RiskfactorsforacquiringHIV infection among 75 women No
Risk factors Injecting drug misuse Blood transfusions in Africa Sexual partner an intravenous drug misuser Sexual partner bisexual Sexual partner or partners abroad Under investigation
24 2
2 40 2
J G AINSWORTH S M MURPHY J R W HARRIS
Department of Genitourinary Medicine, St Mary's Hospital, London W2 INY
Vaccines for HIV infected pregnant women? SIR, -It is premature to consider a programme of vaccination for pregnant women infected with HIV' when the nature of transmission of the virus from mother to infant is still poorly understood. Presumably the trial's designers hope that viral components would induce a neutralising antibody response to reduce the viral load; this assumes that the HIV load is directly related to the risk of transmission and that neutralising antibodies control HIV infection in vivo. The main control of HIV in vivo is probably mediated by HIV specific cytotoxic T lymphocytes, which are highly active in HIV infection,2 and, to a lesser extent, by neutralising antibodies or antibody dependent cellular cytotoxicity mechanisms.' In HIV positive pregnant women active immunisation with proteins based on a single or limited number of strains of virus may accelerate both cytotoxic T lymphocytes and antibody driven HIV escape mutants2; passive immunisation may include transfusion of enhancing antibodies and could drive antibody mediated viral mutation to produce highly virulent strains. No "protective" immune response has been identified in those mothers who do not transmit HIV to their infants: the report of protective antibodies has not been borne out by larger studies (J-P Allain et al, seventh international conference on AIDS, Florence, 1991). Before such a vaccine trial is initiated the factors that influence the transmission rate need to be established. Reported rates diverge widely-from 13% in the European collaborative centre study4 to 30% in one African study (P LePage et al, seventh international conference on AIDS, Florence, 1991). The use of zidovudine during pregnancy and the reduction of postnatal transmission in breast milk could help spare the many hundreds of thousands of unborn children at risk of HIV infection. It is estimated that by the end of 1992 nearly one million infants born to HIV infected mothers will be infected worldwide.5 The urgent need for reducing transmission from mothers to infants is not disputed, and potential vaccine manufacturers are probably reluctant to collaborate VOLUME 303
DOUGLAS NIXON Virology Department, John Radcliffe Hospital, Oxford OX3 9DU
5
arrived in the United Kingdom; three (one Australian and two British) had been sexually assaulted abroad; and the remaining three (two British and one Dutch) had had partners abroad one from central Africa, one from the United States, and one from Holland. Thirty nine of the 40 women first attended these hospitals after the beginning of 1989, and 35 had acquired the infection during heterosexual contact in Africa. This study supports the contention that most female patients infected with HIV during heterosexual contact who attend departments of genitourinary medicine were infected in Africa and imported the infection into the United Kingdom. Further efforts to identify and help such patients must use this knowledge.
BMJ
with such a trial until a valid rationale for it has been established.
26 OCTOBER 1991
1 McBride G. Vaccines for HIV infected pregnant women? BMJ 1991;303:665. (21 September.) 2 Nixon DF, McMichael AJ. Cytotoxic T-cell recognition of HIV proteins and peptides. AIDS 1991;5:1049-59. 3 Broliden K, Broliden PA, Wahren B. HIV-specific antibodydependent cellular cytotoxicity and neutralization. In: Janossy G, ed. The immunology of HIV in section. Basle: Karger (in press). 4 Ades AE, Newell ML, Peckham CS. European collaborative study. Children born to women with HIV infection: natural history and risk of transmission. Lancet 1991;337:253-60. 5 Chin J. Current and future dimensions of the HIV/AIDS pandemic in women and children. Lancet 1990;336:221-4.
