FALSE POSITIVE ANTI-HIV TESTS WITH WELLCOME KITS

996 EPITHELIOID ANGIOMATOSIS IN HIV INFECTION: NEOPLASM OR CAT-SCRATCH DISEASE?

SIR,-Cockerell et al’ reported a new clinicopathological entity in patients infected with HIV-namely, "epithelioid

five

angiomatosis", an unusual cutaneous vascular neoplasm distinct from Kaposi sarcoma. The cutaneous lesions were solitary or multiple papules and nodules. In some patients the lesions also affected internal organs. Histopathologically, the "neoplasms" were composed of proliferating blood vessels lined by cuboidal endothelial cells with abundant pale-staining cytoplasm. The close adherence of these cells to one another resulted in an epithelioid appearance. Brooks and Fisher2 commented that the lesions described were virtually identical to those of AIDS-associated Kaposi sarcoma but in reply, Webster and Cockere113 stated that their cases showed no histological similarities with Kaposi sarcoma: the cells lining the vessels were cuboidal, plump, and not spindle shaped; there were few if any extravasated erythrocytes; there were no siderophages or hyaline globules; and the epithelioid angioma

had a superficial pyogenic granuloma-like component not described previously in Kaposi sarcoma. In 1983 Stoler et af reported a patient with AIDS who had a subcutaneous infection histopathologically marked by atypical vascular proliferation, inflammation, and bacillary microorganisms on sections stained with Warthin-Starry. Leboit et all and Tuur et al6 have reported atypical cutaneous vascular proliferations with inflammation in patients with AIDS that were associated with the cat-scratch disease bacillus. We are studying a small but growing series of patients who are seropositive for HIV and who exhibit similar clinicopathological lesions either of skin or of lymph node. For example, a 26-year-old patient had a 4-month history of erythematous papules and nodules, some pedunculated, scaly, and/or ulcerated, 03-1 ’0 cm across, that were extensively scattered over the body (including the face and eyelids). Biopsy of a lesion on the chest wall was done (figure). A 31-year-old patient had fever, weight loss, left-sided femoral lymphadenopathy and a history of pneumonia caused by Pneumocystis carinii. Biopsy of the femoral lymph node was done. As in Cockerell’s cases, histopathological sections of cutaneous and lymphadenopathic lesions stained with Movat as well as with haematoxylin and eosin techniques revealed: vascular proliferation with vessels lined by cuboidal endothelial cells protruding into lumina; few if any extravasated erythrocytes; an absence of siderophages or hyaline globules; and a mixed interstitial inflammatory cell infiltrate primarily composed of neutrophils, plasma cells, and lymphocytes (figure, left and middle). However, sections stained by Warthin-Starry revealed several large clusters of entangled silvered bacilli within the walls of vessels and in the interstitium (figure, right). The bacteria were gram-negative (Brown-Hopps technique), branching, 0’2-3’C jlII1, and similar in morphology and location to those described as cat-scratch disease bacilli.7-9 We conclude that the newly described epithelioid angiomatosislike entity in patients infected with HIV is not a neoplasm but that it may histopathologically represent the reactive vascular proliferation and inflammatory response of florid cat-scratch disease. We

recommend Warthin-Starry staining in histopathological sections of tissues from any HIV-seropositive patient with cutaneous or lymphadenopathic lesions where there is vascular proliferation associated with neutrophilic inflammation and/or necrosis and where conventional acid-fast and fungal stains are non-

contributory. Registry of AIDS Pathology, Collaborative Center for the Investigation of AIDS, Department of Infectious and Parasitic Disease Pathology, American Registry of Pathology, Armed Forces Institute of Pathology, Washington, DC 20306, USA

PETER ANGRITT SYLVANA M. TUUR ABE M. MACHER

Department of Dermatopathology, Armed Forces Institute of Pathology

KATHLEEN J. SMITH

DC General Hospital,

Washington DC

CHUNG SOON PARK

Palm Beach Gardens Medical Center, Palm Beach Gardens, Florida

FREDERICK P. HOBIN

George Washington Univesity Medical Center, CARMEN MYRIE-WILLIAMS Washington DC 1. Cockerell

CJ, Whitlow MA, Webster GF, et al. Epithelioid angiomatosis: a distinct vascular disorder in patients with the acquired immunodeficiency syndrome or AIDS-related complex. Lancet 1987; ii: 654-56. 2. Brooks JJ, Fisher C. Epithelioid angiomatosis: a variant of Kaposi’s sarcoma. Lancet 1987; ii: 1214. 3. Webster GF, Cockerell CJ, Whitlow MA, et al. Epithelioid angiomatosis: a variant of Kaposi’s sarcoma. Lancet 1987; ii: 1215. 4. Stoler MH, Bonfiglio T, Steigbigel RT, et al. An atypical subcutaneous infection associated with acquired immune deficiency syndrome. Am J Clin Pathol 1983; 80: 714-18. 5. Leboit P, Berger

