Saturday 9 March
ACUTE AIDS RETROVIRUS INFECTION
Definition of a Clinical Illness Associated with Seroconversion DAVID A. COOPER JULIAN GOLD PRUDENCE MACLEAN BASIL DONOVAN ROBERT FINLAYSON TIMOTHY G. BARNES PETER BROOKE HARRY M. MICHELMORE RONALD PENNY for the Sydney AIDS Study Group* Centre for Immunology, St Vincent’s Hospital, Sydney, NSW 2010, and University of New South Wales, NSW 2033; and Commonwealth Institute of Health, University of Sydney, NSW 2006, Australia
course of a prospective immunoepidemiological study of homosexual men
in Sydney, seroconversion to the AIDS-associated retrovirus (ARV) was observed in 12 subjects. Review of the clinical files
infectious-mononucleosis-like illness in 11
subjects. The illness was of sudden onset, lasted from 3 to 14 days, and was associated with fevers, sweats, malaise, lethargy, anorexia, nausea, myalgia, arthralgia, headaches, sore throat, diarrhoea, generalised lymphadenopathy, a and truncal eruption, erythematous thrombocytopenia. In 1 subject an incubation period of 6 days after presumed exposure to ARV was determined and in 3 subjects seroconversion took place 19, 32, and 56 days after onset. Comparison of T-cell subsets before and after the acute illness showed inversion of T4:T8 ratio in 8 subjects, due to macular
*Sydney AIDS Study Group Consultants: A. I. Adams, W. A. Crawford, D. G. Fox. Project coordinators D. A Cooper, J. Gold. Centre for Immunology, St Vincent’s Hospital, Sydney: R. Penny, W. May, L. McKenzie, K. Bate, P. Maclean, G. Chapman, A. B. Hill, A. Ryan, P. Scheuers, J. Kramer, B. Spinks. Commonwealth Institute of Health, University of Sydney: G. Berry, C. Brown, J Mandryk, P. Mock, J. Watts, J. Burcham. SID Centre, Sydney Hospital: R. Philpot, R. P. Jones, J. Roberts, P. Todd. Participating medical practitioners: T. G. Barnes, P. Brooke, B. Donovan, R Finlayson, P. Haynes, H. M. Michelmore, K. Mutimer, R. Price. G Counselling Service of NSW and AIDS Support Group, Sydney: I Goulden,J Dykes.
increased numbers of circulating T8+ cells. These findings support the notion of an acute clinical, immunological, and serological response to infection with ARV which should be considered in the differential diagnosis of mononucleosis-like syndromes in groups at high risk for the development of AIDS.
compelling evidence that the acquired immunodeficiency syndrome (AIDS) is caused by a lymphocytopathic retrovirus known as lymphadenopathyassociated virus, human T-lymphotropic virus type III,2 or 3 THERE is
AIDS-associated retrovirus (ARV).3 Various clinical expressions of presumptive infection with this retrovirus have been described. These include full-blown AIDS and the AIDS-related complex or lymphadenopathy syndrome, as well as symptomless immunodeficiency. The development of serological tests3-5 has permitted the definition of symptomless persons from high-risk groups who have been exposed to the AIDS virus. Full-blown AIDS is the late result of severe T helper cell immunodeficiency by retrovirus infection after many months or years.6 The likely pathogenesis of the immune disorder in patients with lymphadenopathy syndrome is related to a proliferative immune response to sustained retroviral infection7 and in patients with immune thrombocytopenic purpura to circulating immune complexes.8 Seroconversion has been noted in 4 homosexual men enrolled in a prospective study9 and 1 health-care worker who sustained a needlestick injury.’° A clinical illness consisting of sore throat, headache, neuralgia, rash, malaise, fever, and myalgia, lymphadenopathy was associated with seroconversion in this health-care worker. 10 We report here an acute infectious illness associated with seroconversion in 10 subjects enrolled in a prospective study" and a further 2 subjects evaluated at an
outpatient clinic.’2 Materials and Methods
Patients From February, 1984, to January, 1985, almost 1000 homosexual and bisexual men were enrolled in the Sydney AIDS project. The design of this immunoepidemiological study has been described previously."After enrolment, subjects are seen every six months and data are collected for comparative analysis of epidemiology 8428
(demography, life style, and sexual practices), clinical features (history and physical examination), immunology (T-cell subsets), and serology (antibodies to ARV). Of these 1000 subjects, 140 had completed six-month follow-up by January, 1985. A further 2 homosexual men were seen at the immunology outpatient clinic of St Vincent’s Hospital for evaluation.