Side effects of adjuvant tamoxifen
ophthalmic optician. The ophthalmic opticians recorded visual acuity in 183 (72%) referrals. General practitioners recorded visual acuity in only nine (4%) referrals, and for patients with a complaint of visual loss the figure rose to only 15 (6%). We agree that the measurement of visual acuity is an essential part of any eye examination. Measurement is rapid when a Snellen chart is used, and this should be available in every general practice. The chart gives a simple and repeatable measurement of vision that may distinguish severe from trivial disease and urgent from non-urgent referrals. To omit measurement of visual acuity from the eye examination or a record of it from the referral letter is to do a disservice to the patient. We have suggested that a standard format referral letter should be introduced for patients with eye problems; this would improve communication between general practitioners and ophthalmologists and permit rapid and accurate assessment of the patients' needs. J KWARTZ N P JONES
SIR,-Various gynaecologists in the British Gynaecological Cancer Society have brought to our notice the increasing concern over some side effects experienced by women receiving adjuvant tamoxifen for breast cancer. The society has set up a study group to examine all available information. Adjuvant tamoxifen is associated with a decreased incidence of cancer in the contralateral breast. It is also associated with decreased plasma cholesterol concentration; a decreased incidence of myocardial infarctions, as reported by C C McDonald and H J Stewart for the Scottish Breast Cancer Committee'; and stabilised bone mineral contents.2 Some patients, however, experience abnormal vaginal bleeding, and there are examples of hyperplasia, polyps, and endometriosis.' Cases of endometrial cancer (usually well differentiated and easily treated) have been reported in women receiving tamoxifen, resulting in suggestions of a small increase in incidence.4 A case-control study should be set up to determine the true extent of this problem. Overall, the side effects of adjuvant tamoxifen are beneficial. The drug should not be stopped because of gynaecological symptoms in patients receiving it for breast cancer. If patients receiving tamoxifen experience abnormal vaginal bleeding they should be referred to a gynaecology clinic in exactly the same way as they would be had they not been receiving tamoxifen. R E LEAKE
Director, British Gynaecological Cancer Society Tamoxifen Study Group, Department of Biochemistry, University of Glasgow, Glasgow G12 8QQ 1 McDonald C, Stewart HJ. Fatal myocardial infarction in the Scottish adjuvant tamoxifen trial. BMJ7 1991;303:435-7. (24
August.) 2 Powles TJ, Tillyer CR, Jones AL, Ashley SE, Treleaven J, Davey JB, et al. Prevention of breast cancer with tamoxifen - an update on the Royal Marsden Hospital pilot programme. Eurj Cancer 1990;26:680-4. 3 Buckley CH. Tamoxifen and endometriosis: a case report.
BrJ Obstet Gynaecol 1990;97:645-6. 4 Gusberg S. Tamoxifen for breast cancer: associated endometrial cancer. Cancer 1990;65:1463-4.
Checking visual acuity SIR, -Minerva' rightly draws attention to a recent article in the annual report of the Medical Protection Society2; the article says that not measuring visual acuity is one of the four commonest causes of litigation. Minerva asks how many doctors include this as part of their medical examination. We can answer this question. We recently studied 500 consecutive referrals to an eye hospital from general practitioners.' Of these, 245 were initiated by a general practitioner and 255 by an
Department of Ophthalmology, University of Manchester, Royal Eye Hospital, Manchester M 13 9HW 1 Minerva. BMJ7 1991;303:866. (5 October.) 2 Styles WMcN. First impressions-and the lessons from them. In: Annual report. London: Medical Protection Society, 1991:22. 3 Jones NP, Lloyd IC, Kwartz J. General practitioner referrals to an eye hospital: a standard referral form. J R Soc Med
1990;83:770-2.
High potency factor VIII concentrates SIR,-Dr John D Cash argues against the widespread use of high potency factor VIII concentrates.' We agree with his reasoning: clinically the high potency preparations do not offer any substantial advantage over the intermediate purity concentrates. The development of high purity concentrates is associated with the need to inactivate possible viruses in the preparation. The solvent-detergent method requires purification steps to remove the inactivating ingredients, and heat treatment effective on hepatitis viruses proved difficult with intermediate potency concentrates. High purity is thus more a consequence of other developments than a value itself, but terms such as "ultrahigh purity" have been skilfully used by commercial companies in their marketing campaigns ("why to use anything less than pure"). The high potency concentrates, besides being free of virus, are more convenient to users. The mere convenience does not justify the substantially higher price. There has, however, been a remarkable development as far as the yield of factor VIII is concerned, which is important from the point of view of national self sufficiency. In fact, some purification technologies in skilful hands now offer a clearly higher yield than was possible with intermediate potency concentrates. Our fractionation laboratory developed a high purity concentrate free of virus, but the losses in the biological activity of factor VIII were unacceptably high. We therefore elected to buy a licence to manufacture immunopurified factor VIII. We are currently obtaining about a 30% higher yield with this method compared with our old method. With this yield we have been able to maintain national self sufficiency in Finland. Furthermore, with a careful on demand treatment policy for haemophilia the national consumption of factor VIII is only about 2 units per inhabitant, and this demand we can satisfy exclusively with plasma separated from whole blood donations. We are now dismantling our plasmapheresis programme, which is resulting in substantial savings in the overall economy of the blood transfusion service.
