252
Itraconazole was probably the cause of liver damage in these three other common causes of hepatic injury were excluded and because there was a clear temporal relation between intake and onset of the reaction. Moreover all patients recovered after discontinuation of treatment. Itraconazole is related to miconazole and ketoconazole, for which several cases of symptomatic hepatic injury have been reported.3 The mild and transient liver enzyme elevations, the paucity of immunoallergic signs, the delayed latent period, and delayed reaction to rechallenge are compatible with metabolic idiosyncrasy to a mildly intrinsic
patients because
hepatotoxin. Although the
structures of itraconazole and ketoconazole are similar there are pharmacodynamic differences. Whereas ketoconazole influences microsomal cytochrome P-450-dependent monooxygenases,4 a similar effect has not been demonstrated for itraconazole.4 But both drugs may increase cyclosporin blood concentrations.5,6 We conclude that it is highly likely that itraconazole can cause liver injury. It may be advisable to monitor serum liver enzymes in patients who receive (long-term) therapy with itraconazole.
Department of Dermatology, University Hospital,
A. P. M.
Leiden
LAVRIJSEN
Department of Dermatology, Ziekenhuis Sint Antoniushove, Leidschendam
K. J. BALMUS
Department of Dermatology, Beatrix Ziekenhuis, Gorinchem
Department of Medicine, Bronovoziekenhuis, The
Hague
W. M. NUGTEREN-HUYING A. C. ROLDAAN J. W. VAN’T WOUT
Netherlands Centre for Monitoring of Adverse Reactions to Drugs,
B. H. CH. STRICKER
Rijswijk
Restrepo A, Robledo J, Gómez I, Tabares AM, Gutiérrez R. Itraconazole therapy in lymphangitic and cutaneous sporotrichosis. Arch Dermatol 1986; 122: 413-17. 2. Legendre R, Esola-Macre J. Itraconazole in the treatment of tinea capitis. J Am Acad 1.
Dermatol 1990; 23: 5590-60. 3. Stricter BHC, Blok APR, Bronkhorst FB, Van Parijs
GE, Desmet VJ. Ketoconazoleassociated hepatic injury: a clinicopathological study of 55 cases. J Hepatol 1986; 3: 399-406. 4. Lavrijsen K, van Houdt J, Thijs D, Meuldermans W, Heykants J. Induction potential of antifungals containing an imidazole of triazole moiety: miconazole and ketoconazole, but not itraconazole are able to induce hepatic drug metabolizing enzymes of male rats at high doses. Biochem Pharmacol 1986; 35: 1867-78. 5. Kwan JTC, Foxall PJD, Davidson DGC, Bending MR, Eisinger AJ. Interaction of cyclosporin and itraconazole. Lancet 1987; ii. 282. 6. Back DJ, Fjia JF. Comparative effects of the antimycotic drugs ketoconazole, fluconazole, itraconazole and terbinafine on the metabolism of cyclosporin by human liver microsomes. Br J Clin Pharmacol 1991; 32: 624-26.
Loss of taste and terbinafine SiR,-Professor Juhlin (June 13, p 1483) reported loss of taste in a 46-year-old woman receiving treatment with 250 mg terbinafine (Lamisil, Sandoz) for Trichophyton rubrum infection of her toenails. Since the only other drug taken by the patient was a combined oral contraceptive (lynestrenol plus ethinyloestradiol) Juhlin considered the possibility of drug interaction, and in so doing misinterpreted a paper from my research group.l This paper presented data from an in-vitro study in which two antimycotic drugs, the azole ketoconazole and the allylamine terbinafine, were examined for their effects on the metabolism of several drugs including ethinyloestradiol (EEz). At 50 lmol/1 terbinafine, the enzyme hydroxylating the steroid (EEz 2-hydroxylase) was inhibited by 30%. We speculated that terbinafine and EEz may be substrates for the same cytochrome P-450 isoenzyme but that it is noteworthy that maximum plasma concentrations following 250 mg terbinafine are only 3 pmol/1 (ie, 16 times less than concentrations used in vitro). We were therefore looking specifically at the effect of terbinafine on EE metabolism and not vice-versa; we have no evidence that EE2 is inhibitory towards terbinafine (as stated by Juhlin). We still await definitive identification of the specific isoenzyme(s) responsible for terbinafine metabolism. Terbinafine has a low potential for interactions with other drugs.
