Persistent Generalized Lymphadenopathy Research Articles

Diagnostic fine needle core biopsy of deep lymph nodes for the diagnosis of lymphoma in patients unfit for surgery.

The use of a technique for safe percutaneous fine needle biopsy of inaccessible lymph nodes is described. In a prospective study of 24 patients, including five cases positive for the human immunodeficiency virus (HIV), this technique was used to provide diagnostic material. A firm diagnosis was made in 21 cases; four cases of Hodgkin's disease, 14 non-Hodgkin's lymphomas, one case of Kaposi's sarcoma, one case of mycobacterial infection, and one which showed the features of persistent generalized lymphadenopathy (PGL). In the cases of lymphoma, available serial sections allowed characterization of the tumour with immunocytochemistry. In three cases, no diagnosis could be made, with one of these requiring a subsequent open biopsy. Percutaneous fine needle biospy is ideal for patients unfit or unsuitable for general anaesthesia or surgery. The biopsy obtained gives the pathologist sufficient tissue for an accurate diagnosis in the majority of cases. The preservation of architecture and multiple sections available are advantages over fine needle aspiration.

Polyamines in Lymphocytes from Patients infected by Human Immunodeficiency Virus

Lymphocytes from patients with antibodies against the AIDS associated human immuno-deficiency virus (HIV-1) have elevated concentrations of polyamines. Spermidine and spermine are similar in amount in patients with Persistent Generalized Lymphadenopathy (PGL) and overt AIDS, while putrescine is much higher in the latter. Spermidine-acetyltransferase activity is also increased in lymphocytes from patients with PGL. Diamine-oxidase activity is decreased in serum of patients with PGL, but not in those with AIDS.

Predictive Markers of AIDS: A Follow-up of Lymphocyte Subsets and HIV Serology in a Cohort of Patients with Lymphadenopathy

From 1982 to 1985, 89 HIV-1 seropositive men with persistent generalized lymphadenopathy (PGL) were enrolled into a prospective longitudinal study. In February 1988, after a mean observation time of 45 months, 23 patients had progressed to AIDS with opportunistic infection (AIDS/OI), 4 had developed Kaposi's sarcoma, 47 had developed HIV-related symptoms, 14 still had PGL as only symptom, and 1 was lost to follow-up. Patients with CD4 lymphocytes less than or equal to 0.40 x 10(9)/l as well as patients with HIV antigenaemia and those lacking antibodies to p24 all had a significantly higher risk of developing AIDS/OI within 30 months of observation than other patients. HIV antigen was present in 70% and antibodies to p24 were lacking in 61% of the patients at the time of AIDS/OI diagnosis. All but one (96%) of the AIDS/OI patients had CD4 numbers less than or equal to 0.20 x 10(9)/l at the same time. The estimated median time to AIDS/OI in patients with HIV antigenaemia was 21 months and in patients lacking p24 antibodies 27 months. In patients with CD4 numbers less than or equal to 0.20 and 0.40 x 10(9) cells/l the estimated median time to AIDS/OI was 14 months and longer than 30 months, respectively.

Dermatitis of the face, yellow toe nail changes, hairy leukoplakia and oral candidiasis are clinical indicators of progression to AIDS/opportunistic infection in patients with HIV infection.

In a prospective longitudinal study of 89 men with HIV infection and persistent generalized lymphadenopathy (PGL) we tried to find clinical signs predictive of development to AIDS/opportunistic infection (OI). The mean observation time was 47 months. 27 patients (30%) developed AIDS/OI after a mean of 37 months. The estimated median time from diagnosis of PGL to AIDS/OI was 68 months. Four clinical signs of progression towards AIDS/OI were identified: dermatitis of the face, yellow toe nail changes, hairy leukoplakia and oral candidiasis. One or more of these signs were recorded in 25/27 (93%) of the patients before the development of AIDS/OI. The estimated median time from registration of each sign to AIDS/OI was: dermatitis of the face, 29 months; yellow toe nail changes, 21 months; hairy leukoplakia, 18 months; and oral candidiasis, 10 months. The estimated median time from herpes zoster to AIDS was only slightly shorter than the estimated time from diagnosis of PGL to AIDS/OI.

