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alized lymphadenopathy in homosexual men without opportunistic infections or .... tion, and mediastinal lymphadenopathy was assessed on chest x-ray films.
Persistent generalized lymphadenopathy in homosexual men: clinical, pathological and immunologic characteristics NORBERT J. GILMORE,* PH D, MD JAROSLAV F. PRCHAL,t MD SERGE JOTHY4 MD. PH D

Eighteen homosexual men who had had lymphadenopa- des lymphocytes B circulants etajent normaux chez les thy in two or more extrainguinal sites for more than 5 deux groupes. Sept pieces de biopsie sur neuf des months but had no evidence of other illnesses or infec- ganglions lymphatiques montrajent une hyperplasie cations were studied. All had extreme malaise, and 90 % ract&istique et une confluence des follicules. En conhad additional symptoms (fever, night sweats, weight loss sequence, chez les homosexuels exempts d'infections or gastrointestinal dysfunction). They were compared opportunistes ou de maladies malignes, une lymphadenowith 10 healthy homosexual and 10 healthy heterosexual pathie idiopathique persistante et g.n&alis.e semble .tre male controls. The mean numbers of circulating T8 un syndrome distinct; il pourrait .tre reli. au syndrome (suppressor) lymphocytes were increased equally in the d'immunodeficience acquise. two homosexual groups, but the mean number of T4 (helper) lymphocytes was decreased only in the group Recently the Centers for Disease Control' in Atlanta, with lymphadenopathy. The response to testing for recall Georgia reported a new illness, in which generalized anergy was diminished in both homosexual groups but lymphadenopathy develops in previously healthy homowas significantly lower in the group with lymphadenopa- sexual men. The lymphadenopathy is usually accompathy. The serum immunoglobulin and complement concen- ,nied by a constellation of symptoms: extreme malaise, trations and the numbers of circulating B lymphocytes low-grade fevers, night sweats, weight loss and illwere normal in each group. Seven of nine lymph node defined gastrointestinal dysfunction, such as intermitbiopsy specimens showed characteristic hyperplasia and tent diarrhea, cramps or bloating. These symptoms and confluence of follicles. Thus, idiopathic persistent, gener- the lymphadenopathy appear to persist for months and alized lymphadenopathy in homosexual men without sometimes years. Biopsies of lymph nodes have shown opportunistic infections or malignant diseases appears to only reactive hyperplasia. Immunologic assessment in be a distinct syndrome; it may also be related to the some of the cases has demonstrated abnormalities in the size of the subpopulations of circulating T lymphocytes, acquired immune deficiency syndrome. impaired T-lymphocyte function as assessed by mitogenDix-huit homosexuels qui etaient porteurs de lympha- stimulated blastogenesis, and anergy.' 2 The cause of this d.nopathies dans deux foyers extra-inguinaux ou plus illness is unknown; many of its features resemble those depuis plus de 5 mois et qui n'avaient aucune autre of another recently described illness of unknown origin. maladie ou infection d.montr.e ont &t& .tudi.s. Tous the acquired immune deficiency syndrome (AIDS),38 souffraient d'extr.me malaise, et 90% pr.sentaient des which suggests that they may be related. We report the symptbmes additionnels (fi.vre, sueurs nocturnes, perte baseline results of a prospective study of the clinical, de poids ou probl.me gastro-intestinaux). Ils out . pathological and immunologic features of this illness, a compares . 10 homosexuels sains et . 10 t.moins syndrome of persistent lymphadenopathy in homosexual h.t&osexuels sains. Le nombre moyen des lymphocytes men. T8 (suppresseurs) circulants .tait egalement augmente parmi les deux groupes d'homosexuels, mais seuls ceux Methods qui avaient des lymphad.nopathies montraient une baisse du nombre moyen des lymphocytes T4 (auxiliaires) Subjects circulants. La r.ponse aux tests d'anergie .tait r.duite Thirty-eight volunteers were studied, including 18 chez les deux groupes d'homosexuels, mais elle ne l'.tait de fa.on significative que dans le groupe ayant des homosexual men with idiopathic generalized lymlymphadenopathies. Les concentrations s&iques des im- phadenopathy, 10 apparently healthy homosexual men munoglobulines et du complement ainsi que le d.compte and 10 apparently healthy heterosexual men. All were Caucasian, had been living in North America for the past 10 years, were sexually active and claimed exclu From the divisions of *clinical immunology and thematology. sive sexual behaviour. All laboratory testing was done department of medicine and tthe department of pathology. Royal with coded material, and anergy testing was done by Victoria Hospital and McGill University, Montreal who did not know the sexual orientation of the staff Reprint requests to: Dr. Norbert J. Gilmore, Rm. M 1122. Division control groups. of clinical immunology. Royal Victoria Hospital. 687 Pine Ave. W. Twenty-nine consecutive homosexual men had been Montreal. PQ H3A IAI 960