The only interactions reportedz are decreased elimination with cimetidine (400 mg twice daily) and increased elimination with
rifampicin (600 mg/day). Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool L69 3BX, UK
DAVID BACK
DJ, Tjia JF. Azoles and allylamines: the clinical implications of interaction with cytochrome P-450 enzymes. J Dermatol Treat 1990; 1 (suppl 2): 11-13. 2. Jensen JC. Pharmacokinetics of Lamisil in humans. J Dermatol Treat 1990; 1 (suppl 2): 1. Back
15-18.
Immunisation of infants in Iceland against Haemophilus influenzae type b SIR,-In May, 1989, a national vaccination programme against Haemophilus influenzae type b (Hib) was started in Iceland with the first conjugate vaccine available, a capsular polysaccharide of Hib linked to diphtheria toxoid (PRP-D, Connaught Laboratories). Children aged 3 months to 3 years were offered this vaccine during the first year (about 17 000 children). PRP-D was given to infants at age 3, 4, 6, and 14 months with triple vaccine. Children who were 4-14 months when the programme started received two or three doses according to age, and those who were 15 months to 3 years were given one dose. The age groups up to and including 2t years received PRP-D at a regular visit to a health centre, but children over that age had to come in for an extra visit, and not all came. In Reykjavik (about 50% of the population) a few hundreds older than 21years did not attend although twice invited by letters to their parents.l Infant immunisations in Iceland are free. If an infant does not turn up as scheduled, parents are called and reminded of the visit. Coverage of infant immunisations generally reaches 95-97%. Parents, however, have an option whether to accept immunisation for their children or not. Occasional parents did not want this new vaccine. During 1974-88 H influenzae meningitis was confirmed in 135 children under 5, an incidence of 43 per 100 000. About 70% were under 2,9% under 6 months, and 7% were 4-9 years. Their median age was 16 months. 1 of these children died and a few were left with sequelae. During this period Hib bacteraemia without meningitis was confirmed in 64 children under 5; many had accompanying focal infections but all survived. Their median age was the same as those with Hib meningitis.l In 1989 Hib meningitis was confirmed in 8 children, all of whom were unvaccinated except 1 baby aged 3 months who had received one dose of vaccine 12 days before the illness. These children all survived, but 1 had total hearing loss. Hib bacteraemia without meningitis was confirmed in 4 children in 1989; all survived. 3 of these children were unvaccinated, but 1 had received one dose at 7 months and developed epiglottitis at 12 months.l Since 1989 no case of Hib meningitis has been confirmed in Iceland, but 2 children have had Hib bacteraemia (besides 2 newborn babies). 1 was in January, 1990, at age 4 years (unvaccinated), the other in December, 1991-a 9-month-old child who had received three doses of PRP-D. During 3 months in 1984 and 1986 and from autumn of 1990 until spring of 1992, H influenzae strains isolated from children under 6, swabbed because of respiratory, throat, ear, or conjunctival infections, were typed. The percentage of type b strains diminished during the second and third trimester in 1991. Out of 415 strains H INFLUENZAE STRAINS ISOLATED FROM SWABS FROM CHILDREN AGED 0-5
253
tested since October, 1991, only 1 strain of type b was found (table). Insufficient data are as yet available on Hib carriage in healthy children. 178 children in day-care centres were tested in February and May, 1992. None carried Hib. No data exist on Hib carriage in healthy children before immunisation. It thus seems that after 3 years’ use of PRP-D for infant immunisation in Iceland, Hib invasive disease has nearly disappeared, and Hib carriage in children was most likely to disappear. Department of Microbiology, University of Iceland, Barónsstíg, 121 Reykjavik, Iceland, and Directorate of Public Health, Reykjavík
1.