The clinical prognosis of HIV-1 infection: a review of 32 follow-up studies.

Thirty-two follow-up studies of patients with HIV-1 infection, but without AIDS at baseline, were examined for information on the risk of developing AIDS or other conditions. Disease progression in asymptomatic groups was similar to that found in patients with persistent generalized lymphadenopathy (PGL) without other symptoms. Among these asymptomatic and PGL groups, the risk of developing AIDS reached 10% to 15% between 24 and 36 months of follow up. The risk of progression to AIDS continued to increase in the studies with longer follow-up periods, reaching 36% at 88 months. However, more than 40% of "high-risk" groups (characterized by the presence of constitutional symptoms, oral thrush, herpes zoster, and/or low T4 counts) developed AIDS after only 36 months of follow-up. Reliable information about progression to other states (e.g., AIDS-related complex) has not been consistently provided.

Impaired T-lymphocyte-dependent immune responses to microbial antigens in patients with HIV-1-associated persistent generalized lymphadenopathy.

T-cell mediated and humoral responses directed to microbial antigens were investigated, at the time of the initial visit, in a group of 139 patients with HIV-1-related persistent generalized lymphadenopathy (PGL) enrolled in a longitudinal study. In vivo and in vitro cell-mediated responses to tuberculin were lower in patients than in controls. Differences were not significant for candidin and streptococcal antigen in vitro, whereas higher responses were observed in the patient group for cytomegalovirus antigen. Following immunization, a subgroup of patients did not have a significantly raised serum antitetanus antibody level, whereas in vitro lymphocyte proliferative responses to tetanus toxoid were lower than in controls. No association was found between these abnormalities and other immunological parameters, including the blood level of CD4+ lymphocytes. Lower responses to most microbial antigens were observed in patients with HIV-1-related symptoms in addition to lymphadenopathy, or the patients who progressed to AIDS in the 2 years following the study. Moreover, intravenous drug users showed higher responses than homosexual patients, possibly because of the influence of previous infections on immunological responses to microbial antigens.

Immunohistochemical, electron microscopic and in situ hybridization evidence for the involvement of lymphatics in the spread of HIV-1.

To investigate the role of the lymphatic vessels and the sinus systems of the lymph node in the spread of HIV-1, we evaluated 15 lymph nodes from patients with persistent generalized lymphadenopathy (PGL). Fifteen lymph nodes taken from patients with follicular hyperplasia not related to HIV-1 infection served as controls. Immunohistochemical and in situ hybridization techniques revealed infected cells within the sinuses and the efferent lymphatics of the PGL lymph nodes. In contrast, infected cells could not be detected within the walls of the high endothelial venules nor in the areas immediately adjacent. The parenchymal side of the marginal sinus was lined by a discontinuous endothelium. Macrophages and lymphocytes were located within the gaps of this endothelium. More importantly, when the enlarged follicle extended as far as the wall of the marginal sinus, the processes of follicular dendritic cells could be seen extending through the gaps into the lumen of the sinus. This suggests that these cells could transport antigens (including HIV-1) from the sinuses directly to the germinal centers. In addition, HIV-1 particles within cytoplasmic vacuoles were seen in infected macrophages located in the submarginal zone. Positive cells were also found in the extrafollicular lymphoid parenchyma, especially in the area between the marginal sinus and the follicles. The observed distribution of the virus-positive cells within the PGL lymph nodes strongly implicates the lymphatic vessels in the spread of HIV-1 infection.

The ultrastructural and immunohistochemical demonstration of viral particles in lymph nodes from human immunodeficiency virus-related and non-human immunodeficiency virus-related lymphadenopathy syndromes.

