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HLA ANTIBODIES DETECTED BY ELISA HTLV-IIIANTIBODY KITS

SiR.—Dr Kuhnl and colleagues (May 25, p 1222) provideevidence that HLA-DR4 antibodies may give positive results inenzyme-linked immunosorbent assays (ELISA) used to detectantibodies to human T-cell lymphotropic virus type III

(HTLV-III). 10 of 27 (37%) DR4 alloantisera were positive in theELISA. The 10 monoclonal antisera were ELISA negative;however, this is expected since the second antibody, anti-humanIgG, would not react with the mouse monoclonals even if theybound to the bead. The data suggest that HLA-DR4 antigen is

present on the test beads used in the ELISA and, therefore, on H9,the cell line from which viral antigen is isolated for use in

commercially available test kits. Professor Weiss and colleagues(July 20, p 156) typed H9 and confirmed the presence ofDR4 as wellas HLA Al, Bw62, Bw6, Cw3, and DQw3.To examine whether the ELISA positives are caused by DR4

antibodies, we tested HLA antisera, procured locally from

multiparous women, with Abbott ELISA kits. Class I antiseradirected against HLA A, B, C found on H9 and DR antisera specificfor non-H9 associated specificities were ELISA negative. 1 of 5 anti-DR4 and 3/4 anti-DQw3 sera were reproducibly ELISA positive.All sera tested were negative for HTLV-III antibodies by westernblot.To extend the evidence that not only DR4 but also DQw3

antibodies give positive results in HTLV-111 ELISA tests we didHLA antibody analysis on sera from 20 ELISA repeatedly reactiveblood donors. 6 of the donors were also HTLV-111 antibody positiveby western blot. 4 of the 20 sera have DQw3 or DR4 specificity andan additional 5 reacted with some DR4 and DQw3 cells:Donors pOSlln’e for HTL h111 antibody Anll-HLA speciflcltzes detectedELISA positive/western blot negative 2 DQw3, 1 DR4, 1 DQwl,

(n= = 14) 1 non-specific,* 9 negativeELISA positive/western blot positive 1 DQw3, 1 A9+,* 3 non-specific,* *

(n=6) 1 negative*Reactivity not sufficient to assign specificity; however, sera preferentially reacted withDR4 and DQw3 positive B cells

These data indicate that reactivity in HTLV-III ELISA assays canbe due to DR4 and also DQw3 antibodies. However, we agree withWeiss et al that HLA antibody evaluation does not distinguish falsepositive ELISA results since one of our 6 western blot positivedonors also has anti-DQw3 and 3 have non-specific class II HLAantibody.Western blot results are currently used for verification of HTLV-

III antibodies detected by ELISA. The validity of this approach issupported by our finding that none of the HLA typing sera werepositive by western blot and that 89% of western blot positivedonors reported in the US by the Council of Community BloodCenters are males. Nevertheless, there is an urgent need to confirmthis assumption by viral cultures or HTLV-III antigen specifictesting. In addition, we strongly urge commercial manufacturers ofELISA kits to eliminate non-HTLV-III antigens from their testsystems to decrease the proportionately large number of falsepositive tests results that occur currently.

JAY B. HUNTERJAY E. MENITOVE

Blood Center ofSoutheastern Wisconsin, Inc,

Milwaukee, Wisconsin, USA

OVERINVESTIGATION

SIR,-The patient Dr Jenkins describes (May 25, p 1213) sawseveral specialists. Damage to the spinal accessory nerve wasidentified by one, deltoid atrophy by another, decreased sensationby a third, a positive Adson’s manoeuvre by a fourth, and thoracicoutlet syndrome was diagnosed by a fifth. Even the electromyogramwas felt to be abnormal. Ultimately, the man was shown by theinsurance company involved to be malingering. This is a strongcomment on the limitations of our clinical method and on our needto make a diagnosis. When five of twelve doctors identifyabnormalities that are not there, we have to reflect on how we mightimprove our skills.Every test, both in physical examination and in diagnostic

investigation, has inherent limitations which depend upon the test’s

sensitivity and specificity and upon the likelihood of the diseasebeing present. Even for a very sensitive and specific test, a singlepositive finding, such as deltoid atrophy or a positive Adson’smanoeuvre, is more likely to represent a false positive than truedisease, if the clinical picture suggests that the disease is unlikely.

