Macrophage-mediated destruction of human malignant cells in vivo.

Macrophages require a plasma component, designated "recognition factor" (RF), for the expression of optimal function. The RF activity was profoundly depleted in plasma from patients with malignant disease, and the degree of depletion and the severity of the malignant state seemed to be related. Since experiments demonstrated that an active RF significantly inhibited tumor growth, clinical studies were initiated to investigate the influence of intratumor administration of an active RF fraction. Glucan, a potent macrophage activator, was also employed alone or combined with RF. These studies were undertaken to enhance the recognition of malignant cells by macrophages and to mobilize and activate macrophages intralesionally. The initial 9 patients studied had malignant melanoma, adenosquamous carcinoma of the lung, or carcinoma of the breast. Control and experimental lesions were injected; subsequently biopsies were performed at varying intervals for histologic evaluation. Always when glucan or glucan and RF fraction were administered intralesionally, the size of the lesion was strikingly reduced in as short a period as 5 days. This reduction was associated with necrosis of the tumor and a monocytic infiltrate. In small lesions, resolution was complete, whereas in large lesions, resolution was partial. The amount of glucan injected and the quantity of residual tumor appeared to be related. The induced necrosis of the tumor nodule was associated with an increase in plasma levels of circulating RF activity.

Delayed hypersensitivity to 5-fluorouracil following topical chemotherapy of cutaneous cancers.

Skin tests to various common antigens, dinitrochlorobenzene, and 5-fluorouracil (5-FU) were performed on patients being treated for cutaneous neoplasms with topical 5-FU cream. Eleven of 15 patients tested both before and after therapy converted from skin test negative to positive with respect to 5-FU. This conversion correlated with positive dinitrochlorobenzene skin tests and therapeutic cure. The relation between the induction of delayed hypersensitivity reactions to 5-FU following treatment with topical 5-FU and the cure rate for cutaneous neoplasms showed a trend toward correlation.

Immunological characterizations of patients with acquired immune deficiency syndrome, acquired immune deficiency syndrome-related symptom complex, and a related life-style.

Immunological, hematological, and biochemical studies were done at the time of referral in 135 homosexual subjects, 28 of whom were symptom free (SF), 74 of whom had the acquired immune deficiency syndrome (AIDS)-related symptom complex (ARC), and 33 of whom had AIDS with Kaposi's sarcoma, opportunistic infection, or both. Of 38 laboratory parameters, 11 were significantly different than controls in the SF patients, 19 in the ARC patients, and 20 in the AIDS patients. In SF patients, delayed hypersensitivity was significantly suppressed for 6 of 12 recall antigens. In addition, the percentage of circulating lymphocytes, the percentage of T3+ cells, the percentage and absolute number of T4+ cells, the T4/T8 ratio, the blastogenic responses to phytohemagglutinin, pokeweed mitogen, and concanavalin A were depressed significantly in this group. In contrast, the percentage and absolute granulocyte count, the serum lysozyme, and the serum thymosin alpha 1 were significantly elevated in these patients. In patients with more advanced disease (ARC and AIDS), immunological and hematological parameters tended to worsen. Thus, in the AIDS patients the white blood cell count, percentage, and absolute T11+ cells, absolute T3+ cells, percentage of T4+ cells and absolute level of B-cells, as well as the monocyte adherence and delayed hypersensitivity responses to 12 of 12 recall antigens were depressed. Serum levels of thymosin alpha 1 were equally elevated in all three groups. Serum interferon was found in 15 of 18 opportunistic infection patients with or without Kaposi's sarcoma, in 3 of 9 Kaposi's sarcoma patients without opportunistic infection, but in none of the ARC or SF patients. This study has demonstrated that SF sexually active homosexuals have a characteristic pattern of immune deficiency and that immunodeficiency worsens as one compares SF to ARC to AIDS patients. The study has provided a data base for the development of prognostic criteria and for characterization and evaluation of immunorestorative and immunomodulatory therapy.

Impaired in vitro interferon, blastogenic, and natural killer cell responses to viral stimulation in acquired immune deficiency syndrome.