Viral particles have been demonstrated by electron microscopy in lymph nodes from patients with acquired immune deficiency syndrome AIDS-related persistent generalized lymphadenopathy (PGL) syndrome. Immunohistochemical and in situ hybridization studies have identified these viruses as the human immunodeficiency virus (HIV). In this study, we examined 20 PGL lymph nodes and found viral particles in 18 cases. Immunohistochemical studies on these cases revealed positive staining for the HIV core protein P24 within germinal centers of secondary follicles. In addition we found viral particles, morphologically indistinguishable from those observed in PGL lymph nodes, in 13 of 15 non-HIV related reactive lymph nodes. Immunohistochemical staining of these lymph nodes for the P24 core protein was negative. None of the patients in this group had risk factors for developing AIDS and none exhibited clinical evidence of immune deficiency. We conclude that the viral particles observed in PGL lymph nodes are most likely HIV, but similar particles can be seen in reactive lymph nodes not associated with HIV infection. The discrete localization of these particles within germinal centers has been observed for other viruses and immune complexes and a possible mechanism of this antigen deposition is discussed.

HIV isolation from cerebrospinal fluid in relation to immunological deficiency and neurological symptoms.

Human immunodeficiency virus (HIV) could be isolated from the cerebrospinal fluid (CSF) of the majority (62%) of 72 patients in various stages of HIV infection. This high rate of successful virus isolation was achieved only when the time from lumbar puncture to initiation of the cell cultures was short, i.e. not exceeding 5 h. The HIV isolation rates were equally high in patients with persistent generalized lymphadenopathy (PGL), AIDS-related complex (ARC) and AIDS. Although the HIV recovery rate was low in patients with normal immunological parameters it was not correlated with the degree of severity of the immunodeficiency in the other patients. Furthermore, the recovery rates were not significantly correlated to the duration of the infection. HIV was recovered as often from patients with neurological symptoms as from patients without such symptoms. These findings suggest that in the majority of patients there is central nervous system (CNS) involvement early in the course of HIV infection and that HIV replication in the CNS may occur in the absence of a pronounced systemic cellular immunodeficiency and frequently without causing overt neurological symptoms.

Circulation of HIV antigen in blood according to stage of infection, risk group, age and geographic origin.

Human immunodeficiency virus antigen (HIV-ag) was determined by enzyme immunoassay (EIA) in HIV-antibody (anti-HIV) positive as well as pre-anti-HIV seroconversion sera and the results analysed according to stage of infection, risk group, age and geographic origin. Eleven (19%) of 58 homosexual men tested showed HIV-ag in a serum taken 3-4 months before or one at the time of anti-HIV seroconversion. In another eight (14%) HIV-ag persisted after seroconversion and half of them developed AIDS or AIDS-related complex (ARC) in contrast to none of the other 50 anti-HIV seroconversions. Two (13%) of 16 haemophiliacs tested had HIV-ag only in the first anti-HIV seropositive sample. HIV-ag was present in 86% (30/35) of Dutch homosexual men with AIDS, in 32% (7/22) of men with ARC and in 17% (24/145) of men with persistent generalized lymphadenopathy (PGL) or without symptoms. Three percent (2/60) of sera of asymptomatic i.v. drug users from Amsterdam were HIV-ag positive. Ten percent (1 of 10) of sera from Central Africans with 'Slim Disease' were HIV-ag positive. Among infected children from the USA or Europe 89-100% (8/9 and 2/2) of AIDS cases, 67-100% (6/9 and 3/3) of children with ARC and 75% (3/4) of asymptomatic children were HIV-ag positive. The HIV-ag EIA appears to be able to identify HIV infection earlier than the available anti-HIV assays in a significant number of cases. Since persistence of HIV-ag, except possibly in African cases, is strongly associated with clinical deterioration, HIV-ag appears to be a suitable marker for, independent of their clinical status, selecting individuals for antiviral therapy and also for monitoring the efficiency of such therapy.

Human immunodeficiency virus (HIV) seropositivity in intravenous (i.v.) drug abusers in three cities of Italy: possible natural history of HIV infection in i.v. drug addicts in Italy.