K.
E. JÓNSDÓTTIR Ó. STEINGRÍMSSON Ó. ÓLAFSSON
Ólafsson Ó, Jónsdóttir KE, Hansen H, Barreto L, Sigthórsson T. The launch of an infant Haemophilus influenzae type b immunisation programme in Iceland. Proceedings of the 8th international congress on circumpolar health, Whitehorse, Yukon, Canada, May 20-25, 1990. 341-43.
Factor VIII inhibitors in
haemophiliacs
SiR,—Dr Verbruggen and colleagues (May 23, p 1301) suggest that a possible cause for our reported (March 7, p 594) high incidence of factor VIII (FVIII) inhibitors in haemophiliacs is the Bethesda assay used, which may overestimate the activity and therefore the incidence of these inhibitors. We agree that modifications of the original Bethesda test’ (eg, plasma dilutionseries, imidazole buffer, incubation-time, FVIII-deficient plasma) are important for accurate detection of inhibitor activities. The Bethesda assay we used was similar to Verbruggen et al, and was modified by use of immunodepleted FVIII deficient plasma and imidazole buffer to maintain the pH of the assay and control mixtures (7-4-7-6). We are well aware of the dilution effect (increase of inhibitor-activity in proportion to dilution), so we did various geometric dilution-series of all patients’ plasma. To detect supposed weak inhibitors, FVIII inhibitor-free plasma (undiluted and diluted 1 in 2) was tested as negative control. Weak FVIII inhibitors could sometimes be detected only if patient plasma was incubated for a longer time (24 h) before testing with appropriate controls.2-4 However, there are some points that should be emphasised. First, if in-vitro assays repeatedly suggest the presence of an inhibitor and there are clinical features of inhibitor development, we do FVIII in-vivo recoveries in which plasma FVIII concentrations are measured before and 10 and 30 min after a challenge dose of FVIII (50 IU/kg bodyweight). We also determine the plasma FVIII half-life before classsifying a patient as having inhibitors. Second, Verbruggen and colleagues report inhibitor activities of between 0-2 and 0-9 Bethesda units (BU). These activities (detected only once?) are clinically unimportant and should be regarded with caution. We have noted that FVIII recovery is reduced if the inhibitor-titre exceeds 0-8 BU. Thus, patients with inhibitor activities below 0-8 BU and normal recovery were excluded from our incidence calculations. The low inhibitor titres were only initial values, as mentioned in table 11 of our original article, and later increased to 6-5 BU, which emphasises the importance of close monitoring. Modifications can increase the sensitivity of the Bethesda assay but in-vivo tests based on the FVIII recovery and plasma FVIII half-life are more sensitive than any modification. Third, initially mild inhibitors are much more likely to be overlooked (because they are not always evident in the Bethesda test or are masked by FVIII replacement therapy) than are weak ( < 0-8 BU) antibodies and therefore incidence to be over estimated. Dr Ciavarella and Dr Schiavoni (May 23, p 1301) report, by contrast with our results, a low frequency (about 5%) of FVIII inhibitor development among their haemophilia patients. Their presentation of the results of two different study groups was confusing, lacking specific patient data. First, they describe a group of 21 haemophiliacs (one inhibitor patient), followed up since 1985 within a study on virus safety of different FVIII products. As we pointed out, it is essential to consider certain influential indices when estimating the incidence and prevalence of FVIII inhibitors in haemophiliacs-ie,
