Effect of antineoplastic agents on gamma-interferon production in human peripheral blood mononuclear cells.

Since gamma-interferon (IFN-gamma) is a potent immunomodulator and patients receiving certain antineoplastic agents are at risk of unusual infections, we have determined the effect of certain antineoplastic agents on IFN-gamma production. Induction of peripheral blood mononuclear cells from normal donors in the presence and absence of various antineoplastic agents was achieved using phytohemagglutinin (8 micrograms/ml). Supernatants were then separated by centrifugation, dialyzed, and assayed for interferon. Cell viability was always greater than 85% with or without the presence of drugs. Hydrocortisone was found to eliminate IFN-gamma production if added within 24 hr after the phytohemagglutinin. The suppression of IFN-gamma production occurred with hydrocortisone concentrations as low as 0.65 microgram/ml, was associated with a diminished proliferative response to the lectin, and occurred with other interferon inducers including staphylococcal enterotoxin A. Adriamycin (0.4 microgram/ml) and vincristine (0.08 microgram/ml) also diminished IFN-gamma production, but only if the peripheral blood mononuclear cells were pretreated with the drugs. Methotrexate, 5-fluorouracil, and 6-mercaptopurine failed to influence the yield of IFN-gamma. These results are significantly different from experiments previously reported using alpha- and beta-interferons and suggest an important mechanism by which these drugs can produce immunosuppression.

Bacterial meningitis in the elderly.

To assess the implications of meningitis in a more mature population, we reviewed the records of patients with meningitis: 71 aged 50 years and older and 138 patients aged 15 to 49 years. Among the older population, 54 (76%) had bacterial, nine (13%) had granulomatous, and eight (11%) had aseptic meningitis. Among the cases of bacterial meningitis in the older age group, Streptococcus pneumoniae accounted for 24% (13/54) and enteric bacilli accounted for 17% (9/54). Serious complications occurred in 38 elderly patients (70%) with bacterial meningitis, and mortality occurred in 24 (44%). In the younger age group with bacterial meningitis, the complication rate and mortality were 41% (13/32) and 13% (4/32), respectively. Meningitis in the elderly is likely to be bacterial and to cause greater morbidity and mortality.

Relative efficacy and toxicity of netilmicin and tobramycin in oncology patients.

We prospectively compared the efficacy and safety of netilmicin sulfate or tobramycin sulfate in conjunction with piperacillin sodium in 118 immunocompromised patients with presumed severe infections. The two treatment regimens were equally efficacious. Nephrotoxicity occurred in a similar proportion in patients treated with netilmicin and tobramycin (17% vs 11%). Ototoxicity occurred in four (9.5%) of 42 netilmicin and piperacillin and in 12 (22%) of 54 tobramycin and piperacillin-treated patients. Of those evaluated with posttherapy audiograms, three of four netilmicin and piperacillin-treated patients had auditory thresholds return to baseline compared with one of nine tobramycin and piperacillin-treated patients. The number of greater than or equal to 15-dB increases in auditory threshold as a proportion of total greater than or equal to 15-dB changes (increases and decreases) was significantly lower in netilmicin and piperacillin- vs tobramycin and piperacillin-treated patients (18 of 78 vs 67 of 115). We conclude that aminoglycoside-associated ototoxicity was less severe and more often reversible with netilmicin than with tobramycin.

Nontuberculous mycobacterial disease. Experience in a southern California hospital.

The experience with nontuberculous mycobacterial disease at an "acute-care" hospital in southern California between 1971 and 1981 is reported. Forty-five patients with nontuberculous mycobacterial or Mycobacterium bovis-caused disease were identified by retrospective review. Of these, 31 patients (69%) had pulmonary infection alone, nine (20%) had cervical lymphadenitis, two (4%) had disseminated disease, two (4%) had cutaneous infection, and one had soft tissue infection. Nonmycobacterial pulmonary disease was noted in 15 (33%) of the patients and underlying malignant neoplasms were noted in eight (18%). Symptoms most frequently reported at initial examinations of patients with pulmonary disease were cough, weight loss, sputum production, and fatigue. Response to therapy was more successful in patients with Mycobacterium kansasii-caused disease than in those with Mycobacterium avium-intracellulare-caused pulmonary disease. We conclude that nontuberculous mycobacterial disease is not rare in the general hospital setting in southern California.

