck BJ, Proano S Jr, Mackenzie CD. Onchocerciasis m Ecuador, 1980-86: epidemiological evaluation of the disease m the Esmeraldas province Eur J Epidemiol 1989; 5: 294-302. 4. Mackenzie CD, Gudenan RH, Proano S Jr, Herdoiza M. Un caso de dermatitis reactivo oncocercotica (sowda) en la provincia de Esmerelda, Ecuador FCM Rev Fac Cienc Med ( Quito ) 1985; 10: 121-24. 5. Ghalib HW, Mackenzie CD, Williams JF, Sisley BM, El Khalifa MY Immunology and the development of pathology in Onchocerciasis. studies m Sudan. Sud Med J 1985; 21 (suppl): 59-64. 6. Buttner DW, Laer G, Mannweiler E, Buttner M Clinical parasitological and serological studies on onchocerciasis in the Yemen Arab Republic Tropenmed Parasitol 1982; 33: 201-12. 7. Mackenzie CD, Kron MA Diethylcarbamazine a review of its action in onchocerciasis, lymphatic filariasts and inflammation Trop Dis Bull 1985, 82: R1-37
Decline in incidence of
Adverse reactions to ivermectin in reactive onchodermatitis SiR,—In field trials in West Africa ivermectin has been shown to
RONALD H. GUDERIAN MARIELA ANSELMI ROBERT SEMPERTEGUI PHILIP J. COOPER
pneumonia
SiR,—Dr Khan and colleagues (Oct 13, p 939) report from their
investigation
in Abbottabad that the incidence of moderate and
respiratory infection (ARI) in children declined as a result of community based management. Although the full results are not yet published, we have three reservations. First, Khan and colleagues’ case definition of moderate and severe ARI includes otitis media. They do not tell us how much of severe acute
the fall in incidence of moderate or severe ARI was attributable to a reduction in otitis rather than in acute lower respiratory infections. One would expect the incidence of otitis media, but not of pneumonia, to decline as mothers became aware of the management of upper respiratory infections. Second, the reported two-week incidence of moderate and severe ARI (6-7 attacks per 100 children) is equal to 17 attacks per child-year. This is nearly twelve times higher than that which we noted in an ARI morbidity study at Gadchiroli,l and is much higher than those seen elsewhere. In the first year, the Abbottabad group classified nearly a third of ARI attacks as moderate or severe ARI whereas we identified about 3% ARI attacks as pneumonia. Was there a difficulty in case defmition? Third, without a control area environmental or methodological changes cannot be ruled out as causes of reduced incidence. Moreover, an active case finding from two visits each month to every child is difficult to repeat in large scale operations in primary health care where each health worker takes part in many other health programmes. SEARCH, Gadchiroli (Maharashtra), 442605 India
1
ABHAY BANG RANI BANG
Bang AT, Bang RA, Tale O, et al. Reduction m pneumonia mortality and total childhood mortality by means of community-based intervention trial m GadchiroliIndia Lancet 1990, 336: 201-06
for the controls in study 1. The potential bias in the way the data were collected and the difference in eligibility for cases and controls in study 1 may have distorted the fenoterol effect; study 2 should be relatively free of this distortion. Both studies show that the fenoterol effect is greater in those presumed to have more severe disease. The fact that risk increases with severity has been proposed4 as a compelling argument that the fenoterol effect is not due to true
confounding by severity. To summarise, this multivariate analysis confirms the conclusions of the original articlesl,2 and the recommendation by the New Zealand Department of Health that fenoterol be prescribed with caution. According to analyses in the original reports the effect seems to be specific to fenoterol among the P-agonists; a comparison of fenoterol with salbutamol users would be helpful here, but this is not possible from the published data. Other plausible interpretations remain, however, outstanding issues being the reasons for and timing of prescriptions of fenoterol and other medications and the validity of the variables used to represent severity. We note the greater consistency when hospital admissions and steroids are used as markers of severity; "number of drug categories" is inevitably more difficult to interpret because this could include fenoterol and steroids, both of which are themselves of interest.
S. D. WALTER D. L. SACKETT H. S. SHANNON M. LEVINE G. P. BROWNMAN
Department of Clinical Epidemiology and Biostatistics and Department of Medicine, McMaster Univeristy, Hamilton, Ontario L8N 3ZS, Canada
for the twofold higher prevalence in women than in men.’ might be "protected" by testicular ACE, which is under androgenic controlbut to our knowledge testicular ACE has not been demonstrated in lung tissue. A more likely explanation is that women have a lower threshold for cough.8 Genetic polymorphism of the ACE gene could be related to cough in some other way but our hypothesis could readily be tested by genotyping patients with this side-effect.