The prevalence of human immunodeficiency virus (HIV) antibodies and the symptoms induced [persistent generalized lymphadenopathy (PGL), AIDS-related complex (ARC), acquired immunodeficiency syndrome (AIDS)] was evaluated in several groups of intravenous (IV) drug abusers in three large Italian cities (Milan, Bologna, and Rome). The earliest evidence of seropositivity in sera collected from patients with acute viral hepatitis dates back to 1979 in Milan and to 1981 in Bologna with peaks in 1983 in both cities. In two groups of IV drug addicts on methadone-maintenance treatment at assistance centers, the prevalence of seropositivity differed sharply between Rome (33.3%) and Milan (69.3%) in 1985. Rates of seroconversion were also found to be higher in Milan than in Bologna and Rome. When a population of IV drug abusers voluntarily attending centers for surveillance of AIDS and/or ARC were investigated, high levels (range 55.2-81.5%) of seropositivity were found in the three cities. ARC prevalence among seropositives was very high (range 48.1-64.2% in 1985) in the three cities. The evolution rate to AIDS in Milan was higher among those attending a center for AIDS surveillance (7.4%) than among those attending an assistance center for methadone treatment (0.9%). These data are compatible with the hypothesis that virus infection among IV drug abusers originated in and then spread widely in Northern Italy (Milan first and then Bologna). Both the first appearance and subsequent spread of virus infection are in keeping with the reported occurrence of AIDS cases in the corresponding three regions of Milan, Bologna, and Rome.

Progressive histopathologic abnormalities in the persistent generalized lymphadenopathy syndrome.

Using a quantitative classification, we evaluated serial lymph node biopsies in 20 homosexual men with Persistent Generalized Lymphadenopathy (PGL), and correlated the results with peripheral blood lymphocyte counts and clinical findings. In a median follow-up interval of 19 months, ten patients (50%) had progression from one histologic subtype of this disorder to another. Lymph nodes from the other 10 patients also demonstrated decreased numbers of organized follicles in the most recent specimens, in addition to progressive abnormalities of other histologic parameters and peripheral blood T4 counts. This suggests that these patients do not have stable disease. However, in a median follow-up interval of 19 months, only one (5%) of the patients had developed AIDS. We conclude that progressive lymph node histopathologic subtypes do not correlate well with decreased T4 lymphocyte counts or clinical course over a short time interval.

Ophthalmic findings in a group of ambulatory patients infected by human immunodeficiency virus (HIV): a prospective study.

Twenty-eight patients with either the acquired immune deficiency syndrome (AIDS) or persistent generalised lymphadenopathy (PGL) were studied prospectively as outpatients for up to one year. Six patients had fundal cotton wool spots at some stage of their follow-up and all six suffered opportunistic infections associated with AIDS. We suggest that ocular abnormalities may be prognostic for opportunistic infection in AIDS and discuss the wide range of ophthalmic complications consequent to HIV infection.

Immunohistology of persistent generalized lymphadenopathy. Evidence for progressive lymph node abnormalities in some patients.

Immunohistologic analysis of cellular changes in serial lymph node biopsies of eight patients with persistent generalized lymphadenopathy (PGL) syndrome was performed and correlated with clinical and laboratory findings to better determine the natural history of human immunodeficiency virus (HIV) infection. The authors observed decreased follicle size and area in the second biopsies of six of the eight patients, associated in some with increased numbers of B-cells in medullary regions (four of eight) and more involuted follicles (four of eight). Five cases showed progressively increased paracortical areas in the second biopsies, with increased numbers of T-cytotoxic/suppressor cells and decreased T-helper cells. Seven of the patients also had a progressive loss of T-helper cells in the peripheral blood. These findings provide tissue and peripheral blood evidence for progressive immunologic deterioration in some patients with PGL.