Induction of immune responses to HIV-1 by canarypox virus (ALVAC) HIV-1 and gp120 SF-2 recombinant vaccines in uninfected volunteers. NIAID AIDS Vaccine Evaluation Group.

OBJECTIVE: To determine the ability of live attenuated canarypox virus expressing HIV antigens to induce CD8+ cytotoxic T-cell responses and to prime for neutralizing antibody responses to boosting with purified recombinant gp120 subunit vaccine. DESIGN: A prospective, double-blind, randomized, immunogenicity and safety study was conducted in healthy adults at low risk for acquiring HIV infection and who were seronegative for HIV. METHODS: CD8+ cytotoxic T-cells directed against Env or Gag expressing target cells were measured after live recombinant canarypox-HIV-1 vaccine priming (vaccine given at days 0, 7, 14 and 21). Neutralizing antibodies were measured after subunit boosting (vaccine given at days 28 and 84). RESULTS: CD8+ CTL were induced in 64% of volunteers by the live recombinant canarypox-HIV-1 vaccine. All volunteers who received two doses of subunit vaccine after live recombinant canarypox priming developed neutralizing antibodies directed against laboratory strains of HIV-1 and seven out of eight volunteers tested developed neutralizing antibodies to the primary isolate, BZ167, but to none of eight other primary isolates. Unprimed controls had low or absent neutralizing antibodies after two doses of subunit vaccine. CONCLUSIONS: The live canarypox vector was safe, stimulated cytotoxic T-cells and primed for a vigorous neutralizing antibody response upon boosting with subunit gp120 vaccine. This vaccine combination should be evaluated further for inducing protection against HIV infection.

Tuberculous spondylitis. A report of six cases and a review of the literature.

Tuberculous spondylitis in the United States is a disease of decreasing incidence and, when the incidence is compared to that of developing nations, affects an older population. The thoracic and lumbar spine is most frequently involved, and in advanced disease several vertebrae may be destroyed with resulting significant morbidity and mortality. The usual clinical presentation consists of fever, back pain, and nonspecific systemic symptoms of varying duration. More advanced disease presents with neurological deficits, kyphotic deformities of the spinal column, and paravertebral cold abscesses. Treatment has changed in the past 50 years not only because of the introduction of highly effective anti-tuberculous chemotherapeutic agents, but also because of the development of new surgical approaches. Controlled studies comparing various surgical and more conservative therapeutic regimens have been conducted within the past decade. Despite these new data, controversy remains regarding the indications for surgical treatment, since anti-tuberculous chemotherapy alone is successful in a large proportion of cases. However, in situations where rapid loss of neurologic function is evident or in which progressive deterioration in spinal cord function continues in the face of apparently adequate drug therapy, it appears that anterior surgical decompression of the spinal cord is indicated to prevent irreversible neurologic deficits. Needle biopsy of bone lesions under fluoroscopic or computed tomographic control is essential in the initial evaluation of patients in order to obtain cultural confirmation of tuberculosis.

CNS infection and bacteremia due to clostridium septicum.

Central nervous system infection with Clostridium septicum is rare. We report two fulminant cases of such infection with accompanying bacteremia. The presence of extensive brain necrosis was striking in our two cases. The association of C septicum bacteremia with hematologic disease, and with solid tumors, was present in our cases. We conclude that C septicum should be considered as a potential cause of life-threatening bacteremia and meningitis in the compromised host.

HIV type 1 vaccine-induced T cell memory and cytotoxic T lymphocyte responses in HIV type 1-uninfected volunteers.