account
Men
University Department of Medicine and Pharmacology, Royal Hallamshire Hospital, Sheffield S10 2JF, UK
W. W. YEO L. E. RAMSAY A. H. MORICE
Just PM The positive association of cough with angiotensin-converting enzyme inhibitors. Pharmacotherapy 1989; 9: 82-87. 2. McEwan JR, Choudry N, Street R, Fuller RW. Change in cough reflex after treatment with enalapril and ramipril. Br Med J 1989; 299: 13-16. 3. Yeo WW, Maclean D, Richardson PJ, Ramsay LE. Cough and enalapril: assessment by spontaneous reporting and visual analogue scale under double-blind conditions. BrJ Clin Pharmacol (in press). 4. Rigat B, Hubert C, Athenc-Gelas F, Cambien F, Corvol P, Soubrier F. An insertion/deletion polymorphism m the angiotensin 1-converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest 1990; 86: 1.
1343-46. 5. Monce AH, Lowry R, Brown MJ, Higenbottam T. Angiotensin-converting enzyme and the cough reflex. Lancet 1987; ii: 1116-18. 6. McEwan JR, Choudry NB, Fuller RW. The effect of sulindac on the abnormal cough reflex associated with dry cough. J Pharmacol Exp Ther 1990; 225: 161-64. 7. Ehlers MRW, Fox EA, Strydom DJ, Riordan JF. Molecular cloning of human testicular angiotensin-converting enzyme: the testis isoenzyme is identical to the C-terminal half of endothelial angiotensin-converting enzyme. Proc Natl Acad Sci USA 1989; 86: 7741-45. 8. Fujimura M, Sakamoto S, Kamio Y, Matsuda T. Sex difference m the inhaled tartaric acid cough threshold in non-atopic healthy subjects. Thorax 1990; 45: 633-34.
1. Crane J, Flatt A, Jackson R, et al. Prescribed fenoterol and death from asthma in New
Zealand 1981-83: case-control study. Lancet 1989; i: 917-22 Grainger J, Atkinson M, et al. Case-control study of prescribed fenoterol and death from asthma in New Zealand, 1977-81. Thorax 1990, 45: 170-75. 3 Mantel N, Haenszel W Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 1959, 22: 719-48. 4. Sackett DL, Shannon HS, Browman GW. Fenoterol and fatal asthma. Lancet 1990; 335: 45-46.
Medical rubber anaphylaxis
2 Pearce N,
ACE inhibitor
cough:
a
genetic link?
SIR,-Persistent dry cough is the most common side-effect of angiotensin-converting enzyme (ACE) inhibitors, with a frequency of about 15%. Why only certain individuals are affected is unclear.’=However, those with cough have a shift to the left in the cough response to challenge with capsaicin,2arelatively specific C-fibre stimulant, and this shift seems to be limited to the 15 % or so of patients in whom a cough develops. When cough frequency was measured in patients on ACE inhibitors high scores were observed in 2l %, with no change in cough score in the whole population treatedThese observations might suggest that persistent cough is an adverse reaction related to a genetic polymorphism of drug metabolism, but variation in drug metabolism is an unlikely explanation since cough is a class effect of ACE inhibitors, including those which are cleared by the kidney. Rigat et all have described a polymorphism in the gene for ACE with a frequency of 0-4 for the longer allele. About 16% of the population are homozygous for the longer allele and have significantly reduced serum ACE concentrations. The similarity in frequencies for the homozygous genotype and for persistent dry cough led us to speculate that this polymorphism may be involved in the genesis of cough. Perhaps low concentrations of perineuronal ACE’ in the larynx and lung of homo zygotes, rather than low serum ACE, predispose to cough. ACE inactivates bradykinin and substance P, both stimulants of unmyelinated C-fibres which may cause cough directly.’ Bradykinin also enhances production of prostaglandins, including PGE2, which cause cough.! PG synthetase inhibitors apparently reduce the cough threshold in patients with ACE-inhibitor-induced cough.’ Low tissue ACE might therefore be expected to promote cough by increasing bradykmm and prostaglandins. If homozygotes for the longer allele in the ACE gene have reduced tissue ACE levels, ACE inhibitor treatment may decrease tissue ACE to a critical level which causes spontaneous cough. Any explanation of ACE inhibitor cough must
Sip,—Dr Hamilton (Dec 8, p 1453) mentions studies implicating rubber accelerators, their byproducts, and preservatives in hypersensitivity reactions, including anaphylaxis. Readers should be aware that recent work strongly suggests that type-II hypersensitivity to natural rubber is triggered by protein antigens, not haptens. Patients with rubber-induced urticaria, rhinitis, and anaphylaxis were shown to have positive skin prick tests and basophil histamine release with preservative-free latex preparations as well as with extracts from the leaves of Hevea brasiliensis, the commercial rubber tree.! Western blot analysis of these and other patients has shown the presence of IgE that is specific for latex peptides of various molecular weights 23 These plant peptides are derived from Hbrasiliensis and are present in substantial amounts in natural rubber products.4 As yet, there is no evidence that changes in the accelerator, stabiliser, or preservative content of natural rubber products will lead to a reduction in the frequency of type-I reactions. However, rubber-allergic patients can tolerate products made of synthetic elastomers, such as neoprene or styrene-butadiene block-
copolymer. Department of Allergy and Immunology, Children’s National Medical Center, Washington DC 20010, USA
JAY E. SLATER
1. Slater
JE Rubber anaphylaxis. N Engl J Med 1989; 320: 1126-30. C, Basomba A, Carreira J, Sastre A. Anaphylaxis produced by rubber glove contact. case reports and immunological identification of the antigens involved. Clin Exp Allergy 1989; 19: 425-30. Slater JE Human antibody response to rubber proteins. Ann Allergy 1990; 64: 93. St Cyr DR. Rubber, natural. In: Kirk-Othmer encyclopedia of chemical technology. Vol 20 New York: John Wiley, 1982: 468-91.