Clinicians should also recognise that their judgment may beaffected by the priority they place on making a diagnosis. Aphysician who thinks that making a diagnosis is all-important mayzealously pursue a diagnosis "because it is there"’ or may follow themaxim "when in doubt make a diagnosis". The attitude that it ismuch worse to call a sick person well, than to call a well person sickis deeply engrained in the medical profession and is supported bylegal sanction (especially in the USA).3 This attitude underlies the"minimax" decision strategy or "better safe than sorry" approach,through which the doctor aims to minimise the chances ofmaximum possible loss or the worst outcome by directing investi-gation towards the most serious, though improbable, diagnosis.4 Allthese biases in decision making may result in overdiagnosis ormisdiagnosis.As Jenkins implies, his patient and the community would have

been better served if the physicians involved had recognised thelimitations of their tests and curbed their desires to make a

diagnosis. As family physicians we would have liked to know howthe patient reacted to the revelation of his fitness and what the finaloutcome was.

Department of Family Medicine,University of Western Ontario,London, Ontario, Canada N6A 5C I

MARTIN J. BASSROGER P. STRASSER

1 Editorial. Iatrogenesis Just what the doctor ordered. J Community Health 1980, 5:149-57.

2 Wulff HR Rational diagnosis and treatment Oxford Blackwell, 1976: 1143 Reiser SJ Medicine and the reign of technology Cambridge Cambridge University

Press, 1978, 1924 Bursztajn H, Feinbloom RI, Hamm RM, Brodsky A Medical choices, medical

chances New York: Merloyd Lawrence, 1981 189-90

DIFFUSE HYPEROSTOSIS ASSOCIATED WITHETRETINATE

SIR,-The retinoids are now the drugs of choice for the

management of severe disorders of keratin is at ion such as ichthyosis.Isotretinoin (’Accutane’) has been used widely in the United States,and widespread hyperostosis as a complication oflong-term therapyhas been reported. In contrast, in patients receiving etretinate(’Tigason’), there has hitherto been only one report of a disorder ofossification, and this was localised to the forearms. 3A 38-year-old man with a recessive form of ichthyosis (congenital

non-bullous ichthyosiform erythroderma) started taking etretinate50 mg/daily (0 - 6 mg/kg) in March, 1980. His skin improved. Thedaily dose was increased to 75 mg and then, after 5 months, wasreduced to a maintenance level of 50 mg. In November, 1984, thedose was reduced to 25 mg and he took this dose until April, 1985.

In June, 1984, he noted vague musculoskeletal pains when liftingheavy objects. He practises the martial arts and noted increasingstiffness and discomfort, mainly in the thoracic spine and ribs. InApril, 1985, there was limitation of movement of the thoracic spineand tenderness over the costal cartilages. X-rays suggested diffuseidiopathic skeletal hyerostosis (figure). There was ossification at theinsertion of muscles around the pelvis and upper femora,ossification of the iliolumbar ligaments, and bridging of the anteriorborders of the thoracic vertebral bodies. Isotope bone scans

demonstrated focal areas of increased activity around the ossifiediliolumbar ligaments, at the inferior borders of both sacroiliac

joints, and along the anterior aspect of the cervicothoracic junction,confirming a predominantly axial hyperostosis. Serum calcium,phosphate, alkaline phosphatase, renal function, liver function, andfasting lipids were normal.Between October, 1957, and November, 1964, the patient had

been treated with oral vitamin A (200 000-300 000 units daily). InNovember, 1958, signs of vitamin A toxicity developed. He hadpains in the wrists and knees, bone tenderness, and hepatomegaly,but a liver biopsy showed no irreversible changes. Symptomsresolved when vitamin A was stopped temporarily and he was ableto continue treatment for another six years. Topical vitamin A acidand topical retinoic acid were also used for prolonged periods.