T, Egbert B, et al Atypical cutaneous vascular proliferations in patients with AIDS are associated with the cat scratch disease bacillus. Lab Invest 1988; 58 (53A); abstr 314 6 Tuur S, Wear D, Hobin F, et al. Anergic cat scratch disease (CSD) in patients with AIDS. Lab Invest 1988; 58 (96A): abstr 572. 7. English CK, Wear DJ, Margileth AM, et al Cat-scratch disease: Isolation and culture of the bacterial agent. JAMA 1988, 259: 1347-52 8. Wear DJ, Malaty RH, Zimmerman L, et al. Cat scratch disease bacilli in the conjunctiva of patients with Parinaud’s oculoglandular syndrome. Ophthalmology 1985; 92: 1282-87. 9. Margileth AW, Wear DJ, Hadfield TL, et al. Cat scratch disease: bacteria in skin at the primary inoculation site. JAMA 1984; 252: 928-31.

FALSE POSITIVE ANTI-HIV TESTS WITH WELLCOME KITS

SIR,-Dr Mitchell and colleagues (Feb 6, p 197) and Mr Puckett colleagues (March 26, p 714) comment on apparently

and

falsely-positive results for HIV antibodies detected by ’Wellcozyme’ anti-HIV kits. False-positive samples are repeatedly positive samples which cannot be confirmed by reference centres. The frequency of false-positive results with the wellcozyme test is much lower (002-005%) than that for other kits (0’2-0.5%).1 The factor causing the effect was non-dialysable (and hence is probably not a drug or metabolite) in 10/10 false-positive samples we have tested. On fractionation the factor co-purifies with IgG. Use of a sequential assay in which the sample is washed away before the enzyme-labelled conjugate is added has overcome the effect in

Histopathological findings. Left: intradermal ectatic vascular proliferation with mixed interstitial inflammation (haematoxylin and eosin; x 14).

Middle:

intradermal

ectatic

vascular

proliferation and interstitial inflammation, with plump cuboidal endothelial cells protruding into lumina of variably sized vessels (haematoxylin and eosin;

x

250).

Right: intradermal silveredclusters of catscratch disease bacilli within walls of vessels and in interstitium (Warthin-Starry stain; x 350).

997

samples tested. Furthermore, using the standard (nonsequential) format for the test but replacing the peroxidase-labelled antibody with alkaline-phosphatase-labelled antibodies overcame the effect in all of 54 samples tested. All true positive samples tested in these ways continue to give positive results. These results show that the sample must come into contact with peroxidase in the conjugate to cause false positivity in most, if not all, cases. If the factor is a peroxidase inhibitor it should be possible to show inhibition of both native peroxidase and the conjugate used in the Wellcome assays when testing the enzyme in the presence of a false-positive sample. In fact it has been possible to demonstrate this on only 1 of the false positives available to us. Furthermore, conjugates of peroxidase prepared from antisera other than those normally used in the test do not necessarily detect the same samples as falsely positive. Mitchell et al have suggested that inhibitory anti-peroxidase might be the cause of the effect but there is little evidence for this (ie, a non-dialysable factor in the IgG fraction). It is unlikely that there is a single explanation for all of these false-positive results. As Puckett et al point out, and as described above, use of the sequential format will often discriminate between a true and a false positive result. However, this modification has not yet been fully validated and in view of the very small proportion of samples giving anomalous results we feel that such samples should continue to be submitted for confirmatory testing.

TABLE II-DETAILS OF DRUGS OF ABUSE

all of 61

We thank our collaborators in the UK and abroad who have made many of their interesting samples available to us.

C.A. ROBERTS C. H. BERRISFORD R. J. S. DUNCAN

Wellcome Diagnostics Research, Beckenham, Kent BR3 3BS 1. Menitove

JE, Richards WA, Bauer P. donation. Lancet 1987; ii: 1213.

False-positive

anti-HIV

tests

and blood

DRUG ABUSE AND MENTAL ILLNESS

SiR,—The term "flashback" refers to a brief psychotic experience long after exposure to a hallucinogenic drug. The possibility that some drugs might trigger psychosis was emphasised by Daniels and Latcham,l who described petrol sniffing preceding

schizophrenia, and we too have seen cases that seem to conform to this model. Dopamine agonists such as cocaine2 and amphetamine, which can induce schizophreniform psychoses in previously healthy people in a single large dosemight be especially dangerous. To look for such associations we inquired into drug abuse of all acutely admitted patients over the 12 months April, 1981, to April 1982. Our preliminary findings were reported on in 1984.4 Questions were asked during the normal admission procedures and patients were not pressurised. By "drug abuse" we mean illicitly used psychoactive drugs, taken up to the point of addiction. The acute admissions numbered 110. We excluded the following: 10 schizophrenic patients whose self-reports were considered suspect, 3 with uncertain diagnoses, 5 primary drug abusers (all psychotic), 2 with suspected drug-induced psychosis, 13 alcoholics, 2 with confusional states, and 1 patient with cerebral infarction with