CAN MED ASSOC J, VOL. 129, NOVEMBER 1, 1983

referred for evaluation of lymphadenopathy. For entry into this study, subjects had to have had lymphadenopathy in at least two noncontiguous extrainguinal areas for more than 5 months, as documented by a physician. All were evaluated to exclude recognized causes of generalized lymphadenopathy and other illnesses that might confound the results. Other reasons for exclusion were the following: evidence of active hepatocellular disease; bacterial infections treated within the previous 2 months or evidence of persisting illness from such infections (e.g., gonorrhea or syphilis); serologic evidence of active herpes simplex, toxoplasmosis or syphilis; immunization within the previous 60 days; presence of atypical mononuclear cells on a blood smear; topical or systemic use of corticosteroids within the previous 5 years; use of metronidazole within the previous 60 days; current use of any prescription medication; intravenous drug abuse; or recent travel to the tropics or developing countries. Eleven of the 29 potential subjects were excluded from the study for the following reasons, with the number of subjects in parenthesis: active hepatitis (2), secondary syphilis (2), probable Guillain-Barr. syndrome (1), Bowen's disease of the rectum (1), hairy cell leukemia (1), Hodgkin's disease (I), viral exanthem (1), chronic infectious mononucleosis (1) and acute herpangina (1). The remaining 18 homosexual men with idiopathic lymphadenopathy ranged in age from 23 to 41 years, the mean age ± one standard deviation (SD) being 29 ± 5 years. In each of these men we tested for rheumatoid factor by latex agglutination, antinuclear antibodies by chrythidia assay, syphilis by the VDRL test, hepatitis B surface antigen and surface and core antibodies by radioimmunoassay, cytomegalovirus antibodies (acute and convalescent titres) by complement fixation, Toxoplasma antibodies by indirect hemagglutination and heterophil antibodies by the Paul-Bunnell test. Nine patients agreed to excisional lymph node biopsy, and the specimens were subjected to routine histopathological analyses. The 10 healthy homosexual men forming one of the two control groups had no evidence of adenopathy and were asymptomatic. Their ages ranged from 24 to 42 years, with a mean ± SD of 34 + 5 years. All denied any of the exclusion criteria. Ten healthy heterosexual men were also studied as controls. Their ages ranged from 26 to 42 years, with a mean ± SD of 35 ± 5 years. All denied any of the exclusion criteria. Assessment of adenopathy Adenopathy was graded from the number of noncontiguous anatomic sites in which lymph nodes with a diameter greater than 0.5 cm were present. These sites included the left and right sides of the neck, the axillae, and the epitrochlear and inguinal areas. The extent of the adenopathy was expressed as the sum of the areas involved. Epitrochlear adenopathy was not found in any individual, so the maximum score was 6. The number of nodes larger than 3 cm in any dimension were also noted. Splenomegaly was assessed by clinical examination, and mediastinal lymphadenopathy was assessed on chest x-ray films.