1061
Technologies giving the highest possible yield of safe plasma products, and their appropriate and weighed clinical use, are key factors in national self sufficiency. J LEIKOLA G MYLLYLA
Finnish Red Cross Blood Transfusion Service, 003 10 Helsinki, Finland 1 Cash JD. High potency factor VIII concentrates: value not proved? BAIJ 1991;303:633-4. (14 September.)
SIR, -It is both puzzling and surprising to read that the medical and scientific director of the Scottish National Blood Transfusion Service, Dr John D Cash, is uncertain whether high potency factor VIII is scientifically justified in clinical practice and safe in use with a justifiable costbenefit ratio.' It is puzzling in that Dr Cash ventilates these concerns in public at a time when the Scottish National Blood Transfusion Service has recently announced its intention to market such a product2; and surprising in that the issue is surely one of purity and not of potency. It should be noted that these views are not shared by Bio Products Laboratory, and the laboratory's decision to provide patients in England and Wales with high purity factor VIII was based on its consistent empirical policy to work continually towards increasing the purity, safety, and quality of all products derived from human plasma. Thus Bio Products Laboratory has issued licensed monoclonal antibody purified factor VIII to NHS patients since early this year. With regard to the new high purity factor VIII products, it would be interesting to know what evidence Dr Cash has of "the hasty issue of product licences by medicine control authorities" in the United States and the United Kingdom, and, of course, the promotion of Bio Products Laboratory's high purity factor VIII is limited to its quality profile and its dependence on plasma given by our national voluntary, unremunerated donors. The Scottish National Blood Transfusion Service has followed Bio Products Laboratory's practice by signing a technology agreement with foreign organisations to enable future manufacture of high purity factor VIII in Scotland. The matter of the resultant high cost, ultimately to the tax payer, of supplying to haemophiliac patients high purity factor VIII funded by the public sector is confused in Dr Cash's paper; whether the product is charged to hospitals or distributed without charge, as by the Scottish National Blood Transfusion Service, is immaterial. Both English and Scottish high purity factor VIII products attract royalties for technology licensed from overseas institutions. In deciding to provide NHS patients in England and Wales with a high purity factor VIII Bio Products Laboratory took into consideration the views of expert physicians in haemophilia care and the wishes of their patients. R S LANE
low purity products and in vivo evidence that there is a beneficial influence on depletion of CD4 cells in patients positive for HIV antibody2-4 (K Fukutake et al, XIIth congress of the International Society on Thrombosis and Haemostasis, Amsterdam, 30 June-6 July, 1991). It seems inconsistent to write off this evidence as not substantive while raising the spectre of inhibitor development on the basis of a few limited reports whose importance is far from clear. In my experience, issue of product licences has been far from "hasty." High technology products are rightly subjected to intense scrutiny by all health authorities, and enormous amounts of data on safety and efficacy are demanded before a licence is granted. Apart from the licences granted under the provisions of the National Health Service and Community Care Act 1990, which revoked crown immunity, there is absolutely no evidence that this process has been short circuited to permiit the early release of high purity factor VIII concentrates. It is, of course, true that pharmaceutical development is aimed at product improvement; if this was not so we would still be providing crude thyroid powder-extracts ofbeeftesticles or ovaries and liver extracts, for example-to treat hormone or vitamin deficiencies. Surely Dr Cash is not indicating that such progress is counterproductive and should not proceed until absolute clinical benefit is established. Clinical studies on the various potential benefits of pure factor VIII concentrates are proceeding, but it should also be borne in mind that other benefits may accrue, such as opportunities for alternative and improved delivery systems, as a result of improved purity. Finally, promotion to patients is forbidden by both the code of practice of the Association of the British Pharmaceutical Industry and the Medicines Act. Pharmaceutical companies are most careful regarding potential infringement. People with haemophilia are well informed about their condition and treatments available through information provided by their very active society and the World Federation of Haemophilia. I suggest that this is the source of their information, not direct promotion by manufacturers. Armour Pharmaceutical, Eastbourne, East Sussex BN21 3YG 1 Cash JD. High potency factor VIII concentrates: value not
proved? B._ 1991;303:633-4. (14 September.)
2 Rocino A, Niiraglia E, Mastrullo L, Quirino AA, Ziello L, De Biasi R. Prospective controlled trial of an ultra-pure factor VIII concentrate to evaluate the effects on the immune status of HIV antibody-positive hemophilia patients (preliminary results). Estratto da "Acta Toxicologica et Therapeutica" 1990;
11:49-58. 3 Green D, Deutsche J, Tang M, Goldsmith J. Effect of HIV-I infection on CD4 cells in a hemophilia cohort. Haematologica 1990;75(5): 132-41. 4 Ludlam CA. Effects of alloantigens in blood products on immunity. Semin Hematol 1988;25(suppl 1):3-7.