prospective study design; investigation mainly of infants and children; patients with severe and moderate disease (basal factor VIII level 5%); FVIII replacement therapy at least once; frequent inhibitor testing; and use of modified Bethesda assay for detecting inhibitor activities. Nevertheless, as many workers have done before, Ciavarella and Schiavoni do not provide any information about distribution of patient age, number of severely affected patients, length of treatment, amount of FVIII exposure in patients with no inhibitor, frequency of inhibitor testing, form of inhibitor monitoring (prospective or retrospective), or information on low-responder patients. Some patients could still be at risk of developing an inhibitor. Second, they describe a group of 31 patients treated exclusively with FVIII concentrates that have been virus inactivated by solvent/detergent. These patients were investigated over an unknown time for the presence of FVIII inhibitors every third 1 patient an inhibitor was detected. All other information about risk indices is missing. Additionally, Ciavarella and Schiavoni report that natural FVIII inhibitors have been found in 17% of plasma samples from 5000 healthy donors without any coagulation disorders. We were surprised that they compared FVIII antibodies observed in paediatric haemophiliacs with those from healthy adult donors. They have themselves shown doubtful clinical relevance of inhibitor in donors since they describe the normal plasma values of FVIII activity despite the presence of FVIII inhibitors. Furthermore, it is well known that FVIII inhibitors from non-haemophiliacs differ in their origin and immunobiochemical characteristics from those seen in two These haemophilia.5,6 types of FVIII antibodies should not be compared, especially not with respect to incidence. Ciavarella and Schiavoni’s published data lead to misinterpretations and underestimate the real risk of FVIII inhibitor development in haemophilia patients since it seems that the most important indices were not considered or closely monitored. It is important to keep in mind that FVIII inhibitors arise most often in severely affected infants and children who have received FVIII replacement therapy.
month, and in
S. EHRENFORTH W. KREUZ I. SCHARRER B. KORNHUBER
Centre of Paediatrics, Department of Haematology and Oncology, J. W Goethe University Hospital, 6000 Frankfurt am Main, Germany
et al. A more uniform measurement of factor VIII inhibitors. Thromb Diath Haemorrh 1975; 34: 869. 2. Kasper CK, Ewing NP. Experience with the Bethesda assay and other methods of inhibitor detection. In: Mariani G, Russo MA, Mandelli F, eds. Activated prothrombin complex concentrates: managing hemophilia with factor VIII inhibitor. New York. Praeger, 1982 17-21. 3. Ewing NP, Kasper CK. In vitro detection of mild inhibitors to factor VIII in hemophilia. Am J Clin Pathol 1982; 77: 749. 4. Ewing NP, Kasper CK. Sensitive methods for detecting mild inhibitors in severe classic hemophilia. (Presented at joint meeting of the 18th Congress of the International Society of Hematology and 16th Congress of the International Society of Blood Transfusion, Montreal, Quebec, Canada, August 16-22, 1980: abstract 1049). 5. Bloom AL, Peake IR, Furlong RA. The characterisation of factor VIII inhibitors as antibodies to factor VIIIC and its associated antigen (VIIICAg). In: Manani G, Russo MA, Mandelli F, eds. New York: Praeger, 1982: 3-14. 6. Roberts HR, Cromartie R. Overview of inhibitors to factor VIII and IX. In: Factor VIII inhibitors. New York. Alan R. Liss, 1984: 1-18.
1.