TABLE I-CHANGES IN T-CELL SUBSETS AND TITRE OF ARV ANTIBODY
Laboratory Tests The absolute number of circulating lymphocytes was determined Coulter Counter Model S Plus IV (Hialeah, Florida, USA). Peripheral blood mononuclear cells (PMBC) were isolated from blood collected into acid-citrate-dextrose on ’Ficoll-Paque’ separation mixtures (Pharmacia, Uppsala, Sweden). PBMC were labelled by indirect immunofluorescence with monoclonal antibodies directed at T4 (helper-inducer) and T8 (suppressorcytotoxic) T cell surface antigens (Ortho Corporation, Raritan, New Jersey, USA) and analysed on a flow cytometer (Epics C, Coulter Corporation, USA). Antibodies to ARV were determined by indirect immunofluorescence at a 1 in 10 screening dilution of serum on an ARV-infected permissive T-cell line. Sera that were negative at a 1 in 10 dilution were rechecked at 1 in 5. Precise titres of antibody were then obtained by doubling dilution. Seroconversion was defined by 4-fold or greater increase in titre of on a
*Pre= laboratory results at enrolment; post=laboratory results at follow-up. fHospital and laboratory staff.
antibody. Results Seroconversion Of the 150
examination, 10 showed ARV antibody seroconversion. A further 2 subjects seen at the immunology outpatient clinic were noted to seroconvert. Table I shows the titres of antibodies to ARV; at the first study none of the 12 subjects had detectable antibodies to ARV whereas at six months their titres ranged from 1 in 20 to 1 in 640. In 3 subjects (patients 3, 5, and 11) the collection of multiple serum samples allowed determination of the time of seroconversion, which was 56, 32, and 19 days after onset of the acute illness. In these 3 subjects titres of antibody to Epstein-Barr virus and cytomegalovirus did not change through the course of the
of Acute Illness
The clinical files of all 12 subjects who seroconverted were reviewed, and as a result some subjects were interviewed again. The outstanding finding was that, in all but 1 subject a mononucleosis-like illness of sudden onset had been noted by the patient and his doctor in the intervening period. The clinical features of this illness are shown in table n. The duration of the acute illness ranged from 3 to 14 days. The major clinical features were fevers and sweats in 11, myalgias and arthralgias in 11, lethargy and malaise in 10, sore throat in 9, anorexia, nausea, and vomiting in 8, headaches and photophobia in 7, and diarrhoea in 4. Generalised enlargement of lymph nodes and spleen was noted by the doctor in 9 patients at various times (usually several days) after the onset of the illness. Moreover a macular erythematous rash in the truncal area was noted in 6 subjects. Other features included severe shooting pains (2), sacral hyperaesthesia (1), major weight loss (1), desquamation of palms and soles (1), and raised serum transaminases (1). The case histories of 3 patients are briefly recorded.
temperature of 38, 20C. He had a coated dry tongue, red throat, anterior cervical and right inguinal lymph node enlargement, and splenic tenderness. After admission to hospital and rehydration for several days his acute symptoms settled over 2 weeks. However, he continues to have intermittent lethargy, myalgias, mild elevations of temperature, depression, generalised lymphadenopathy, and
splenomegaly. Case 5.-A male homosexual student
November, 1984, 3 days after the sudden onset of severe malaise, frontal headache, photophobia, vertigo, fevers and sweats, myalgia, weakness, lethargy, severe nausea, and anorexia. There was a history of herpes simplex proctitis in 1983, with a recurrence beginning on Oct 23, 1984. On Nov 3, after abstaining from sexual intercourse for 6 weeks, he had had anal receptive intercourse; and the acute illness developed 6 days thereafter. On examination he looked pale and ill, with a temperature of38-5°C, tachycardia, and a coated tongue. There was mild pharyngeal erythema as well as axillary and inguinal lymphadenopathy. He was treated with intravenous fluids, antipyretics, and antiemetics. The temperature became normal 4 days after admission, along with clinical improvement, and he was discharged on the 6th day. 10 days later he was still complaining of persisting mild fevers, myalgias, and lethargy. He had noted desquamation of his palms and soles. These
37-year-old homosexual man presented in September, 2 day history of fever, severe myalgias, and a truncal rash followed by watery diarrhoea. His medical history included insulin-dependent diabetes mellitus, severe hepatitis B, and possible Crohn’s disease with appendiceal and large-bowel granulomas. On physical examination he was pale with a
TABLE II-FEATURES IN
12 CASES OF ACUTE AIDS VIRUS INFECTION
— — i_
*Others included shooting pams in arms and legs, desquamation of and severe chest and back pains.