*Lysergide (6), psilocybin (1). 22 of the 36 drug abusing patients (17 schizophrenics and 5 with affective illness) volunteered drug histories which we believed were complete and 12 had urine analyses that confirmed their accounts of their current drug abuse. The remaining 3 depressed patients might have abused some unspecified drug on one or two occasions in addition to cannabis, and the remaining schizophrenic patient was a polydrug abuser who was confused about his full drug history. There was an over-representation of the frequent abuse of the hallucinogens lysergide and psilocybin, and of amphetamines alone or in combination with cocaine among the schizophrenic patients

(table ll). Schizophrenia might have been diagnosed erroneously when a patient had an acute drug-induced schizophreniform psychosis but follow-up interviews by independent assessors confirmed the diagnosis of schizophrenia, except in 2 patients lost to follow-up. 3 of the affectively ill patients were diagnosed as having schizophrenia on a subsequent admission; 2 had been heavy drug abusers. Our small numbers caution against too great a reliance on subgrouping by drug types but tend to support our suspicions that hallucinogens and dopamine agonists are likely to trigger a long-lasting psychosis. Cannabis abuse was common in both groups; nevertheless our impression and that of others" is that cannabis often exacerbates psychotic symptoms. We have seen long-lasting psychoses after cannabis abuse in previously stable patients, and prolonged use of cannabis has been associated with eventual schizophrenia over a 15-year follow-up8 (though the cannabis may have been a marker for other drugs).8,9 Our data suggest a continuing pattern of drug abuse in the patients admitted which may be contributing to the relapsing pattern seen in many cases. We do not know if an incipient schizophrenic disorder predisposes to drug abuse or whether drugs induce an otherwise avoidable illness or bring that illness forward in time. Our results suggest that agents with dopamine agonist properties may be especially dangerous, and this makes the growth in amphetamine and cocaine abuse very worrying. Thirteen illicit laboratories producing amphetamine were identified in the UK in 1987, and one survey of 2000 drug takers has revealed that 80 % had abused amphetamines. In the UK (Times, Jan 14, 1988) and in the United States (Times, March 12, 1988) cocaine seizures by drug enforcement agencies are sharply on the increase. We thank Dr Monica Leighton for advice, our librarians and Mr D. Badenoch for assistance, and the National Schizophrenia Fellowship and May & Baker for financial help.

memory loss.

Schizophrenic patients were more likely to have taken illicit drugs than the affectively ill patients (table I), and the excess was maintained when the schizophrenic patients were compared with the endogenous affective subgroup who were very close in age to the schizophrenics. 9 schizophrenic patients had abused drugs more than sixty times as against 1 affectively ill patient. In 32 schizophrenic patients in whom the age of onset was known reliably, the 13 who had abused drugs before their illness developed schizophrenia earlier than the 19 who had not abused drugs (219 years vs 33-4 years;

Mann-Whitney U = 365, p < 0001, two tailed).

TABLE I-HISTORY OF DRUG ABUSE

Fnem

Hospital,

London N1 1 3BP

MALCOLM p.I. WELLER P.C.ANG D. T. LATIMER-SAYER A.ZACHARY

AM, Latcham RW. Petrol sniffing and schizophrenia in a paradise. Lancet 1984; i. 389. Ritz MC, Lamb RJ, Goldberg SR, Kuhar MJ. Cocaine receptors

1. Daniels

Pacific island

2.

on

dopamine

transporters are related to self-administration of cocaine. Science 1987; 237: 1219-23. 3 Connell PH. Amphetamine psychosis (Maudsley Monogr no 5). London. Chapman and Hall, for the Institute of Psychiatry 1958 4. Weller MPI, Ang PC, Zachary A, Latimer-Sayer DT. Substance abuse in schizophrenia. Lancet 1984, i: 573. 5. Treffert DA. Marijuana use in schizophrenia a clear hazard Am J Psychiatry 1978; 135: 1213-15 6. Negrete J, Wemer PK, Douglas DE, Smith WB. Cannabis affects the severity of schizophrenic symptoms: results of a clinical survey. Psychol Med 1986; 16: 515-20. 7. Kolansky H, Moore WT. Effects of marihuana on adolescents and young adults. JAMA 1971; 216: 486-92. 8. Andreasson S, Allebeck P, Engstrom A, Trydberg U. Cannabis and schizophrenia. a longitudinal study of Swedish conscripts. Lancet 1987; ii: 1483-85. 9. Johnson BA, Smith BL, Taylor P. Cannabis and schizophrenia Lancet 1988; i: 592-93.