Medically unexplained physical symptoms
I Cash JD. High potency factor V111 concentrates: value not
SIR,-Dr Richard Mayou is right to say that patients "often complain of feeling frustrated at being told that results ofinvestigations are negative but not receiving any convincing explanation of persistent distressing symptoms."' He does not, however, sufficiently emphasise the need to make a clear positive diagnosis which would be the basis of such an explanation, and he is right that "preoccupation with traditional psychiatric diagnostic categories may have hindered understanding." It is usually possible, however, to make a diagnosis, as in the following example. "This 45 year old patient's pain in the left side of the face for the past three months results from ischaemia in persistently clenching jaw muscles
proved? BM7 1991;303:633-4. (14 September.)
SIR,-Dr John D Cash's article discussing the value of high potency factor VIII concentrates contains several inaccurate suggestions that cannot pass unchallenged. ' At least 12 published papers have reported immunological abnormalities in people with haemophilia who have received repeated treatments with clotting factor concentrates of low purity over several years. There is also growing evidence, mainly in vitro, that high purity concentrates are less immunosuppressive than the older,
1062
SAMUEL I COHEN
Department of Psychiatry, Royal London Hospital Medical College, London El 2AD I Mayou R. Medically unexplained physical symptoms. BMJ7
1991;303:534-5. (7 September.)
R B CHRISTIE
Bio Products Laboratory, Elstree, Hertfordshire WD6 3BX
2 Vive I'alliance. Bloodletter 1991;48:1.
(bruxism). The pain is unilateral because the bite is asymmetric. The patient has always been rather tense and anxious, and the basis for the present symptoms is a rise in the level of his anxiety in the past three months as evidenced by other features of this such as sleeplessness, palpitations, and frequency of micturition. The reason for this increase in his anxiety is . " Most symptoms of the kind under discussion that come to psychiatrists are the somatic manifestations of anxiety. The common causes of anxiety in my regular outpatient clinics are major emotional conflicts or personal disasters in about half of cases and, in the remaining half, the use of alcohol, often not in what may be called "alcoholic" amounts, or the continuing use of benzodiazepine drugs. Dr Mayou uses the terms unexplained, nonspecific, and atypical. These say what the disorder is not but not what it is. The atypical facial pain in the example above is absolutely typical of numerous patients with a disorder that is far commoner than trigeminal neuralgia, the disorder of which this pain is supposed to be atypical. The pain in the chest after myocardial infarction which Dr Mayou refers to as atypical is typical of the pain in many such patients and almost certainly arises in contracting chest muscles resulting from fear, as evidenced by the fact that it is commonly associated with other symptoms of muscular contraction such as tension headaches, tightness in the neck, or aching in the shoulders. How can you give symptomatic treatment if you do not know the pathogenesis, and how can you reassure if you do not know what is wrong but only the negative results of a series of investigations? Of course these patients are difficult to treat as long as they remain diagnostic puzzles. It is, however, perfectly possible as a rule to make a sufficiently precise statement about the disorder to allow some worthwhile intervention to be made and so to relieve the patient.