The in vitro immune response to herpes simplex virus (HSV), type 1, strain 539, HSV type 2, strain 316D, and cytomegalovirus was studied in 20 patients (14 with acquired immune deficiency syndrome, four with the acquired immune deficiency syndrome-related symptom complex, and two sexually active asymptomatic homosexuals) and 18 heterosexual healthy controls. Peripheral blood mononuclear cells were cultured with 2 X 10(5) plaque-forming units of heat-inactivated viruses, their lymphocyte blastogenic responses were measured after 5 days in culture by [3H]-thymidine incorporation, their interferon production was measured after 24 hr and 5 days, and natural killer (NK) cell activation was measured after 24 hr and 5 days of culture. Blastogenic responses to viruses were significantly low for only HSV, type 1:1.75 X 10(3) cpm in patients' cells compared to 6.36 for controls. Interferon responses to all three viruses were significantly low at both 24 hr and 5 days; e.g., HSV, type 1:139 IU/ml in patients' cells compared to 777 for controls at 24 hr. NK cell responses of patients were lower than those of controls when tested fresh and after 24 hr of incubation: 6.1 versus 11.7% and 9.2 versus 16.8% target cell lysis, respectively. Exposure to viruses boosted NK cell responses of both patients' and controls' cells, but boosting was generally greater among the normal rather than the patients' cells. The abnormalities of response were present in all three patient groups. Addition of interleukin-2 in vitro increased the patient and control blastogenic and NK responses but did not augment the interferon responses. The in vitro responses to both HSV, type 1, and HSV, type 2, correlated significantly with our conventional assays of the percentage and absolute level of T4+-helper lymphocytes in the blood and the blastogenic responses to mitogens, such as phytohemagglutinin, pokeweed mitogen, and concanavalin A. This system should be useful for the study of host defense in acquired immune deficiency syndrome patients and those in high-risk groups, and also for the in vitro evaluation of immunomodulators.

Pharmacokinetics of recombinant interleukin 2 in humans.

This report summarizes the pharmacokinetics in humans of recombinant interleukin 2 (IL-2) given as an i.v. bolus, i.v. or i.p. infusion, and i.m. or s.c. injection. Immediately after an i.v. bolus the serum IL-2 level equals the dose divided by the plasma volume, in a typical human 650 units/ml for a dose of 10(6) units/m2. The level initially decreases with a half-life of 12.9 min, followed by a slower phase with a half-life of 85 min out to 4 h after the bolus. The median steady state level during an i.v. infusion of 10(6) units/m2 over 6 h is 41 units/ml. A clearance rate of approximately 120 ml/min is obtained from either the i.v. bolus or infusion data and is consistent with the renal filtration being the major route of clearance. Serum levels remain fairly constant for about 8 h after s.c. or i.m. injection but are approximately 2% of the level seen immediately after an i.v. bolus. The area under the time-concentration curve suggests that about 30% of the IL-2 activity is transported from the site of an i.m. injection to the blood. After i.p. infusion IL-2 is only slowly transported to the blood. The median serum IL-2 levels are 430-fold lower than levels in the i.p. fluid and decrease with a median half-life of 6.3 h.

Immunological characterization of homosexual males.

To help clarify the nature and pathogenesis of the syndrome of severely opportunistic infection associated with immune deficiency in young homosexual males, we investigated the immunological characteristics of a group of 33 young homosexual men. These young men all had the prodrome to the syndrome which included a history of multiple sexual partners and multiple sexually transmitted diseases. In addition, they all had a past history of mild to moderate viral, bacterial, parasitic, or fungal infections and had used recreational drugs. Within this group of patients, there were five men who had Kaposi's sarcoma. Compared to the 21 normal heterosexual individuals, the homosexual men were found to be anergic to a battery of recall antigens (52% versus 19%); to be hyporesponsive to mitogen stimulation (pokeweed, 30.7 x 10(-3) versus 65.3 x 10(-3) cpm, p less than or equal to 0.005; concanavalin A, 32.2 x 10(-3) versus 60.1 x 10(-3) cpm, p less than or equal to 0.006); and to have lower helper T-cells (18% versus 34.6%, p less than or equal to 0.01), inverted helper:suppressor T-cell ratios (0.85 versus 1.92, p less than or equal to 0.01), and an elevated serum thymosin alpha 1 level (1473 versus 524 pg/ml, p less than or equal to 0.001). These data suggest that the immunological defect precedes the syndrome. The mechanism of this phenomenon is unclear; however, the repeated viral infection combined with drug usage may be responsible. The five patients with Kaposi's sarcoma were compared as a group to the other patients without cancer and found to be more severely immunodeficient. This suggests that the immune suppression by the malignant disease is superimposed on the preexisting deficiency.