Kasper CK, Aledort LM, Counts RB,
Loss of
red-green
colour vision after
exposure to
arc
light
SIR,-Hardy colleagues’1 report of impairment of colourcontrast sensitivity in doctors using medical lasers served to elucidate a problem of reduced colour contrast sensitivity that I and
encountered in two patients. The first patient was a 67-year-old electrician who was also a private pilot. He had successfully completed the biennial aviation medical examination during the preceding 30 years, passing the six panel Ishihara test pattern on both the Keystone telebinocular and the Titmus vision tester. In November, 1987, he was exposed to an intense arc light when he inadvertently laid his screwdriver across the bus bars of a 440 V fuse box. The resulting intense flash caused first degree bums of his arms and face, and slight conjunctivitis. He
Itraconazole was probably the cause of liver damage in these three other common causes of hepatic injury were excluded and because there was a clear temporal relation between intake and onset of the reaction. Moreover all patients recovered after discontinuation of treatment. Itraconazole is related to miconazole and ketoconazole, for which several cases of symptomatic hepatic injury have been reported.3 The mild and transient liver enzyme elevations, the paucity of immunoallergic signs, the delayed latent period, and delayed reaction to rechallenge are compatible with metabolic idiosyncrasy to a mildly intrinsic
patients because
hepatotoxin. Although the
structures of itraconazole and ketoconazole are similar there are pharmacodynamic differences. Whereas ketoconazole influences microsomal cytochrome P-450-dependent monooxygenases,4 a similar effect has not been demonstrated for itraconazole.4 But both drugs may increase cyclosporin blood concentrations.5,6 We conclude that it is highly likely that itraconazole can cause liver injury. It may be advisable to monitor serum liver enzymes in patients who receive (long-term) therapy with itraconazole.
Department of Dermatology, University Hospital,
A. P. M.
Leiden
LAVRIJSEN
Department of Dermatology, Ziekenhuis Sint Antoniushove, Leidschendam
K. J. BALMUS
Department of Dermatology, Beatrix Ziekenhuis, Gorinchem
Department of Medicine, Bronovoziekenhuis, The
Hague
W. M. NUGTEREN-HUYING A. C. ROLDAAN J. W. VAN’T WOUT
Netherlands Centre for Monitoring of Adverse Reactions to Drugs,
B. H. CH. STRICKER
Rijswijk
Restrepo A, Robledo J, Gómez I, Tabares AM, Gutiérrez R. Itraconazole therapy in lymphangitic and cutaneous sporotrichosis. Arch Dermatol 1986; 122: 413-17. 2. Legendre R, Esola-Macre J. Itraconazole in the treatment of tinea capitis. J Am Acad 1.
Dermatol 1990; 23: 5590-60. 3. Stricter BHC, Blok APR, Bronkhorst FB, Van Parijs
GE, Desmet VJ. Ketoconazoleassociated hepatic injury: a clinicopathological study of 55 cases. J Hepatol 1986; 3: 399-406. 4. Lavrijsen K, van Houdt J, Thijs D, Meuldermans W, Heykants J. Induction potential of antifungals containing an imidazole of triazole moiety: miconazole and ketoconazole, but not itraconazole are able to induce hepatic drug metabolizing enzymes of male rats at high doses. Biochem Pharmacol 1986; 35: 1867-78. 5. Kwan JTC, Foxall PJD, Davidson DGC, Bending MR, Eisinger AJ. Interaction of cyclosporin and itraconazole. Lancet 1987; ii. 282. 6. Back DJ, Fjia JF. Comparative effects of the antimycotic drugs ketoconazole, fluconazole, itraconazole and terbinafine on the metabolism of cyclosporin by human liver microsomes. Br J Clin Pharmacol 1991; 32: 624-26.
Loss of taste and terbinafine SiR,-Professor Juhlin (June 13, p 1483) reported loss of taste in a 46-year-old woman receiving treatment with 250 mg terbinafine (Lamisil, Sandoz) for Trichophyton rubrum infection of her toenails. Since the only other drug taken by the patient was a combined oral contraceptive (lynestrenol plus ethinyloestradiol) Juhlin considered the possibility of drug interaction, and in so doing misinterpreted a paper from my research group.l This paper presented data from an in-vitro study in which two antimycotic drugs, the azole ketoconazole and the allylamine terbinafine, were examined for their effects on the metabolism of several drugs including ethinyloestradiol (EEz). At 50 lmol/1 terbinafine, the enzyme hydroxylating the steroid (EEz 2-hydroxylase) was inhibited by 30%. We speculated that terbinafine and EEz may be substrates for the same cytochrome P-450 isoenzyme but that it is noteworthy that maximum plasma concentrations following 250 mg terbinafine are only 3 pmol/1 (ie, 16 times less than concentrations used in vitro). We were therefore looking specifically at the effect of terbinafine on EE metabolism and not vice-versa; we have no evidence that EE2 is inhibitory towards terbinafine (as stated by Juhlin). We still await definitive identification of the specific isoenzyme(s) responsible for terbinafine metabolism. Terbinafine has a low potential for interactions with other drugs.