Use of thalidomide in leprosy SIR,-Despite Dr M F R Waters's reassurance' neither the most recent report from the World Health Organisation's expert committee on leprosy,2 nor the most recent review3 contains any reference to thalidomide neuropathy. We should be told if the manufacturers, Chemie-Grunenthal, Andrulis Research Corporation, and Interbras, which are currently supplying thalidomide, include a warning about its neuropathic side effects. Even the very existence of the side effect was aggressively denied in 1976 by the then Secretary of State for Health and Social Security, Dr David Owen: supporting the use of thalidomide in leprosy treatment, he wrote to Jack Ashley MP, stating, "You will also wish to know that Sir Ludwig Gutmmann among others is satisfied that allegations of neurotoxicity are unfounded and has given evidence to this effect." Even if the high figure for nodular prurigo is excluded, neuropathy occurred in 15 out of 60,4 three out of nine,5 and two out of six6 patients given the drug for other disorders, making the cited frequency of 0 5% much too low. ' In patients other than patients with leprosy given the drug careful, frequent clinical examinations are routinely carried out and are supplemented by electrophysiological testing, enabling early detection of neuropathy. Stopping the drug at this stage offers the best chance of recovery. Even when the treatment has been successful, as in life threatening graft versus host disease, the drug has had to be withdrawn
BMJ VOLUME 303
26 OCTOBER 1991
Risk factors Injecting drug misuse Blood transfusions in Africa Sexual partner an intravenous drug misuser Sexual partner bisexual Sexual partner or partners abroad Under investigation
24 2
2 40 2
J G AINSWORTH S M MURPHY J R W HARRIS
Department of Genitourinary Medicine, St Mary's Hospital, London W2 INY
Vaccines for HIV infected pregnant women? SIR, -It is premature to consider a programme of vaccination for pregnant women infected with HIV' when the nature of transmission of the virus from mother to infant is still poorly understood. Presumably the trial's designers hope that viral components would induce a neutralising antibody response to reduce the viral load; this assumes that the HIV load is directly related to the risk of transmission and that neutralising antibodies control HIV infection in vivo. The main control of HIV in vivo is probably mediated by HIV specific cytotoxic T lymphocytes, which are highly active in HIV infection,2 and, to a lesser extent, by neutralising antibodies or antibody dependent cellular cytotoxicity mechanisms.' In HIV positive pregnant women active immunisation with proteins based on a single or limited number of strains of virus may accelerate both cytotoxic T lymphocytes and antibody driven HIV escape mutants2; passive immunisation may include transfusion of enhancing antibodies and could drive antibody mediated viral mutation to produce highly virulent strains. No "protective" immune response has been identified in those mothers who do not transmit HIV to their infants: the report of protective antibodies has not been borne out by larger studies (J-P Allain et al, seventh international conference on AIDS, Florence, 1991). Before such a vaccine trial is initiated the factors that influence the transmission rate need to be established. Reported rates diverge widely-from 13% in the European collaborative centre study4 to 30% in one African study (P LePage et al, seventh international conference on AIDS, Florence, 1991). The use of zidovudine during pregnancy and the reduction of postnatal transmission in breast milk could help spare the many hundreds of thousands of unborn children at risk of HIV infection. It is estimated that by the end of 1992 nearly one million infants born to HIV infected mothers will be infected worldwide.5 The urgent need for reducing transmission from mothers to infants is not disputed, and potential vaccine manufacturers are probably reluctant to collaborate VOLUME 303
DOUGLAS NIXON Virology Department, John Radcliffe Hospital, Oxford OX3 9DU
5
arrived in the United Kingdom; three (one Australian and two British) had been sexually assaulted abroad; and the remaining three (two British and one Dutch) had had partners abroad one from central Africa, one from the United States, and one from Holland. Thirty nine of the 40 women first attended these hospitals after the beginning of 1989, and 35 had acquired the infection during heterosexual contact in Africa. This study supports the contention that most female patients infected with HIV during heterosexual contact who attend departments of genitourinary medicine were infected in Africa and imported the infection into the United Kingdom. Further efforts to identify and help such patients must use this knowledge.
BMJ
with such a trial until a valid rationale for it has been established.
26 OCTOBER 1991
1 McBride G. Vaccines for HIV infected pregnant women? BMJ 1991;303:665. (21 September.) 2 Nixon DF, McMichael AJ. Cytotoxic T-cell recognition of HIV proteins and peptides. AIDS 1991;5:1049-59. 3 Broliden K, Broliden PA, Wahren B. HIV-specific antibodydependent cellular cytotoxicity and neutralization. In: Janossy G, ed. The immunology of HIV in section. Basle: Karger (in press). 4 Ades AE, Newell ML, Peckham CS. European collaborative study. Children born to women with HIV infection: natural history and risk of transmission. Lancet 1991;337:253-60. 5 Chin J. Current and future dimensions of the HIV/AIDS pandemic in women and children. Lancet 1990;336:221-4.