Skin testing for delayed hypersensitivity (recall anergy) All of the subjects were skin tested with six antigens derived from the following killed organisms or inactivated viruses: Candida (Dermatophytin-O, 1:100 v/v; Hollister Stier, Rexdale, Ont.) and Trichophyton (Trichophyton mix 5285, 1000 protein nitrogen units/ml; Hollister Stier); mumps antigen, undiluted (Eli Lilly & Co., Scarborough, Ont.); streptokinase/streptodornase (Vandase for local use, 100 U SK/ml, 25 U SD/ml; Lederle products department, Cyanamid Canada Inc., Montreal); tetanus toxoid (10 Lf U/ml; Institut Armand-Frappier, Laval-des-Rapides, PQ); and PPD (tuberculin purified protein derivative, 5 TU/ml; Connaught Laboratories Ltd., Willowdale, Ont.). We injected 0.1 ml of each reagent intradermally into the volar skin of the forearm and measured the resulting induration in two dimensions at 24 and 48 hours. The results were expressed in three ways: as the area of induration in square millimetres at 48 hours, as the number of antigens eliciting an area of induration greater than 5 mm in diameter at 48 hours, and as a delayed-type hypersensitivity (DTH) score, obtained by the method of Morris and associates.9 In this method the diameter of an area of induration is assigned a value of zero if less than 5 mm, 1 ifS to 14 mm, 2 if 15 to 24 mm and 3 if greater than 25 mm. The values for the six antigens tested are then summed. The maximum sum possible is 18. Immunologic analyses In all the subjects the numbers of leukocytes and lymphocytes in the peripheral blood were quantitated by Hemalog-6000. In addition, blood smears were examined for cellular abnormalities, especially atypical mononuclear cells. I ymphocytes were isolated from h.parinized blood samples by buoyant density centrifugation with Ficoll-Hypaque (Pharmacia [Canada] Inc., Dorval, PQ). B lymphocytes were quantitated by immunofluorescence microscopy with fluorescein-conj ugated goat F(ab')2 anti-human IgG-A-M antibody (Cappel Laboratories, West Chester, Pennsylvania). T rosettes were quantitated by allowing isolated lymphocytes to react with sheep erythrocytes overnight at 40C and counting the rosettes containing more than three erythrocytes per mononuclear cell. T lymphocytes bearing the T3 ("pan-T") antigen were counted by direct immunofluorescence microscopy with the aid of the monoclonal OKT3 antibody (Ortho Pharmaceutical [Canada] Ltd., Don Mills, Ont.). T-lymphocyte subsets were counted in a similar manner with the use of monoclonal OKT4 (helper) and OKT8 (suppressor) antibodies. The levels of serum immunoglobulins (IgG, IgA and 1gM) and the concentrations of the third and fourth components of complement (C3 and C4) were quantitated by nephelometry (Hyland Division of Travenol Laboratories, Inc., Costa Mesa, California). Statistical analyses We have expressed the results as means ± one SD unless otherwise noted. We used analysis of variance and, when appropriate, the t-test with the Bonferroni CAN MED ASSOC J, VOL. 129, NOVEMBER 1, 1983

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Table I-Clinical characteristics of the persistent lymphadenopathy syndrome in 18 homosexual men Characteristic* Adenopathy Duration (mo) Anatomic areas affected (no.) Lymph node > 3 cm in diameter

Mean . standard deviation (SD) or no. of patients (and %) 10.6 . 8.2 4.7. . 1.2 9/18 Fever 12/18

(50) (67)

Duration (mo) 5.3 . 2.1 Night sweats 10/18 (56) Duration (mo) 6.5 . 3.7 Weight loss 11/18 (61) Amount lost (kg) 5.1 ± 3.3 Gastrointestinal complaints 11 / 18 (61) History of amebic infection 6/11 (55) Respiratory complaints 0/18 (0) Rashes 2/18 (11) Drug abuse Nitrites 11/18 (61) Marihuana 9/18 (50) Cocaine 2/18 (11) *Adenopathy: included only lymph nodes larger than 0.5 cm in diameter. Weight loss: unexplained and in excess of 2 kg. Gastrointestinal complaints: included intermittent diarrhea, cramps and bloating. Respiratory complaints: persistent dyspnea or cough. Rashes: had lasted about 2 months, were diagnosed as idiopathic leukocytoclastic vasculitis, and had resolved spontaneously more than 3 months before the subject entered the study. Drug abuse was recorded here if the listed drugs were used at least once per week.