T cell memory to human immunodeficiency virus type 1 (HIV-1) antigens and anti-HIV-1 cytotoxic T lymphocyte (CTL) activity were assessed after administration of live canarypox virus (ALVAC) expressing HIV-1 env, gag, and protease (vCP205) vaccine given alone, vCP205 given with SF-2 recombinant gp120 (rgp120) vaccine, and placebos at 0, 1, 3, and 6 months. Healthy, HIV-1-uninfected subjects reporting high-risk and low-risk behavior for HIV-1 were enrolled. Anti-HIV-1 Env CD8(+) CTLs (HIV-1(MN) and/or HIV-1 subtype B and C primary isolate sequences) were detected in 12 (60%) and anti-HIV-1 Gag CD8(+) CTLs in 7 (35%) of the 20 vCP205 vaccine recipients tested by CTL assay 3.5 months after the final immunization. Fourteen days after the fourth immunization, lymphocyte proliferation in response to HIV-1 Gag antigen was detected in 14 (48%) of 29 vCP205 vaccine recipients, but secreted cytokine levels to HIV-1 Gag antigen were not above unstimulated levels. Coadministration of SF-2 rgp120 vaccine with vCP205 vaccine enhanced lymphocyte proliferation in response to HIV-1 envelope glycoprotein and broadened the envelope-stimulated cytokine secretion pattern, so that it consisted of both Th1 and Th2 cytokines compared with only interferon gamma (IFN-gamma) after vCP205 vaccine given alone. There was a possible association between HIV-1 envelope glycoprotein-stimulated interleukin 2 secretion and CD8(+) CTLs against HIV-1 envelope glycoprotein, and an inverse relation between lymphocyte proliferation and CTLs against HIV-1 Gag antigens. Thus, a durable anti-HIV-1 CD8(+) CTL response was detected after immunization with the live canarypox virus vaccine and preexisting helper T cell memory responses did not necessarily predict later CD8(+) CTL activity.

MN and IIIB recombinant glycoprotein 120 vaccine-induced binding antibodies to native envelope glycoprotein of human immunodeficiency virus type 1 primary isolates. National Institute of Allergy and Infectious Disease Aids Vaccine Evaluation Group.

The ability of antibody induced by MN and IIIB recombinant gp120 (rgp120) human immunodeficiency virus type 1 (HIV-1) vaccines to bind to oligomeric native HIV-1 envelope glycoproteins of primary isolates of HIV-1 was measured by flow cytometric indirect immunofluorescence assay (FIFA) in 25 uninfected, healthy adults. After three immunizations, MN rgp120 HIV-1 vaccine given alone and coadministered with IIIB rgp120 HIV-1 vaccine elicited antibody that bound to cells infected with each of a panel of six subtype B strains of HIV-1. Lower levels of vaccine-induced binding antibody were detected against envelope subtype A, D, and (EA) strains of HIV-1 than against subtype B strains. Priming immunization with IIIB rgp120 HIV-1 vaccine alone induced low levels of antibody capable of binding to envelope glycoprotein of primary isolate strains of HIV-1, and booster immunizations with MN rgp120 HIV-1 vaccine resulted in much higher antibody levels. We conclude that MN rgp120 HIV-1 vaccine was an effective inducer of antibody to native envelope glycoproteins of antigenically diverse primary isolates of HIV-1.

Advancing AIDSVAX to phase 3. Safety, immunogenicity, and plans for phase 3.

AIDSVAX (VaxGen, Inc., South San Francisco, CA), a possible vaccine to protect against human immunodeficiency virus type 1 (HIV-1) infection, is being tested for efficacy in phase 3 studies. It has been tested for potential efficacy in chimpanzees, and tested for safety and immunogenicity in human clinical studies. Four candidate vaccines, each with a different envelope protein antigen or combination of antigens, have been produced in alum formulations. In both design and clinical testing, AIDSVAX has an excellent safety profile. Because these highly purified proteins were prepared using recombinant DNA technology, there is no possibility of these vaccines causing HIV infection. Having been administered to over 1200 people, the only side effects attributable to AIDSVAX have been local pain and inflammation at the injection site. After immunization, essentially all recipients developed a robust antibody response, including binding and neutralizing antibodies. The neutralizing antibodies peaked after a 12-month boost. Excellent memory is induced. Two phase 3 trials of two bivalent formulations will evaluate their efficacy. One trial will use a bivalent subtype B formulation. This trial in North America will involve 5000 men who have sex with men and heterosexual women at high risk. The other study will use a bivalent subtype B/subtype E formulation. This trial in Thailand and will involve 2500 intravenous drug users. Both studies will be randomized, double-blinded and placebo controlled. The volunteers will be followed for 3 years. The end points of the studies are infection, as defined by seroconversion to standard diagnostic tests, and viral load, as defined by commercial polymerase chain reaction (PCR) tests.