Side effects of adjuvant tamoxifen
ophthalmic optician. The ophthalmic opticians recorded visual acuity in 183 (72%) referrals. General practitioners recorded visual acuity in only nine (4%) referrals, and for patients with a complaint of visual loss the figure rose to only 15 (6%). We agree that the measurement of visual acuity is an essential part of any eye examination. Measurement is rapid when a Snellen chart is used, and this should be available in every general practice. The chart gives a simple and repeatable measurement of vision that may distinguish severe from trivial disease and urgent from non-urgent referrals. To omit measurement of visual acuity from the eye examination or a record of it from the referral letter is to do a disservice to the patient. We have suggested that a standard format referral letter should be introduced for patients with eye problems; this would improve communication between general practitioners and ophthalmologists and permit rapid and accurate assessment of the patients' needs. J KWARTZ N P JONES
SIR,-Various gynaecologists in the British Gynaecological Cancer Society have brought to our notice the increasing concern over some side effects experienced by women receiving adjuvant tamoxifen for breast cancer. The society has set up a study group to examine all available information. Adjuvant tamoxifen is associated with a decreased incidence of cancer in the contralateral breast. It is also associated with decreased plasma cholesterol concentration; a decreased incidence of myocardial infarctions, as reported by C C McDonald and H J Stewart for the Scottish Breast Cancer Committee'; and stabilised bone mineral contents.2 Some patients, however, experience abnormal vaginal bleeding, and there are examples of hyperplasia, polyps, and endometriosis.' Cases of endometrial cancer (usually well differentiated and easily treated) have been reported in women receiving tamoxifen, resulting in suggestions of a small increase in incidence.4 A case-control study should be set up to determine the true extent of this problem. Overall, the side effects of adjuvant tamoxifen are beneficial. The drug should not be stopped because of gynaecological symptoms in patients receiving it for breast cancer. If patients receiving tamoxifen experience abnormal vaginal bleeding they should be referred to a gynaecology clinic in exactly the same way as they would be had they not been receiving tamoxifen. R E LEAKE
Director, British Gynaecological Cancer Society Tamoxifen Study Group, Department of Biochemistry, University of Glasgow, Glasgow G12 8QQ 1 McDonald C, Stewart HJ. Fatal myocardial infarction in the Scottish adjuvant tamoxifen trial. BMJ7 1991;303:435-7. (24
August.) 2 Powles TJ, Tillyer CR, Jones AL, Ashley SE, Treleaven J, Davey JB, et al. Prevention of breast cancer with tamoxifen - an update on the Royal Marsden Hospital pilot programme. Eurj Cancer 1990;26:680-4. 3 Buckley CH. Tamoxifen and endometriosis: a case report.
BrJ Obstet Gynaecol 1990;97:645-6. 4 Gusberg S. Tamoxifen for breast cancer: associated endometrial cancer. Cancer 1990;65:1463-4.
Checking visual acuity SIR, -Minerva' rightly draws attention to a recent article in the annual report of the Medical Protection Society2; the article says that not measuring visual acuity is one of the four commonest causes of litigation. Minerva asks how many doctors include this as part of their medical examination. We can answer this question. We recently studied 500 consecutive referrals to an eye hospital from general practitioners.' Of these, 245 were initiated by a general practitioner and 255 by an
Department of Ophthalmology, University of Manchester, Royal Eye Hospital, Manchester M 13 9HW 1 Minerva. BMJ7 1991;303:866. (5 October.) 2 Styles WMcN. First impressions-and the lessons from them. In: Annual report. London: Medical Protection Society, 1991:22. 3 Jones NP, Lloyd IC, Kwartz J. General practitioner referrals to an eye hospital: a standard referral form. J R Soc Med
1990;83:770-2.
High potency factor VIII concentrates SIR,-Dr John D Cash argues against the widespread use of high potency factor VIII concentrates.' We agree with his reasoning: clinically the high potency preparations do not offer any substantial advantage over the intermediate purity concentrates. The development of high purity concentrates is associated with the need to inactivate possible viruses in the preparation. The solvent-detergent method requires purification steps to remove the inactivating ingredients, and heat treatment effective on hepatitis viruses proved difficult with intermediate potency concentrates. High purity is thus more a consequence of other developments than a value itself, but terms such as "ultrahigh purity" have been skilfully used by commercial companies in their marketing campaigns ("why to use anything less than pure"). The high potency concentrates, besides being free of virus, are more convenient to users. The mere convenience does not justify the substantially higher price. There has, however, been a remarkable development as far as the yield of factor VIII is concerned, which is important from the point of view of national self sufficiency. In fact, some purification technologies in skilful hands now offer a clearly higher yield than was possible with intermediate potency concentrates. Our fractionation laboratory developed a high purity concentrate free of virus, but the losses in the biological activity of factor VIII were unacceptably high. We therefore elected to buy a licence to manufacture immunopurified factor VIII. We are currently obtaining about a 30% higher yield with this method compared with our old method. With this yield we have been able to maintain national self sufficiency in Finland. Furthermore, with a careful on demand treatment policy for haemophilia the national consumption of factor VIII is only about 2 units per inhabitant, and this demand we can satisfy exclusively with plasma separated from whole blood donations. We are now dismantling our plasmapheresis programme, which is resulting in substantial savings in the overall economy of the blood transfusion service.