Acquired immunodeficiency syndrome (AIDS). II. Clinical aspects with special reference to neuropsychiatric manifestations

Opportunistic infections and neoplasias, which led to the identification and characterisation of AIDS, are the most common manifestations of this disease. The present review gives a comprehensive presentation of the current knowledge on the opportunistic infectious agents concerned and on the resulting clinical pictures with special emphasis on neuropsychiatric symptomatology. Prior to the development of the full syndrome of AIDS, a number of intermediate steps can be observed, the most important of which is persistent generalised lymphadenopathy (PGL). For all stages of the disease, problems of clinical course, risk of transmission, and prognosis are discussed in detail. Neuropsychiatric manifestations of AIDS can occur as sequelae of opportunistic infections, AIDS-associated neoplastic processes or of the retrovirus infection itself. In a number of cases neuropsychiatric manifestations are the presenting symptoms of the disease. Since neuropsychiatric symptoms such as organic brain syndrome or dementia represent crucial determinants of prognosis, they have to be considered in the planning of long-term care for the AIDS patient. Due to certain epidemiological features such as an exponential increase of its incidence during the last few years and the preferential occurrence in homosexuals and drug addicts, AIDS has brought about a number of important psychosocial effects. Since an efficient chemotherapy is not yet available and long-term prognosis is poor, AIDS patients often become isolated, and even medical professionals avoid to have contact with them. To reduce an exaggerated fear of being infected by the AIDS virus and to gain the competence for realistic assessment of the remaining risks, it is necessary to acquire a profound knowledge of the disease.

HISTOPATHOLOGY AND IMMUNOHISTOLOGY OF HTLV‐III/LAV RELATED LYMPHADENOPATHY AND AIDS.

Fifty-nine lymph node biopsies from homosexual men with serum antibodies to HTLV-III/LAV were the subject of a detailed histopathological and immunohistochemical study. The histological findings were correlated to the patients clinical status, and the T4/T8 ratios in blood and lymph nodes. Four histological patterns predominated and were defined as follicular hyperplasia (FH), follicular fragmentation (FF), follicular atrophy (FA), and follicular depletion (FD). Immunocytochemical studies indicated that destruction of follicular dendritic cells is related to the initiation of follicular involution from FH to FF, but the possible role of follicular infiltrating T-cells cannot be excluded. Marked individual variations in lymph node angiogenesis increasing during involution were observed, which suggests that the degree of angiogenic host response may predispose for evolution of Kaposi's sarcoma. The majority of the patients with the clinical diagnosis of persistent generalized lymphadenopathy (PGL) were morphologically staged as FH or FF (89%), whereas most of the AIDS patients showed lymph node changes compatible with FA and FD (89%). Patients with AIDS-related complex (ARC) had a wider spectrum of morphological lymph node changes but a majority of cases (62%) were also classified as FA or FD. Clinical follow-up showed progression from PGL to ARC in seven of 21 cases with the FF pattern and only in three of 19 cases with FH, indicating a possible prognostic value in differentiating between FH and FF. Three cases with FD and one with FA progressed to AIDS during the time of observation. T4/T8 ratios in blood and lymph nodes were significantly lower in patients with FD histology compared to patients of the other histological groups. At autopsy, all AIDS cases showed the FD pattern of lymphadenopathy. Autopsy findings in seven patients emphasized the importance of post-mortem studies in clarifying the spectrum of opportunistic diseases, including tumors which afflict the AIDS patients.

Human immunodeficiency virus (HIV) infection in the regular sexual partners of homosexual men with AIDS and persistent generalised lymphadenopathy.

Thirty-five homosexual men who had been the regular sexual partners (for at least 6 months) of anti-HIV-positive patients with AIDS (N = 18) or PGL (N = 17) were studied. Twenty-one (60%) were seropositive, but 14 (40%) were consistently anti-HIV-negative. The duration of relationship with the index case was not statistically different in seropositive compared to seronegative partners; median 26 months (range 7-60) vs 30 months (range 7-60). However, seropositive partners had a significantly higher monthly number of other sexual partners and sexually transmitted diseases and a higher frequency of insertive and receptive anal intercourse in the preceding five years. The risk of acquiring HIV infection was significantly increased by frequent receptive anal intercourse when the frequency of insertive was controlled for but not the converse. Seronegative partners had undetectable antibodies by live and fixed cell immunofluorescence and by radioimmunoprecipitation and were repeatedly negative by competitive enzyme immunoassay. Furthermore, the sera of seronegative partners lacked HIV neutralising activity. Peripheral blood mononuclear cells (PBMCs) from seronegative partners, stained with monoclonal antibodies to seven different CD4 epitopes, revealed no differences when compared to those from heterosexual controls and no qualitative differences from cells from seropositive individuals. In addition, PBMCs from seronegative partners could be productively infected by HIV in vitro. If resistance to infection in seronegative partners exists, then it is likely that mechanisms other than a specific humoral immunity or CD4 polymorphisms are involved.