HIV-1MN recombinant glycoprotein 160 vaccine-induced cellular and humoral immunity boosted by HIV-1MN recombinant glycoprotein 120 vaccine. National Institute of Allergy and Infectious Diseases AIDS Vaccine Evaluation Group.

We evaluated prime-boost immunization with two recombinant envelope glycoprotein subunit vaccines (HIV-1MN recombinant gp160 vaccine in alum adjuvant [MN rgp160] and HIV-1MN recombinant gp120 vaccine in alum adjuvant [MN rgp120]) for safety and immunogenicity in healthy, HIV-1-uninfected adults. The rationale was to combine the helper T cell memory and binding antibody responses typically induced by rgp160 vaccines with the superior neutralizing antibody responses induced by rgp120 vaccines. In a double-blinded, controlled trial, volunteers were randomly assigned to receive MN rgp160 or adjuvant placebo, and a subset later received MN rgp120. The two vaccines were safe, but reactions to MN rgp160 and its adjuvant placebo exceeded those to MN rgp120. MN rgp160 induced IgG binding antibodies, including all IgG subclasses, to MN rgp160 in all vaccine recipients. HIV-1MN-neutralizing and anti-V3 MN peptide-binding antibodies were observed in a majority of volunteers after the fourth MN rgp160 immunization, but at lower levels compared with immunization with MN rgp120 in historical controls. HIV-1-binding, neutralizing, and fusion inhibition antibodies were boosted to the highest levels among MN rgp160 recipients after MN rgp120 booster injections. MN rgp120 boosting appeared to alter the distribution of MN rgp160 vaccine-induced, anti-MN rgp160 IgG subclass antibodies. MN rgp160 induced helper T cell memory, measured by lymphocyte proliferation, Thl and Th2 cytokine production, and skin testing. Strategies including both subunit vaccines may help maximize antibody and helper T cell memory responses to HIV-1 envelope glycoprotein.

Safety profile of phase I and II preventive HIV type 1 envelope vaccination: experience of the NIAID AIDS Vaccine Evaluation Group.

The NIAID-sponsored AIDS Vaccine Evaluation Group was established in 1988 to perform phase I/II clinical trials with candidate preventive HIV-1 vaccines. This report includes safety data from 1398 HIV-negative, healthy volunteers who were enrolled into 25 phase I and 1 phase H multicentered, randomized, double-blind studies evaluating seven recombinant HIV-1 envelope vaccines, two V3 loop synthetic peptide vaccines, and two live poxvirus-vectored recombinant envelope vaccines. All studies but three were placebo controlled; the placebo was either the adjuvant alone or, in studies of recombinant poxvirus vaccines, it was the vector with no gene insert or a non-HIV gene insert. All candidate vaccines were generally well tolerated. The only adverse effects that were clearly related to vaccination were occasional acute local and systemic reactions that were associated with the adjuvants. Three adjuvants in particular were associated with moderate to severe local reactions: alum plus deoxycholate (ImmunoAg), MTP-PE (Biocine Corp.), and QS21 (Genentech, Inc.). MTP-PE was also associated with self-limited severe systemic reactions. There were no serious adverse laboratory toxicities and no evidence of significant immunosuppressive events after receipt of the candidate vaccines. A few volunteers experienced symptoms that might relate to an underlying immunopathologic mechanism (rash, hemolytic anemia, arthralgia), but their presentations were mild and their incidence was low. Eleven volunteers were diagnosed with malignancies during or after their participation, which was within the 95% confidence interval of the number of cases predicted by the National Cancer Institute SEER (Program for cancer surveillance, epidemiology, and end result reporting) database. In conclusion, the envelope-based recombinant or synthetic candidate HIV-1 vaccines appear to be safe and this work has prepared the way for the testing of increasingly complex candidate HIV-1 vaccines.