The only interactions reportedz are decreased elimination with cimetidine (400 mg twice daily) and increased elimination with
rifampicin (600 mg/day). Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool L69 3BX, UK
DAVID BACK
DJ, Tjia JF. Azoles and allylamines: the clinical implications of interaction with cytochrome P-450 enzymes. J Dermatol Treat 1990; 1 (suppl 2): 11-13. 2. Jensen JC. Pharmacokinetics of Lamisil in humans. J Dermatol Treat 1990; 1 (suppl 2): 1. Back
15-18.
Immunisation of infants in Iceland against Haemophilus influenzae type b SIR,-In May, 1989, a national vaccination programme against Haemophilus influenzae type b (Hib) was started in Iceland with the first conjugate vaccine available, a capsular polysaccharide of Hib linked to diphtheria toxoid (PRP-D, Connaught Laboratories). Children aged 3 months to 3 years were offered this vaccine during the first year (about 17 000 children). PRP-D was given to infants at age 3, 4, 6, and 14 months with triple vaccine. Children who were 4-14 months when the programme started received two or three doses according to age, and those who were 15 months to 3 years were given one dose. The age groups up to and including 2t years received PRP-D at a regular visit to a health centre, but children over that age had to come in for an extra visit, and not all came. In Reykjavik (about 50% of the population) a few hundreds older than 21years did not attend although twice invited by letters to their parents.l Infant immunisations in Iceland are free. If an infant does not turn up as scheduled, parents are called and reminded of the visit. Coverage of infant immunisations generally reaches 95-97%. Parents, however, have an option whether to accept immunisation for their children or not. Occasional parents did not want this new vaccine. During 1974-88 H influenzae meningitis was confirmed in 135 children under 5, an incidence of 43 per 100 000. About 70% were under 2,9% under 6 months, and 7% were 4-9 years. Their median age was 16 months. 1 of these children died and a few were left with sequelae. During this period Hib bacteraemia without meningitis was confirmed in 64 children under 5; many had accompanying focal infections but all survived. Their median age was the same as those with Hib meningitis.l In 1989 Hib meningitis was confirmed in 8 children, all of whom were unvaccinated except 1 baby aged 3 months who had received one dose of vaccine 12 days before the illness. These children all survived, but 1 had total hearing loss. Hib bacteraemia without meningitis was confirmed in 4 children in 1989; all survived. 3 of these children were unvaccinated, but 1 had received one dose at 7 months and developed epiglottitis at 12 months.l Since 1989 no case of Hib meningitis has been confirmed in Iceland, but 2 children have had Hib bacteraemia (besides 2 newborn babies). 1 was in January, 1990, at age 4 years (unvaccinated), the other in December, 1991-a 9-month-old child who had received three doses of PRP-D. During 3 months in 1984 and 1986 and from autumn of 1990 until spring of 1992, H influenzae strains isolated from children under 6, swabbed because of respiratory, throat, ear, or conjunctival infections, were typed. The percentage of type b strains diminished during the second and third trimester in 1991. Out of 415 strains H INFLUENZAE STRAINS ISOLATED FROM SWABS FROM CHILDREN AGED 0-5
253
tested since October, 1991, only 1 strain of type b was found (table). Insufficient data are as yet available on Hib carriage in healthy children. 178 children in day-care centres were tested in February and May, 1992. None carried Hib. No data exist on Hib carriage in healthy children before immunisation. It thus seems that after 3 years’ use of PRP-D for infant immunisation in Iceland, Hib invasive disease has nearly disappeared, and Hib carriage in children was most likely to disappear. Department of Microbiology, University of Iceland, Barónsstíg, 121 Reykjavik, Iceland, and Directorate of Public Health, Reykjavík
1.