Characterization of immunologic function in homosexual men with persistent, generalized lymphadenopathy and acquired immune deficiency Syndrome

A syndrome of persistent, generalized lymphadenopathy (PGL), related to the acquired immune deficiency syndrome (AIDS), has been described in homosexual men. To further characterize and correlate the immunologic status of patients with PGL with those in AIDS, we studied spontaneous and pokeweed mitogen (PWM)-induced IgG synthesis by B-cells, T-cell subsets in peripheral blood (PB), natural cytotoxicity (NC), and Interleukins (IL)-1 and IL-2 production in 39 homosexual patients (21 PGL; 13 AIDS; five asymptomatic homosexual men), in whom 32 of 35 tested (91%) had antibodies to human T-lymphotropic virus-III (HTLV-III). A profound abnormality in B-cell function was found in AIDS and PGL, consisting of high spontaneous IgG production, with paradoxic suppression of IgG synthesis after PWM. IL-2 values were more often low in AIDS when compared with PGL (P less than 0.001). The PB lymphocyte count was normal in PGL and reduced in AIDS (P less than 0.001). OKT4 "helper" cells were decreased in PGL, but even lower in AIDS (P less than 0.001), while OKT8 "cytotoxic/suppressor" cells were normal in AIDS and increased in PGL (P less than 0.01). The T4:T8 ratio was reversed in both, but more abnormal in AIDS (P less than 0.001). A decrease in NC killing was observed in AIDS when compared with heterosexual controls. Thus, patients with PGL and AIDS both demonstrate a spectrum of immunologic dysfunction, involving the cellular and humoral arms of the immune system.

Relationship between antibody to LAV/HTLV-III and the natural course of subclinical cellular immune dysfunction in homosexual men.

To assess the epidemiology and natural history of persistent generalized lymphadenopathy (PGL) and subclinical immunodeficiency in relation to serologic evidence of lymphadenopathy-associated virus/human T-lymphotropic virus type III (LAV/HTLV-III) infection, 109 homosexual men with PGL, 47 homosexual men without lymphadenopathy who attended a sexually transmitted disease (STD) clinic, 25 homosexual male university students, and 26 heterosexual men who attended the STD clinic were studied. In 1982-1983 antibody to LAV/HTLV-III was present in 97%, 35%, 21%, and 4% of the four groups, respectively (P less than .001). Subclinical immunodeficiency was more closely associated with LAV/HTLV-III seropositivity than with lymphadenopathy. Cohorts of 78 homosexual subjects with PGL, 35 homosexual subjects from STD clinic, and 15 homosexual university students were followed for median periods of 13.5, 20, and 14.5 months, respectively. The seroconversion rate was 23% per year among seronegative subjects, and 4% of seropositive subjects developed overt acquired immunodeficiency syndrome (AIDS). Among seronegative subjects, there was significant improvement in T4:T8 ratios (P = .001), whereas most seropositive subjects continued to have subnormal total counts of T4 lymphocytes and low T4:T8 ratios. Some cases of subclinical cellular immunodeficiency apparently are unrelated to LAV/HTLV-III infection, and the presence of antibody to this virus is associated with an unfavorable immunologic prognosis.

HLA‐A, B and DR antigen frequencies in patients with AIDS‐related persistent generalized lymphadenopathy (PGL) and thrombocytopenia

HLA-A, B, DR phenotype frequencies were studied in 69 homosexual patients with persistent generalized lymphadenopathy (PGL), in 8 patients with LAV/HTLV III related thrombocytopenic purpura and in 21 homosexual controls. Antigen DR5 was significantly increased in PGL patient groups as compared to controls. Our findings suggest that genetic factors associated with HLA-DR5 antigen may predispose individuals infected by the LAV/HTLV III virus to the occurrence of PGL and/or thrombocytopenia.