Superiority of live attenuated compared with inactivated influenza A virus vaccines in older, chronically ill adults.

Forty-eight older adults with chronic diseases were vaccinated intranasally with live attenuated influenza A/Korea/1/82 (H3N2), CR59 virus. Forty-two (88 percent) CR59 virus recipients became infected with vaccine virus without adverse effects or change in mean pulmonary function even among the 29 infected recipients with moderate to severe chronic obstructive pulmonary disease. Among control groups who received either monovalent or trivalent inactivated influenza virus vaccines intramuscularly, the rates of fourfold rises in serum antibody titer to hemagglutinin (HA) were not different from the rate following CR59 virus inoculation. However, CR59 virus was superior to inactivated virus vaccine at stimulating secretory antibody to HA. Vaccinees age 65 years and older were more likely to shed CR59 virus in nasal secretions than were younger vaccinees, but antibody responses were not different. CR59 virus vaccine was safe and immunogenic in this population and more often induced a nasal wash IgA antibody response than the inactivated virus vaccines.

Influenza virus vaccination of patients with chronic lung disease.

STUDY OBJECTIVES: To evaluate the safety of, and mucosal and systemic immune responses induced by two influenza virus vaccine regimens in subjects with COPD. DESIGN: Single-center, blinded, randomized, prospective clinical trial evaluating two vaccine regimens. SETTING: Outpatient clinics of St. Louis Department of Veterans Affairs Medical Center. PARTICIPANTS: Volunteers (age range, 42 to 88 years) had preexisting COPD with severe obstruction to airflow on average, were male, and were not receiving immunosuppressive medication. INTERVENTIONS: Twenty-nine volunteers were randomly assigned to receive either bivalent live attenuated influenza A virus vaccine (CAV) or saline solution placebo intranasally. All subjects also received an i.m. injection of trivalent inactivated influenza virus vaccine (TVV) simultaneously. MEASUREMENTS AND RESULTS: Clinical status and pulmonary function measured by spirometry did not change significantly after vaccination. Using hemagglutinins (H1 and H3 HA) which more closely resembled those in CAV, mean levels of anti-HA immunoglobulin A (IgA) antibodies in nasal washings increased significantly after vaccination with CAV and TVV compared to prevaccination, but they did not increase significantly after TVV and intranasal placebo. Mean levels of influenza A virus-stimulated interleukin-2 and -4 produced by peripheral blood mononuclear cells in vitro increased significantly after administration of the combination vaccine regimen and to a lesser extent after TVV and intranasal placebo compared to respective prevaccination levels. The timing of the cytokine response appeared different following CAV and TVV compared to TVV and intranasal placebo. CONCLUSIONS: Intranasally administered CAV was safe when given with i.m. administered TVV and there may be an immunologic advantage to administration of the combination vaccine regimen compared to TVV with intranasal placebo.

Infection control practices in gastrointestinal endoscopy in the United States: a national survey.

OBJECTIVE: To ascertain current infection control practices, endoscope cleaning procedures, perceived risks of infection, and implementation of universal precautions in gastrointestinal endoscopy units in the United States. DESIGN: National mailed survey of gastroenterology nurses and associates conducted anonymously in March 1988. SETTING: Completed surveys were received from all 50 states and Puerto Rico and from all practice settings. The most common practice setting was private/community hospitals (66%). PARTICIPANTS: Of the 4,952 survey forms mailed to all members and to interested nonmembers of the Society of Gastrointestinal Nurses and Associates, 2,158 (44%) were returned and 2,030 (41%) were completed and evaluable. Of the respondents, 1,487 (73%) were registered nurses. RESULTS: Sixty-seven percent (n = 1,358) of the respondents routinely used an enzymatic cleaner as a step in the instrument decontamination process; 93% (n = 1,879) chemically disinfected instruments after each case; and 88% (n = 1,779) disinfected endoscopes with an aqueous glutaraldehyde product. Respondents reported that they and a significantly smaller proportion of physicians (p less than .001) employed barrier precautions for all endoscopic cases involving possible contact with blood/body fluids of patients known (66% versus 57%, respectively) and not known (12% versus 8%, respectively) to have a bloodborne infection. Endoscopy-related infections, usually bacterial, were reported to have occurred at their institutions by 6% (n = 116) of respondents. CONCLUSIONS: We conclude that cleaning, disinfection, and sterilization procedures for gastrointestinal endoscopic instruments vary, that appropriate protective apparel is not always worn, and that some practices may lead to preventable endoscopy-related infection in patients.