K.
E. JÓNSDÓTTIR Ó. STEINGRÍMSSON Ó. ÓLAFSSON
Ólafsson Ó, Jónsdóttir KE, Hansen H, Barreto L, Sigthórsson T. The launch of an infant Haemophilus influenzae type b immunisation programme in Iceland. Proceedings of the 8th international congress on circumpolar health, Whitehorse, Yukon, Canada, May 20-25, 1990. 341-43.
Factor VIII inhibitors in
haemophiliacs
SiR,—Dr Verbruggen and colleagues (May 23, p 1301) suggest that a possible cause for our reported (March 7, p 594) high incidence of factor VIII (FVIII) inhibitors in haemophiliacs is the Bethesda assay used, which may overestimate the activity and therefore the incidence of these inhibitors. We agree that modifications of the original Bethesda test’ (eg, plasma dilutionseries, imidazole buffer, incubation-time, FVIII-deficient plasma) are important for accurate detection of inhibitor activities. The Bethesda assay we used was similar to Verbruggen et al, and was modified by use of immunodepleted FVIII deficient plasma and imidazole buffer to maintain the pH of the assay and control mixtures (7-4-7-6). We are well aware of the dilution effect (increase of inhibitor-activity in proportion to dilution), so we did various geometric dilution-series of all patients’ plasma. To detect supposed weak inhibitors, FVIII inhibitor-free plasma (undiluted and diluted 1 in 2) was tested as negative control. Weak FVIII inhibitors could sometimes be detected only if patient plasma was incubated for a longer time (24 h) before testing with appropriate controls.2-4 However, there are some points that should be emphasised. First, if in-vitro assays repeatedly suggest the presence of an inhibitor and there are clinical features of inhibitor development, we do FVIII in-vivo recoveries in which plasma FVIII concentrations are measured before and 10 and 30 min after a challenge dose of FVIII (50 IU/kg bodyweight). We also determine the plasma FVIII half-life before classsifying a patient as having inhibitors. Second, Verbruggen and colleagues report inhibitor activities of between 0-2 and 0-9 Bethesda units (BU). These activities (detected only once?) are clinically unimportant and should be regarded with caution. We have noted that FVIII recovery is reduced if the inhibitor-titre exceeds 0-8 BU. Thus, patients with inhibitor activities below 0-8 BU and normal recovery were excluded from our incidence calculations. The low inhibitor titres were only initial values, as mentioned in table 11 of our original article, and later increased to 6-5 BU, which emphasises the importance of close monitoring. Modifications can increase the sensitivity of the Bethesda assay but in-vivo tests based on the FVIII recovery and plasma FVIII half-life are more sensitive than any modification. Third, initially mild inhibitors are much more likely to be overlooked (because they are not always evident in the Bethesda test or are masked by FVIII replacement therapy) than are weak ( < 0-8 BU) antibodies and therefore incidence to be over estimated. Dr Ciavarella and Dr Schiavoni (May 23, p 1301) report, by contrast with our results, a low frequency (about 5%) of FVIII inhibitor development among their haemophilia patients. Their presentation of the results of two different study groups was confusing, lacking specific patient data. First, they describe a group of 21 haemophiliacs (one inhibitor patient), followed up since 1985 within a study on virus safety of different FVIII products. As we pointed out, it is essential to consider certain influential indices when estimating the incidence and prevalence of FVIII inhibitors in haemophiliacs-ie,