Treatment of acquired immunodeficiency syndrome--related Kaposi's sarcoma with lymphoblastoid interferon.

Twelve homosexual patients with Kaposi's sarcoma associated with the acquired immune deficiency syndrome (AIDS) were treated with a preparation of purified human lymphoblastoid interferon (Wellferon [Burroughs Wellcome, Research Triangle Park, NC]). They were given a dose of 20 X 10(6) U/m2 intramuscularly daily for approximately two months. Responders continued their treatment on a maintenance schedule of 20 X 10(6) U/m2 three times a week. Four patients experienced complete remissions, and four experienced partial remissions that resulted in a total response rate of 67%. The median duration of treatment was 14 weeks (7 to 28+ weeks), and the median response duration was 28+ weeks (19 to 29+ weeks). Of the four patients in complete remission, one relapsed at 25 weeks and one at 26 weeks; the other two remained in complete remission at 28 and 29+ weeks. The clinical toxicity consisted of chills, fever, fatigue, and asthenia. Hematologic toxicity was similar to that previously described for other preparations of alpha-interferon and consisted of moderate leukopenia and thrombocytopenia. Asthenia, a condition present in all 12 patients, was severe in 50%. A minimal tumor burden, the absence of circulating interferon before treatment, and a performance status of greater than or equal to 90% on the Karnofsky scale were related to an improved response rate. Measurement of immunologic parameters showed significant declines in the already impaired T cell levels, lymphocyte blastogenic response to concanavalin A, monocyte-mediated antibody-dependent cellular cytotoxicity, and monocyte-adherence. Activation of natural killer cells was not noted, and no life-threatening infections occurred during treatment. These data suggest that human lymphoblastoid interferon is an active agent in the treatment of Kaposi's sarcoma, and its use warrants further study in a larger number of patients.

A multicenter clinical trial of oral ribavirin in HIV-infected patients with lymphadenopathy. The Ribavirin-LAS Collaborative Group.

A double-blind, randomized, placebo-controlled trial comparing two daily doses of oral ribavirin and placebo was conducted at four medical centers. One hundred sixty-four adult men with lymphadenopathy were enrolled over a 2-month period and randomized to receive ribavirin 800 mg (53 subjects), ribavirin 600 mg (55 subjects), or placebo (56 subjects). Active treatment was administered for 24 weeks followed by a 4-week washout period. Nine subjects receiving placebo, four receiving ribavirin 600 mg, and none in the 800 mg group developed AIDS during the 24 weeks of active treatment. One patient randomized to the 800 mg group had Kaposi's sarcoma at study entry and was included in the intent-to-treat analysis. An overall significant difference in progression to AIDS was observed among the three treatment groups (p = 0.028) with patients randomized to receive 800 mg having a significantly longer time to AIDS than placebo patients (p = 0.012; relative risk, 9.0; 95% confidence interval, 1.1 to 70.8). There was no significant difference between the 600 mg and placebo groups (p = 0.15; relative risk, 2.3; 95% confidence interval, 0.7 to 7.6). Baseline CD4 cell count and hematocrit made independent contributions and formed a multivariate prognostic set for these progression data. The significant treatment superiority of 800 mg compared to placebo remained after adjustment for these factors (p = 0.019). After deletion of patients with major protocol violations at entry, the difference between the 800 mg and placebo treatment remained significant (p = 0.021).(ABSTRACT TRUNCATED AT 250 WORDS)

Progressive disseminated histoplasmosis in patients with acquired immunodeficiency syndrome.

PURPOSE: Progressive disseminated histoplasmosis is now diagnosed frequently in patients with the acquired immunodeficiency syndrome (AIDS) living in the central United States. Previous review articles of AIDS have failed to mention this infection. Herein, we describe 48 AIDS patients with progressive disseminated histoplasmosis in an effort to better understand the clinical presentation and diagnosis of the condition in this setting and to assess the efficacy of antifungal chemotherapy. PATIENTS AND METHODS: In the Houston metropolitan area, there were 66 cases of progressive disseminated histoplasmosis among 1,300 confirmed cases of AIDS from January 1983 to July 1987. Of AIDS patients in East Texas with histoplasmosis, 16 patients were available for follow-up by one of us, and the histories of 32 were obtained by examination of hospital charts and physician records. RESULTS: Fever, weight loss, and splenomegaly were the most common presenting signs and symptoms, occurring in 81, 52, and 31 percent, respectively. One-third of the patients had hematologic abnormalities. Infiltrates on chest roentgenograms were observed in 52 percent. Progressive disseminated histoplasmosis was the initial manifestation of AIDS in almost three-fourths of our patients. Biopsy and culture of the bone marrow established the diagnosis of progressive disseminated histoplasmosis in 69 percent. Clinical or autopsy proof of relapse occurred in three patients despite an initial course of more than 2 g of amphotericin B chemotherapy followed by ketoconazole suppression. CONCLUSION: Progressive disseminated histoplasmosis is often the first sign of immunodeficiency in patients with AIDS, and the diagnosis of this condition is most often established by bone marrow biopsy and culture. Because of the permanence of the immunodeficient state in these patients, progressive disseminated histoplasmosis is resistant to treatment.