soles, weight loss,
539 TABLE III-RESULTS OF BLOOD TESTS IN PATIENT
symptoms have continued intermittently for several weeks and have been associated with increasing generalised lymphadenopathy. He has also had minor infections including thrush, tinea cruris, and mouth ulcers. The results of laboratory investigations are summarised in table III. ’
Case 11.-A 34-year-old homosexual man presented 3 days after of fevers, sweats, chest and back pain, sore throat, diarrhoea, anorexia, and vomiting. His medical history was unremarkable apart from syphilis and hepatitis B. He was pale and thin, his throat was red, he had right cervical and bilateral submandibular lymphadenopathy, and his temperature was 39-4°C. The illness lasted 11 days and was associated with 4 kg weight loss, a macular erythematous eruption on the trunk, generalised lympadenopathy, and mild thrombocytopenia. He recovered completely over 8 weeks. onset
Associated with seroconversion were prominent changes in immunological status (table I). There was no characteristic change in the absolute numbers ofT4 + cells before and after seroconversion, but the T4:T8 ratio inverted in 8 subjects. This inversion was due to an increase in circulating numbers ofT8+cells. In 3 subjects (1, 8, 9) the ratio did not change strikingly. Follow-up T-cell subset data were not obtained in
subject 4. In subject
5 lymphocyte count and T-cell subsets were in relation to seroconversion (table ill), by monitored closely 6 of the acute illness he was lymphopenic (200 x 106 day with a normal T4:T8 ratio, and also mildly lymphocytes/1) thrombocytopenic. Thereafter the lymphocyte count climbed steadily, reaching a peak of 7300 x 106/134 days after onset of the acute illness. At this time the T4:T8 ratio was inverted. As soon as the lymphocyte count started to increase from its nadir, atypical mononuclear cells were noted on the peripheral blood film. Over the subsequent month the lymphocyte count decreased to 3300 x 1O6/land the ratio remained inverted. ’
Discussion responses were not determined in this 4-fold or greater increase in titre is commonly accepted as evidence for acute viral infection. An earlier prospective study in the USA9 identified 4 seroconversions in 66 subjects followed for 1 year. Our finding of 10 seroconversions in 150 subjects followed for six months suggests a comparable rate of seroconversion amongst homosexual men from Sydney. In 3 patients (3, 5, and 11) who were closely followed after the acute illness it was possible to assess the time required for scroconversion as not more than 56, 32, and 19 days, respectively. Moreover, an incubation period of 6 days in patient 5 is strongly suggested by the timing of his sexual
In the British needlestick transmission caselO the incubation period was 13 days and seroconversion was observed at 49 days. All but 1 of the subjects who seroconverted had remarkably similar symptoms and signs. This supports the notion that a single infectious agent was responsible for the illness in this risk-group of homosexual men. The illness lasts up to 14 days and is best described as mononucleosis-like. Fevers, sweats, lethargy, malaise, myalgias, arthralgias, headaches, and sore throat were notably severe and were followed by the development of generalised lymphadenopathy. A macular, erythematous eruption appeared non-specific but further immunopathological studies are needed to define any specific diagnostic features. The development of generalised lymphadenopathy and splenomegaly, so well defined for lymphadenopathy syndrome, also supports the idea that this acute illness is the primary event of AIDS virus infection. The clinical features that we have described bear a remarkable resemblance to those reported in the needlestick transmission case. 10 The illness also has features reminiscent of other infections due to lymphotropic agents, such as contacts.