The mean numbers of leukocytes and lymphocytes in the blood did not differ among the three groups. For the lymphadenopathy group the mean counts were 5.6 . 1.3 and 2.1 + 0.5 >< 10./l respectively. No atypical lymphocytes were seen in blood smears. The B-lymphocyte counts also did not differ significantly between the three groups, whether the results were expressed as proportions of the circulating lymphocytes or as the absolute numbers of B lymphocytes per litre of blood. The mean numbers of T-rosette-forming lymphocytes and of lymphocytes bearing the T3 antigen (total T lymphocytes in blood), whether expressed as a proportion of lymphocytes in blood or the absolute number of these cells in blood, were the same for each of the three groups. The size of the T-lymphocyte subpopulations, however, differed (Table III). The lymphadenopathy group had a significantly lower mean number (p < 0.001) of circulating T4 (helper) lymphocytes than either of the control groups, which did not differ from each other. The mean numbers of circulating T8 (suppressor) lymphocytes for the two homosexual groups were similar, and each significantly exceeded the mean for the heterosexual controls. Thus, the numbers of circulating T8 lymphocytes were similarly increased in the two homosexual groups, but only the lymphadenopathy group had a decreased mean number of circulating T4 lymphocytes. None of the 18 men with lymphadenopathy and only 2 of the healthy homosexual men had proportions of T4 lymphocytes within the 95% confidence limits for the heterosexual control group (greater than 50%), but 3 of those with lymphadenopa-

thy and 7 healthy homosexual men had absolute numbers of T4 lymphocytes within the 95% confidence limits for the heterosexual controls (greater than 0.754 X 10'/1). Three men with lymphadenopathy and four healthy homosexual controls had proportions of T8 lymphocytes that were within the 95% confidence limits for the heterosexual controls (less than 28%). Six men with lymphadenopathy and seven homosexual controls had absolute numbers of T8 lymphocytes within the 95% confidence limits for the heterosexual controls (less than 0.655 X 10'/1). With respect to the ratio of T4 and T8 lymphocytes, the three groups differed significantly. None of the individuals with lymphadenopathy and only two of the healthy homosexual men had ratios within the 95% confidence limits for the heterosexual controls (2.0 to 3.0). Six individuals in the lymphadenopathy group had serum IgG concentrations in excess of 2000 mg/dl, but the mean concentrations of serum IgG, IgA and 1gM and of the complement components C3 and C4 did not differ between the 'three groups. All individuals with hypergammaglobulinemia had polyclonal increases in immunoglobulin levels. Discussion Persistent generalized lymphadenopathy in previously healthy homosexual men appears to be a distinct syndrome of unknown etiologic origin. All of the lymphadenopathy patients referred for evaluation were carefully screened to avoid including in the study individuals who could have had other illnesses or recent

Table Il-Delayed-type hypersensitivity (DTH; recall anergy) responses in the study groups Results of skin testing* (mean ± SD) Total area No. of antigens yielding of induration (mm2)t DTH score response> 5 mm in diameter Study group (no.) Homosexual men 100 ± 48 3.9 ± 2.7 2.2 ± 1.4 with lymphadenopathy (18) 256 ± 36 5.7 ± 2.3 3.6 ± 1.0 Homosexual controls (10) 561 ± 82 8.7 ± 3.7 4.1 ± 1.3 Heterosexual controls (10) *Six antigens were injected intradermally. The DTH score was the sum of values assigned for specified ranges of diameters of the indurated areas.' The means for each variable differ significantly (p