Volatile nitrites. Use and adverse effects related to the current epidemic of the acquired immune deficiency syndrome.

Early reports of the acquired immune deficiency syndrome (AIDS) in homosexual men suggested that the cause might be related to homosexual life-style practices, including use of recreational drugs. Inhalation of volatile nitrites is a possible contributing factor in AIDS because their pharmacologic properties lead to toxicity. Metabolism of N-nitroso compounds produces mutagens, teratogens, and potent carcinogens in 39 different animal species, and volatile nitrites have deleterious effects on human lymphocytes in vitro and in vivo. In relation to the current AIDS epidemic, the timing of production and sales of volatile nitrites for recreational use is the only new life-style factor that might answer the question "why AIDS now?" Prevalence of nitrite use among male homosexuals is very high, and almost every reported case of Kaposi's sarcoma during the past three years includes a history of prior nitrite use. The age of the group of patients in whom Kaposi's sarcoma and AIDS are developing is consistent with a cohort initially exposed seven to 10 years ago. Cessation of nitrite use could reduce the epidemic.

Acquired immune deficiency syndrome: postmortem findings.

The autopsies of 13 male homosexuals with acquired immune deficiency syndrome (AIDS) were reviewed. All patients had laboratory evidence of cellular immune dysfunction. The most common diagnoses made were disseminated cytomegalovirus infection in 12 patients and Kaposi's sarcoma in 10. All patients infected with cytomegalovirus had pulmonary compromise. The adrenal glands and gastrointestinal tract also were involved often by cytomegalovirus. Cytomegalovirus infection of organs uncommonly affected such as heart, meninges, cerebrum, and peripheral nerves was documented in two patients. Skin most frequently was involved by Kaposi's sarcoma, followed by gastrointestinal tract and lymph nodes. Two patients had visceral and/or nodal Kaposi's sarcoma with no skin compromise. Other important diagnoses were Pneumocystis carinii pneumonia, cryptosporidiosis, fungal infections, toxoplasmosis, and brain lymphoma. The cause of death was due to one or more infections in most patients. Kaposi's sarcoma did not contribute substantially to the cause of death, except in one patient with massive multifocal and multiorgan involvement.

Immunologic studies of the acquired immune deficiency syndrome: relationship of immunodeficiency to extent of disease.

Immunologic and conventional laboratory studies were done in 135 previously untreated subjects including 28 (20.7%) symptom-free homosexuals and 74 (54.8%) with ARC and 33 (24.5%) with AIDS. More than half of all patients had abnormal percentages of lymphocytes, percentages of T3+ cells, percentage and absolute number of T4+ cells, percentage of T8+ cells, T4/T8 ratio, monocyte adherence, and serum thymosin alpha 1. Most immune variables worsened with progressive disease. Low lymphocyte 5'nucleotidase increased suppressor cell activity, and impaired IL-2 and alpha interferon production and response suggest diminished mature and increased immature peripheral blood and tissue T cells. These findings suggest approaches to staging, prognostication, and treatment for AIDS.

Glucan-induced keratoderma in acquired immunodeficiency syndrome.

Six of 20 patients with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex receiving intravenous infusions of soluble glucan (beta-1-3 polyglucose) developed a keratoderma of the palms and soles. The eruption began during the first two weeks of therapy and resolved two to four weeks after its discontinuation. The eruption was different in appearance from our previously reported keratoderma blennorrhagica in AIDS-associated psoriasis. None of the other 735 patients with AIDS or AIDS-related complex not treated with soluble glucan developed a similar keratoderma. The correlation between receiving glucan and the hyperkeratosis is highly significant. Since glucan is a naturally occurring component of the cell walls of yeast, fungus, and some bacterial organisms, recognition of its ability to induce such a striking reaction pattern may be of general significance and interest, although the reaction itself may be limited to patients with AIDS.