Epstein-Barr virus, cytomegalovirus, hepatitis viruses, toxoplasma, rubella, and syphilis, most of which have’ increased prevalence in homosexual men. Thus, AIDS virus infection must now be considered in the differential diagnosis of an acute mononucleosis-like syndrome, particularly in persons from groups at high risk for AIDS. The immunological changes with the course of these seroconversions are informative. T-cell subset findings support the idea that AIDS virus infection rather than life style is the likely cause of inversion of T4:T8 ratio.’ 3-15 Moreover, there has been no characteristic change in circulating numbers of T4 + cells during the course of this The profound depletion of circulating numbers cells found in full-blown AIDS or severe lymphadenopathy syndrome is in striking contrast and suggests that other factors including superinfection, repeated ARV infection, host factors such as immunogenetic responses, variations in virulence between viral subtypes, and life style may operate to determine the final outcome of AIDS virus infection. The profound changes in lymphocyte count during the close observation of illness in case 5 are particularly interesting. The initial response to infection seems to be severe lymphopenia, without any alteration in the overall balance between helper and suppressor T cells. However, after gradual resolution of the acute infection there is an acute illness.
of T4 +
proliferative response associated with helper: suppressor ratio and the development of atypical lymphocytosis which parallels the development of lymphadenopathy.
inversion of the
540 The inversion of T4:T8 ratio in these subjects after acute AIDS virus infection is clearly due to an increase in numbers of circulating T8+ cells. This T8 response, found in the infectious mononucleosis of Epstein-Barr virus’6 and cytomegalovirus," is associated with the development of immunity to these lymphotropic viruses. Whether such a response to AIDS virus infection is appropriate as a mechanism of immunity will require further investigation. Morever, we have seen several symptom-free seropositive homosexual men with inverted T4:T8 ratios who have lymphocytosisY Whether this too is an early phase of infection or a continuing response to more prolonged AIDS virus infection is not clear at present. The clinical and laboratory findings reported here suggest that AIDS virus infection should be considered in any highrisk person with acute febrile mononucleosis-like illness. Virus isolation should be possible during the acute phase of the illness, and patients may be highly infectious during the several weeks that seem to elapse before seroconversion. Although it is not known what percentage of individuals seroconvert without symptoms, advice and counselling to those with manifest illness may be useful to limit the spread of AIDS virus infection. This study was supported by special funding from the New South Wales Department of Health and the National Health and Medical Research Council of Australia. We thank Dr Jay Levy and Dr Larry Kaminsky, of the Cancer Research Institute, University of California, San Francisco, for the generous supply of ARV reagents; Dr Michael Hmg for information on case 3; the Sydney gay community for cooperation and participation; and Miss Beverley Spinks for preparation of the script. Correspondence should be addressed to D. A. C., Centre for Immunology, St Vincent’s Hospital, Sydney, NSW 2010, Australia. REFERENCES 1 Barré-Smoussi F, Chermann JC, Rey F, et al. Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS). Science 1983, 220: 868-71. 2. Gallo RC, Salahuddin SZ, Popovic M, et al Frequent detection and isolation of cytopathic retroviruses (HTLV-III) from patients with AIDS and at risk for AIDS. Science 1984; 224: 500-03. 3 Levy JA, Hoffman AD, Kramer SM, Landis JA, Shimabukuro JM, Oshiro LS. Isolation of lymphocytopathic retroviruses from San Francisco patients with AIDS. Science 1984; 225: 840-43. 4. Sarngadharan MG, Popovic M, Bruch L, Schupbach J, Gallo RC. Antibodies reactive with human T-lymphotropic retroviruses (HTLV-III) in the serum of patients with AIDS. Science 1984; 224: 506-08. 5. Brun-Vezinet F, Rouzioux C, Barré-Sinoussi F, et al. Detection of IgG antibodies to lymphadenopathy-associated virus in patients with AIDS or lymphadenopathy syndrome. Lancet 1984; i: 1253-56. 6. Seligmann M, Chess L, Fahey JL, et al AIDS-An immunologic reevaluation. N Engl J Med 1984 311: 1286-92. 