2 Morales
3 4.
Adverse effect of
erythropoietin in myeloproliferative disorders
SiR,—Erythropoietin (EPO) has been used for various types of anaemia due to chronic renal failure and other such diseases.! Because EPO can reduce the need for red cell transfusion and has few side-effects, its clinical application has expanded to include autologous blood donation and surgery.’We report the aggravation
188
of splenomegaly by EPO in two patients with myeloproliferative disorders. A 65-year-old woman with primary chronic myelofibrosis was admitted in September, 1989, for palpitation and abdominal distension. Her haemoglobin concentration was 7-4 g/dl, leucocytes 15.7 x 109/1, platelets 214 x 109/1, and the spleen was palpable beneath the navel. She was being treated for splenomegaly and had had a blood transfusion. 3000 units per day intravenous (iv) recombinant human (rh) EPO was given for 5 consecutive days for anaemia. Her anorexia worsened and the spleen became larger, reaching the left ilium. Haemoglobin concentration did not change during treatment. Within a week after stopping EPO the spleen returned to its former size. A 59-year-old man with chronic myelogenous leukaemia (Philadelphia-chromosome positive) in chronic phase was admitted in August, 1990, for anaemia. He was receiving hydroxyurea 1000 mg daily. His haemoglobin concentration was 7-7 g/dl, leucocytes 28x109/1, platelets 146-2 x 109/l, and the spleen was palpable 5 cm beneath the left hypochondrium. He was given iv rhEPO 3000 units on Aug 14, and 9000 units on Aug 15 and 17. On Aug 17, he had a temperature of 39°C and the spleen was tender and palpable beneath the navel. Haemoglobin concentration did not change during EPO. After stopping the drug his temperature returned to normal; the spleen was not tender and gradually returned to its former size in 7 days. EPO administration in these two patients seems to have resulted in the stimulation of extramedullary haematopoiesis and the aggravation of splenomegaly. EPO might contraindicated for the anaemia of myeloproliferative disorders.
S. IKI Division of Haematology, Kanto Teishin Hospital,
Tokyo 141, Japan
M. YAGISAWA Y. OHBAYASHI H. SATO A. URABE
1. Graber SE, Krantz SB. Erythropoietin: biology and clinical use Hematol Oncol Clin N Am 1989, 3: 369-400. 2. Maeda H, Hitomi Y, Hirata R, et al Erythropoietin and autologous blood donation. Lancet 1989; ii: 284
and immobilisation of the affected limbs, associated with severe localised pruritus that could be controlled only by intravenous corticosteroids (’Celestone’, 4 mg four times a day x 3 days). Each patient presented with fever and tender regional lymphadenopathy which was controlled with analgesics and anti-inflammatory agents. Within 3 days the reactions had subsided and no further medication was needed. 6 months after treatment, all clinical manifestations of sowda had resolved, and follow-up ocular examination and skin
biopsies were negative. Patients with sowda have enhanced cell mediated5 and humoral6 immune responses to Onchocerca volvulus. Severe side-effects should be expected with any microfilaricidal agent that enhances natural killing of microfilariae. This has been well documented for diethylcarbamazineIvermectin seems to produce a similar reaction. Patients with sowda should be identified before ivermectin is used in community-based treatment programmes: they should receive treatment, since it is curative, but only under close medical
supervision. Onchocerciasis Control Project, Ministry of Public Health and Hospital Vozandes, Quito, Ecuador 1.