1061
Technologies giving the highest possible yield of safe plasma products, and their appropriate and weighed clinical use, are key factors in national self sufficiency. J LEIKOLA G MYLLYLA
Finnish Red Cross Blood Transfusion Service, 003 10 Helsinki, Finland 1 Cash JD. High potency factor VIII concentrates: value not proved? BAIJ 1991;303:633-4. (14 September.)
SIR, -It is both puzzling and surprising to read that the medical and scientific director of the Scottish National Blood Transfusion Service, Dr John D Cash, is uncertain whether high potency factor VIII is scientifically justified in clinical practice and safe in use with a justifiable costbenefit ratio.' It is puzzling in that Dr Cash ventilates these concerns in public at a time when the Scottish National Blood Transfusion Service has recently announced its intention to market such a product2; and surprising in that the issue is surely one of purity and not of potency. It should be noted that these views are not shared by Bio Products Laboratory, and the laboratory's decision to provide patients in England and Wales with high purity factor VIII was based on its consistent empirical policy to work continually towards increasing the purity, safety, and quality of all products derived from human plasma. Thus Bio Products Laboratory has issued licensed monoclonal antibody purified factor VIII to NHS patients since early this year. With regard to the new high purity factor VIII products, it would be interesting to know what evidence Dr Cash has of "the hasty issue of product licences by medicine control authorities" in the United States and the United Kingdom, and, of course, the promotion of Bio Products Laboratory's high purity factor VIII is limited to its quality profile and its dependence on plasma given by our national voluntary, unremunerated donors. The Scottish National Blood Transfusion Service has followed Bio Products Laboratory's practice by signing a technology agreement with foreign organisations to enable future manufacture of high purity factor VIII in Scotland. The matter of the resultant high cost, ultimately to the tax payer, of supplying to haemophiliac patients high purity factor VIII funded by the public sector is confused in Dr Cash's paper; whether the product is charged to hospitals or distributed without charge, as by the Scottish National Blood Transfusion Service, is immaterial. Both English and Scottish high purity factor VIII products attract royalties for technology licensed from overseas institutions. In deciding to provide NHS patients in England and Wales with a high purity factor VIII Bio Products Laboratory took into consideration the views of expert physicians in haemophilia care and the wishes of their patients. R S LANE
low purity products and in vivo evidence that there is a beneficial influence on depletion of CD4 cells in patients positive for HIV antibody2-4 (K Fukutake et al, XIIth congress of the International Society on Thrombosis and Haemostasis, Amsterdam, 30 June-6 July, 1991). It seems inconsistent to write off this evidence as not substantive while raising the spectre of inhibitor development on the basis of a few limited reports whose importance is far from clear. In my experience, issue of product licences has been far from "hasty." High technology products are rightly subjected to intense scrutiny by all health authorities, and enormous amounts of data on safety and efficacy are demanded before a licence is granted. Apart from the licences granted under the provisions of the National Health Service and Community Care Act 1990, which revoked crown immunity, there is absolutely no evidence that this process has been short circuited to permiit the early release of high purity factor VIII concentrates. It is, of course, true that pharmaceutical development is aimed at product improvement; if this was not so we would still be providing crude thyroid powder-extracts ofbeeftesticles or ovaries and liver extracts, for example-to treat hormone or vitamin deficiencies. Surely Dr Cash is not indicating that such progress is counterproductive and should not proceed until absolute clinical benefit is established. Clinical studies on the various potential benefits of pure factor VIII concentrates are proceeding, but it should also be borne in mind that other benefits may accrue, such as opportunities for alternative and improved delivery systems, as a result of improved purity. Finally, promotion to patients is forbidden by both the code of practice of the Association of the British Pharmaceutical Industry and the Medicines Act. Pharmaceutical companies are most careful regarding potential infringement. People with haemophilia are well informed about their condition and treatments available through information provided by their very active society and the World Federation of Haemophilia. I suggest that this is the source of their information, not direct promotion by manufacturers. Armour Pharmaceutical, Eastbourne, East Sussex BN21 3YG 1 Cash JD. High potency factor VIII concentrates: value not
proved? B._ 1991;303:633-4. (14 September.)
2 Rocino A, Niiraglia E, Mastrullo L, Quirino AA, Ziello L, De Biasi R. Prospective controlled trial of an ultra-pure factor VIII concentrate to evaluate the effects on the immune status of HIV antibody-positive hemophilia patients (preliminary results). Estratto da "Acta Toxicologica et Therapeutica" 1990;
11:49-58. 3 Green D, Deutsche J, Tang M, Goldsmith J. Effect of HIV-I infection on CD4 cells in a hemophilia cohort. Haematologica 1990;75(5): 132-41. 4 Ludlam CA. Effects of alloantigens in blood products on immunity. Semin Hematol 1988;25(suppl 1):3-7.