7. Guarda LA, Butler JJ, Mansell P, Hersh EM, Reuben J, Newell GR. Lymphadenopathy in homosexual men Morbid anatomy with clinical and immunologic correlations. Am J Clin Pathol 1983; 79: 559-68 8 Walsh CM, Nardi MA, Karpatkin S. On the mechanism of thrombocytopenic purpura in sexually active homosexual men. N Engl J Med 1984; 311: 635-39. 9. Goedert JJ, Sarngadharan MG, Biggar RJ, et al. Determinants of retrovirus (HTLVIII) antibody and immunodeficiency conditions in homosexual men. Lancet 1984; ii: 711-16. 10. Editorial. Needlestick transmission of HTLV-III from a patient infected in Africa. Lancet 1984; ii: 1376-77 11. Sydney AIDS Study Group. The Sydney AIDS protect. Med J Aust 1984; 141: 569-73. 12. Hill AB, May W, Kammsky LS, Levy JA, Penny R, Cooper DA. AIDS and related conditions. One year’s experience in St. Vincent’s Hospital, Sydney. Med J Aust 1984; 141: 573-78. 13. Kornfeld H, Vande Stouwe RA, Lange M, Reddy MM, Grieco MH. T-lymphocyte subpopulations m homosexual men. N Engl J Med 1982; 307: 729-31 14. Detels R, Fahey JL, Schwartz K, Greene RS, Visscher BR, Gottheb MS. Relation between sexual practices and T-cell subsets in homosexually active men. Lancet 1983; i: 609-11 15 Fahey JL, Prince H, Weaver M, et al. Quantitative changes in T helper or T suppressor/cytotoxic lymphocyte subsets that distinguish acquired immune deficiency syndrome from other immune subset disorders. Am J Med 1984; 76: 95-100. 16. Reinherz EL, O’Brien C, Rosenthal P, Schlossman SF The cellular basis for viralinduced immunodeficiency: analysis by monoclonal antibodies J Immunol 1981; 125: 1269-74 17. Carney WP, Rubin RH, Hoffman RA, Hansen WP, Healey K, Hirsch MS. Analysis of T lymphocyte subsets in cytomegalovirus mononucleosis J Immunol 1981; 126: 2114-16.
CONTROLLED TRIAL OF OLIGOANTIGENIC TREATMENT IN THE HYPERKINETIC SYNDROME C. M. CARTER D. GUMLEY F. SOOTHILL
J. EGGER* P. J. GRAHAM
J. Departments of Immunology and Child Psychiatry,
Institute of Child Health and Hospital for Sick Children, London
76 selected overactive children were treated with an oligoantigenic diet. 62 improved, and a normal range of behaviour was achieved in 21 of these. Other symptoms, such as headaches, abdominal pain, and fits, also often improved. 28 of the children who
controlled trial in which foods thought to provoke symptoms were reintroduced. Symptoms returned or were exacerbated much more often when patients were on active material than on placebo. 48 foods were incriminated. Artificial colorants and preservatives were the commonest provoking substances, but no child was sensitive to these alone.
Introduction THE hyperkinetic syndrome is a poorly defined but seriously handicapping behaviour disorder, probably of multiple aetiology. Various forms of treatment, especially
behaviour modification and stimulant medication, have been reported to be effective. It has also been suggested that food colorants and preservatives sometimes cause the hyperkinetic syndrome,2presumably by evoking an idiosyncratic response to their pharmacologically active constituents. However, results of double-blind, controlled trials to test this hypothesis have largely been negative,3-7 though individual8 patients may respond consistently to particular substances.8 A role for food allergy has also been postulated9, 10 but this has not been tested by appropriate trials. During a double-blind, controlled trial that showed that any combination of foods could cause migraine in children, we noted that many of the responders had also been overactive and that their overactivity usually improved with food avoidance, in some instances with avoidance of foods other than those causing migraine. 1We have therefore treated overactive children with an oligoantigenic diet (one containing few varieties of foods); in those who responded we identified provoking foods by re-introducing foods sequentially, then undertook a randomised, crossover, placebo-controlled trial of the effect of reintroduction of these foods on the development of overactivity and associated symptoms. Patients and Methods
Subjects Subjects were attending a special clinic set up to assess and treat by dietary means. The clinic was staffed by a paediatric neurologist (J. E.) and dietitian (C. M. C.). 76 children referred to this clinic were diagnosed on clinical assessment as having either the hyperkinetic syndromel2 or overactivity as a prominent feature of a more widespread behavioural disturbance. The diagnosis was based on a more than 1 year history of short attention span, distractability, and, especially in younger children. poorly organised overactivity. In addition, the children had to have a score of more than 14 (a score exceeded by only 2-5% of US S overactive children
*Present address: Haunersches
Kinderspital, Munich, West Germany.