Toxicity, immunosuppressive effects and carcinogenic potential of volatile nitrites: possible relationship to Kaposi's sarcoma.

Volatile nitrite in the form of amyl nitrite was used for 100 years for the treatment of angina pectoris. In spite of recognized toxicity, its use in this form was considered safe. During the 1960s prescriptions were not required for purchase of amyl nitrite (called poppers) and its use for recreational purposes became popular. With reinstatement of the prescription requirement in 1969, non-medicinal, street-variety volatile nitrites were made commercially available in the form of mixtures of impure butyl and isobutyl nitrite; some of these preparations also included amyl nitrite. These products have been found to be profoundly immunosuppressive for human lymphocytes in vitro, and their by-products when metabolized into N-nitroso compounds have been known to be highly carcinogenic in many animal species. Recreational use of inhaled volatile nitrites is prevalent among male homosexuals and the compounds have been suspected as possible cofactors in Kaposi's sarcoma associated with the Acquired Immune Deficiency Syndrome (AIDS). This association could be explained by nitrite-induced vasodilation of rectal mucosal vessels providing a port of entry for a transmissible agent, by direct immunosuppression of the host allowing expression of a potentially oncogenic virus by co-carcinogenic effects of by-products by themselves or in conjunction with other putative cofactors such as cytomegalovirus. Nitrites should continue to be considered as a possible cofactor in the etiology of Kaposi's Sarcoma among male homosexuals and possibly those with other manifestations of AIDS.

A pilot study of diethyldithiocarbamate in patients with acquired immune deficiency syndrome (AIDS) and the AIDS-related complex.

We investigated the use of diethyldithiocarbamate (DTC, or Imuthiolr, Merieux Institute) as a therapeutic agent in patients with Acquired Immune Deficiency Syndrome (AIDS) and AIDS-Related Complex (ARC). Patients were prospectively stratified and randomized to receive DTC 200 mg/m2 intravenously weekly for 16 weeks or no therapy, followed by crossover to the opposite arm for an equal period. Forty-four patients were entered and forty were evaluable. There was a statistically significant decrease in symptoms in the DTC treated patients compared to the controls (p = .002). There was a significant improvement in lymphadenopathy in the treated patients compared to the controls (p = .005). One patient showed disappearance of splenomegaly, one clearing of antifungal agent-resistant perianal moniliasis, and one clearing of hairy leukoplakia. No significant differences in progression were noted. No changes were seen in any of the immunological parameters measured. There was no significant toxicity. Because of the changes in symptoms and in lymphadenopathy, we suggest that further study of DTC, both alone and in combination with other agents, may be indicated.

Immunological studies of male homosexuals with the prodrome of the acquired immunodeficiency syndrome (AIDS).

Homosexual patients who mainly had the prodrome of the syndrome of opportunistic infection and Kaposi's sarcoma were studied immunologically. Patients showed diminished delayed hypersensitivity to recall antigens, diminished lymphocyte blastogenic responses, a suppressor cell for lymphocyte proliferative responses, low helper cells and an inverted helper:suppressor ratio. The patients had low levels of adherent monocytes. NK cell activity and antibody dependent cellular cytotoxicity were normal. Virtually all patients showed elevated serum thymosin alpha 1 levels and elevated serum lysozyme levels. The most consistent findings were the low helper cells, inverted helper:suppressor ratio and elevated serum thymosin alpha 1 and lysozyme. The patients with the prodrome should be subjected to therapeutic research with immunorestorative drugs.

Current status of AIDS. An overview of statistics, reporting, and at-risk populations.

The acquired immunodeficiency syndrome (AIDS) was first described in 1981. It is estimated that there have now been more than 250,000 cases worldwide, with more than 69,000 in the United States. Probably there are between 5 and 10 million people infected with the causative organism--the human immunodeficiency virus--globally. Current theory holds that the great majority of these infected persons will eventually develop AIDS. Education of high-risk populations, including minorities, is vital since there is no cure and no vaccine at present. Apart from the medical problems of AIDS, there are multitudes of legal, economic, social, philosophic, and theologic problems that the medical practitioner would be well advised to be aware of. AIDS is a threat to society as a whole. In view of current trends, the populations giving most concern for the future are intravenous drug abusers and heterosexually active teenagers and young adults.