Medically unexplained physical symptoms
I Cash JD. High potency factor V111 concentrates: value not
SIR,-Dr Richard Mayou is right to say that patients "often complain of feeling frustrated at being told that results ofinvestigations are negative but not receiving any convincing explanation of persistent distressing symptoms."' He does not, however, sufficiently emphasise the need to make a clear positive diagnosis which would be the basis of such an explanation, and he is right that "preoccupation with traditional psychiatric diagnostic categories may have hindered understanding." It is usually possible, however, to make a diagnosis, as in the following example. "This 45 year old patient's pain in the left side of the face for the past three months results from ischaemia in persistently clenching jaw muscles
proved? BM7 1991;303:633-4. (14 September.)
SIR,-Dr John D Cash's article discussing the value of high potency factor VIII concentrates contains several inaccurate suggestions that cannot pass unchallenged. ' At least 12 published papers have reported immunological abnormalities in people with haemophilia who have received repeated treatments with clotting factor concentrates of low purity over several years. There is also growing evidence, mainly in vitro, that high purity concentrates are less immunosuppressive than the older,
1062
SAMUEL I COHEN
Department of Psychiatry, Royal London Hospital Medical College, London El 2AD I Mayou R. Medically unexplained physical symptoms. BMJ7
1991;303:534-5. (7 September.)
R B CHRISTIE
Bio Products Laboratory, Elstree, Hertfordshire WD6 3BX
2 Vive I'alliance. Bloodletter 1991;48:1.
(bruxism). The pain is unilateral because the bite is asymmetric. The patient has always been rather tense and anxious, and the basis for the present symptoms is a rise in the level of his anxiety in the past three months as evidenced by other features of this such as sleeplessness, palpitations, and frequency of micturition. The reason for this increase in his anxiety is . " Most symptoms of the kind under discussion that come to psychiatrists are the somatic manifestations of anxiety. The common causes of anxiety in my regular outpatient clinics are major emotional conflicts or personal disasters in about half of cases and, in the remaining half, the use of alcohol, often not in what may be called "alcoholic" amounts, or the continuing use of benzodiazepine drugs. Dr Mayou uses the terms unexplained, nonspecific, and atypical. These say what the disorder is not but not what it is. The atypical facial pain in the example above is absolutely typical of numerous patients with a disorder that is far commoner than trigeminal neuralgia, the disorder of which this pain is supposed to be atypical. The pain in the chest after myocardial infarction which Dr Mayou refers to as atypical is typical of the pain in many such patients and almost certainly arises in contracting chest muscles resulting from fear, as evidenced by the fact that it is commonly associated with other symptoms of muscular contraction such as tension headaches, tightness in the neck, or aching in the shoulders. How can you give symptomatic treatment if you do not know the pathogenesis, and how can you reassure if you do not know what is wrong but only the negative results of a series of investigations? Of course these patients are difficult to treat as long as they remain diagnostic puzzles. It is, however, perfectly possible as a rule to make a sufficiently precise statement about the disorder to allow some worthwhile intervention to be made and so to relieve the patient.
Use of thalidomide in leprosy SIR,-Despite Dr M F R Waters's reassurance' neither the most recent report from the World Health Organisation's expert committee on leprosy,2 nor the most recent review3 contains any reference to thalidomide neuropathy. We should be told if the manufacturers, Chemie-Grunenthal, Andrulis Research Corporation, and Interbras, which are currently supplying thalidomide, include a warning about its neuropathic side effects. Even the very existence of the side effect was aggressively denied in 1976 by the then Secretary of State for Health and Social Security, Dr David Owen: supporting the use of thalidomide in leprosy treatment, he wrote to Jack Ashley MP, stating, "You will also wish to know that Sir Ludwig Gutmmann among others is satisfied that allegations of neurotoxicity are unfounded and has given evidence to this effect." Even if the high figure for nodular prurigo is excluded, neuropathy occurred in 15 out of 60,4 three out of nine,5 and two out of six6 patients given the drug for other disorders, making the cited frequency of 0 5% much too low. ' In patients other than patients with leprosy given the drug careful, frequent clinical examinations are routinely carried out and are supplemented by electrophysiological testing, enabling early detection of neuropathy. Stopping the drug at this stage offers the best chance of recovery. Even when the treatment has been successful, as in life threatening graft versus host disease, the drug has had to be withdrawn
BMJ VOLUME 303
26 OCTOBER 1991