Association of malnutrition with nosocomial infection.

To study the association of malnutrition with nosocomial infection in a general medical and surgical inpatient population, we retrospectively compared 45 patients with nosocomial infection to 45 uninfected control patients, matched using several nonnutritional variables known to predispose to nosocomial infection. Univariate and multivariate analyses were done. Poor nutritional score (derived from serum albumin, total lymphocyte count, and unintentional body weight loss), unintentional body weight loss, low serum albumin level at both time of admission and the first nosocomial infection, and worsening in the nutritional score and serum albumin from admission to the first nosocomial infection were associated with the development of nosocomial infection. Nutritional factors were more abnormal in subgroups of patients with nosocomial pneumonia, urinary tract infection, wound infection, and bacteremia than in controls. The findings suggest that further study of correlations between nutritional factors and nosocomial infections is needed.

Improved pressure sore healing with hydrocolloid dressings.

We prospectively followed inpatients receiving treatment for pressure sores to identify the better of two local treatment regimens. Twenty-seven patients with 76 pressure sores received treatment with hydrocolloid dressings (HCDs) and 25 patients with 52 pressure sores received treatment with Dakin's solution (chloramine-T)-soaked wet-to-dry dressings. Thirty-eight (73%) patients initially had severe nutritional depletion. The mean serum albumin value of the pressure sore treatment groups was lower than that of an age-matched group without pressure sores. In the HCD group, 66 (86.8%) pressure sores improved compared with 36 (69.2%) pressure sores in the wet-to-dry dressings group. The HCD regimen was more efficacious even in a subgroup of patients who received inadequate nutritional support during treatment. Adequate nutritional intake during the study was associated with better healing in both local treatment groups.

Characteristics of a population volunteering for human immunodeficiency virus immunization. NIAID AIDS Clinical Trials Network.

A total of 166 volunteers for an AIDS vaccine study (Vaxsyn, baculovirus produced recombinant GP160; MicroGeneSys Inc, West Haven, Connecticut, USA) were interviewed and examined. Blood was collected for routine laboratory testing as well as T-cell counts, HIV ELISA (EIA), Western blot (WB) and p24 Ag. Eighty-five men (mean age 22.2 years, range 18-42) and 81 women (mean age 23.9 years, range 17-50) volunteered; 130/166 (78%) were university students. Most had learned of the study from news media (55%), friends or workplace (37%). The most common causes for exclusion were the presence of indeterminate WB (26.5%) or a change of mind after the initial interview (24%). Other causes were abnormal cell count and differential (7.2%), elevated alanine aminotransferase (3.6%), positive hepatitis B antibody (3.6%), abnormal urinalysis (3.4%), recent venereal disease (3.0%), T4 cell count less than 400 (1.9%), abnormal chest X-ray (1.7%), recognized high-risk behaviour (1.7%), multiple sex partners (1.2%), positive rapid plasma reagin test (1.2%), failure to meet age criteria (1.2%), unable to be available for entire study (1.2%), abnormal physical examination (0.6%) and positive p24 Ag (0.6%). No volunteers had positive EIA, but 14.5% had more than one reason for exclusion. Even in a community with low prevalence for HIV, a large majority of healthy heterosexual volunteers can be expected to be ineligible for enrollment in HIV vaccine trials. An average of 4.8 volunteers were screened for each of 12 vaccinees chosen.