be very effective in the treatment of onchocerciasis and to have few side-effects.!,2 Dr Davidson and colleagues (Oct 20, p 1005) report moderate adverse reactions to ivermectin in expatriates with limited exposure to the disease. Such reactions included fever, rash, pruritus, local swelling, and tender regional lymphadenopathy. In Ecuador in 1990 all onchocercal positive communities on the Rio Santiago, in the province of Esmeraldas,3were treated with ivermectin. Only 4% had moderate adverse reactions (eg, pruritus, localised rash, and fever). However, among those treated were 2 patients with reactive onchodermatitis (sowda),4 and they had severe reactions to ivermectin. Both patients were black (of African origin) and were permanent residents in the hyperendemic focus of onchocerciasis on the Rio Santiago. One was a 45-year-old man who for the previous 10 years had had a severe hyperpigmented pruritic maculopapular dermatitis on the right arm, forearm, and right shoulder, radiating to the upper chest and back. The other was a 27-year-old woman who for the previous 4 years had had similar dermatological changes on her left leg. Both had low average dermal microfilarial densities (3 and 1 mg, respectively) on biopsy samples from both iliac crests. Histological study of skin from the affected areas showed focal hyperkeratosis, parakeratosis, and acanthosis with some follicular plugging. The dermal fibroblasts were large and numerous, while elastic fibres were reduced in number. Lymphocytes, plasma cells, histiocytes, eosinophils, and occasional mast cells were concentrated around blood vessels. Neither patient had eye lesions or palpable onchocercal nodules. Both were given ivermectin 150 mg/kg in a community-based treatment programme. Within 6 hours there was severe swelling
Pacque MC, Munoz B, Greene BM, White AT, Dukuly Z, Taylor HR. Safety of and compliance with community-based ivermectin therapy Lancet 1990; 335: 1377-80
2. Rothova A, Van der Lelij A, Stilma JS, Wilson WR, Barbe RF. Side effects of ivermectin in treatment of onchocerciasis Lancet 1989; i: 1439-42. 3. Guderian RH, Beck BJ, Proano S Jr, Mackenzie CD. Onchocerciasis m Ecuador, 1980-86: epidemiological evaluation of the disease m the Esmeraldas province Eur J Epidemiol 1989; 5: 294-302. 4. Mackenzie CD, Gudenan RH, Proano S Jr, Herdoiza M. Un caso de dermatitis reactivo oncocercotica (sowda) en la provincia de Esmerelda, Ecuador FCM Rev Fac Cienc Med ( Quito ) 1985; 10: 121-24. 5. Ghalib HW, Mackenzie CD, Williams JF, Sisley BM, El Khalifa MY Immunology and the development of pathology in Onchocerciasis. studies m Sudan. Sud Med J 1985; 21 (suppl): 59-64. 6. Buttner DW, Laer G, Mannweiler E, Buttner M Clinical parasitological and serological studies on onchocerciasis in the Yemen Arab Republic Tropenmed Parasitol 1982; 33: 201-12. 7. Mackenzie CD, Kron MA Diethylcarbamazine a review of its action in onchocerciasis, lymphatic filariasts and inflammation Trop Dis Bull 1985, 82: R1-37
Decline in incidence of
Adverse reactions to ivermectin in reactive onchodermatitis SiR,—In field trials in West Africa ivermectin has been shown to
RONALD H. GUDERIAN MARIELA ANSELMI ROBERT SEMPERTEGUI PHILIP J. COOPER
pneumonia
SiR,—Dr Khan and colleagues (Oct 13, p 939) report from their
investigation
in Abbottabad that the incidence of moderate and
respiratory infection (ARI) in children declined as a result of community based management. Although the full results are not yet published, we have three reservations. First, Khan and colleagues’ case definition of moderate and severe ARI includes otitis media. They do not tell us how much of severe acute
the fall in incidence of moderate or severe ARI was attributable to a reduction in otitis rather than in acute lower respiratory infections. One would expect the incidence of otitis media, but not of pneumonia, to decline as mothers became aware of the management of upper respiratory infections. Second, the reported two-week incidence of moderate and severe ARI (6-7 attacks per 100 children) is equal to 17 attacks per child-year. This is nearly twelve times higher than that which we noted in an ARI morbidity study at Gadchiroli,l and is much higher than those seen elsewhere. In the first year, the Abbottabad group classified nearly a third of ARI attacks as moderate or severe ARI whereas we identified about 3% ARI attacks as pneumonia. Was there a difficulty in case defmition? Third, without a control area environmental or methodological changes cannot be ruled out as causes of reduced incidence. Moreover, an active case finding from two visits each month to every child is difficult to repeat in large scale operations in primary health care where each health worker takes part in many other health programmes. SEARCH, Gadchiroli (Maharashtra), 442605 India
1
ABHAY BANG RANI BANG
Bang AT, Bang RA, Tale O, et al. Reduction m pneumonia mortality and total childhood mortality by means of community-based intervention trial m GadchiroliIndia Lancet 1990, 336: 201-06