prospective study design; investigation mainly of infants and children; patients with severe and moderate disease (basal factor VIII level 5%); FVIII replacement therapy at least once; frequent inhibitor testing; and use of modified Bethesda assay for detecting inhibitor activities. Nevertheless, as many workers have done before, Ciavarella and Schiavoni do not provide any information about distribution of patient age, number of severely affected patients, length of treatment, amount of FVIII exposure in patients with no inhibitor, frequency of inhibitor testing, form of inhibitor monitoring (prospective or retrospective), or information on low-responder patients. Some patients could still be at risk of developing an inhibitor. Second, they describe a group of 31 patients treated exclusively with FVIII concentrates that have been virus inactivated by solvent/detergent. These patients were investigated over an unknown time for the presence of FVIII inhibitors every third 1 patient an inhibitor was detected. All other information about risk indices is missing. Additionally, Ciavarella and Schiavoni report that natural FVIII inhibitors have been found in 17% of plasma samples from 5000 healthy donors without any coagulation disorders. We were surprised that they compared FVIII antibodies observed in paediatric haemophiliacs with those from healthy adult donors. They have themselves shown doubtful clinical relevance of inhibitor in donors since they describe the normal plasma values of FVIII activity despite the presence of FVIII inhibitors. Furthermore, it is well known that FVIII inhibitors from non-haemophiliacs differ in their origin and immunobiochemical characteristics from those seen in two These haemophilia.5,6 types of FVIII antibodies should not be compared, especially not with respect to incidence. Ciavarella and Schiavoni’s published data lead to misinterpretations and underestimate the real risk of FVIII inhibitor development in haemophilia patients since it seems that the most important indices were not considered or closely monitored. It is important to keep in mind that FVIII inhibitors arise most often in severely affected infants and children who have received FVIII replacement therapy.
month, and in
S. EHRENFORTH W. KREUZ I. SCHARRER B. KORNHUBER
Centre of Paediatrics, Department of Haematology and Oncology, J. W Goethe University Hospital, 6000 Frankfurt am Main, Germany
et al. A more uniform measurement of factor VIII inhibitors. Thromb Diath Haemorrh 1975; 34: 869. 2. Kasper CK, Ewing NP. Experience with the Bethesda assay and other methods of inhibitor detection. In: Mariani G, Russo MA, Mandelli F, eds. Activated prothrombin complex concentrates: managing hemophilia with factor VIII inhibitor. New York. Praeger, 1982 17-21. 3. Ewing NP, Kasper CK. In vitro detection of mild inhibitors to factor VIII in hemophilia. Am J Clin Pathol 1982; 77: 749. 4. Ewing NP, Kasper CK. Sensitive methods for detecting mild inhibitors in severe classic hemophilia. (Presented at joint meeting of the 18th Congress of the International Society of Hematology and 16th Congress of the International Society of Blood Transfusion, Montreal, Quebec, Canada, August 16-22, 1980: abstract 1049). 5. Bloom AL, Peake IR, Furlong RA. The characterisation of factor VIII inhibitors as antibodies to factor VIIIC and its associated antigen (VIIICAg). In: Manani G, Russo MA, Mandelli F, eds. New York: Praeger, 1982: 3-14. 6. Roberts HR, Cromartie R. Overview of inhibitors to factor VIII and IX. In: Factor VIII inhibitors. New York. Alan R. Liss, 1984: 1-18.
1.
Kasper CK, Aledort LM, Counts RB,
Loss of
red-green
colour vision after
exposure to
arc
light
SIR,-Hardy colleagues’1 report of impairment of colourcontrast sensitivity in doctors using medical lasers served to elucidate a problem of reduced colour contrast sensitivity that I and
encountered in two patients. The first patient was a 67-year-old electrician who was also a private pilot. He had successfully completed the biennial aviation medical examination during the preceding 30 years, passing the six panel Ishihara test pattern on both the Keystone telebinocular and the Titmus vision tester. In November, 1987, he was exposed to an intense arc light when he inadvertently laid his screwdriver across the bus bars of a 440 V fuse box. The resulting intense flash caused first degree bums of his arms and face, and slight conjunctivitis. He
