Immunization against influenza: comparison of various topical and parenteral regimens containing inactivated and/or live attenuated vaccines in healthy adults.

Methods for enhancing immune responses to influenza were explored in 2 double-blind, placebo-controlled trials. Intranasal (inl) immunization with monovalent, live attenuated, cold-adapted recombinant (CR) or inactivated influenza virus (MIV) vaccine and intramuscular (im) immunization with MIV were evaluated in various combinations. Healthy susceptible adults were assigned randomly to receive 10(7.1) TCID(50) of CR (A/H1N1 or A/H3N2), homologous MIV (15 microg), or placebo inl and placebo or homologous MIV im (6 groups in each study). Serum antibody responses were greatest in groups given im vaccine (with or without inl vaccine). A 2-fold increase in nasal wash antibody response frequencies was seen in groups given combined inl (CR or MIV) and im vaccine, compared with subjects given a single im (MIV) or inl (CR or MIV) vaccine. Combined inl and im immunization is a promising approach for enhancing both local and systemic immune responses against influenza.

Human immune response to streptococcal inhibitor of complement, a serotype M1 group A Streptococcus extracellular protein involved in epidemics.

Streptococcal inhibitor of complement (Sic) is a highly polymorphic extracellular protein made by serotype M1 group A Streptococcus strains that contributes to bacterial persistence in the mammalian upper respiratory tract. New variants of the Sic protein arise very rapidly by positive selection in human populations during M1 epidemics. The human antibody response to Sic was analyzed. Of 636 persons living in diverse localities, 43% had anti-Sic serum antibodies, but only 16.4% had anti-M1 protein serum antibody. Anti-Sic antibody was also present in nasal wash specimens in high frequency. Linear B cell epitope mapping showed that serum antibodies recognized epitopes located in structurally variable regions of Sic and the amino terminal hypervariable region of the M1 protein. Phage display analyses confirmed that the polymorphic regions of Sic are primary targets of host antibodies. These results support the hypothesis that selection of Sic variants occurs on mucosal surfaces by a mechanism that involves acquired host antibody.

Endocarditis and Ureaplasma urealyticum osteomyelitis in a hypogammaglobulinemic patient. A case report and review of the literature.

We report a hypogammaglobulinemic patient who developed chronic polyarthritis and osteomyelitis due to Ureaplasma urealyticum. He also had mitral valve endocarditis of uncertain origin. Patients with primary antibody deficiency show increased susceptibility to mycoplasma infections. Early diagnosis and treatment is very important in order to prevent potentially debilitating complications.

Impact of influenza and other community-acquired viruses.

The incidence of community-acquired pneumonia peaks during the winter season each year. Increases in mortality from these pneumonias and influenza-like illnesses (P&I) above an "epidemic threshold" for 2 or more weeks generally signify increased numbers of influenza virus infections in the community, although peaks in P&I mortality typically lag a few weeks behind peaks in influenza virus activity. Most of the pneumonias cases found during influenza virus epidemics are due to secondary bacterial infections, with an increase in the frequency of Staphylococcus aureus over that seen in nonepidemic periods. One interaction between bacteria and influenza viruses that may increase disease severity by increasing growth of the virus is proteolytic cleaving of the hemagglutinin mediated directly or indirectly by bacterial products. Influenza virus infections also have many effects on the host that can enhance secondary bacterial infections; included are impairments of mucus clearance and T cell, polymorphonuclear cell and macrophage functions, as well as alterations in respiratory epithelium that can enhance adherence of bacteria. Recent studies indicate that the role of respiratory syncytial virus infections in causing acute pulmonary syndromes in elderly individuals, including secondary bacterial pneumonia, is essentially equivalent to that of influenza A viruses during years when there is not a severe influenza epidemic. Although other respiratory viruses can occasionally cause or facilitate the development of community-acquired pneumonia, currently available epidemiological data do not support significant roles for them relative to those of influenza and respiratory syncytial viruses.

Improvement of inactivated influenza virus vaccines.

Inactivated influenza virus vaccines (IVVs) are used for prevention of influenza and its complications. Present vaccines are immunogenic, of low reactogenicity, and protective, but protection has varied between 0% and 100%. Increasing the dose of hemagglutinin and neuraminidase antigens with purified proteins significantly increased serum and nasal antibody responses; however, trials with newer adjuvants have not shown increased serum antibody to levels comparable with those in earlier studies using oil emulsion adjuvants. IgA antibody responses in respiratory secretions were enhanced by the respiratory administration of IVVs, but IVVs by the oral route yielded varying results. IVVs appeared less effective for pandemic influenza in 1968 than in 1957. Since IVVs will be the major preventative measure for pandemic influenza in most countries, they need to be improved to provide better protection against pandemic and interpandemic influenza. Increasing the doses of hemagglutinin and neuraminidase, using adjuvants or immunomodulators, and administering IVVs by the mucosal route could improve the performance of these vaccines.

Effects of requiring prior authorization for selected antimicrobials: expenditures, susceptibilities, and clinical outcomes.

Antimicrobial control programs are widely used to decrease drug expenditures, but effects on antimicrobial resistance and outcomes for patients are unknown. When a requirement for prior authorization for selected parenteral antimicrobial agents was initiated at our urban, county teaching hospital, total parenteral antimicrobial expenditures decreased by 32%. Susceptibilities to all beta-lactam and quinolone antibiotics increased, with dramatic increased susceptibilities in isolates recovered in intensive care units, increased susceptibilities in isolates recovered in other inpatient sites, and little change in susceptibilities in isolates recovered in outpatient sites despite no change in infection control practices. For patients with bacteremia due to gram-negative organisms, overall survival did not change with restrictions. No differences occurred in the median time from initial positive blood culture to receipt of an appropriate antibiotic or in the median time from positive blood culture to discharge from the hospital. Thus, requiring preapproval for selected parenteral agents can decrease antimicrobial expenditures and improve susceptibilities to antibiotics without compromising patient outcomes or length of hospital stay.

Efficacy of repeated annual immunization with inactivated influenza virus vaccines over a five year period.

Some reports have suggested that influenza virus vaccine is less effective in persons that have received prior annual vaccination(s) than in those receiving it for the first time. This issue was addressed by evaluating the efficacy of annual influenza vaccinations over a 5 year period in healthy adults employing commercially-available, inactivated whole-virus vaccine. Influenza vaccination had minimal effects on overall respiratory illnesses during epidemic periods. However, it reduced influenza virus shedding by an average of 38.8% and conferred protection against influenza virus infection during each epidemic. Some variation in infection rates were noted between vaccine groups given one or more than one annual immunization, and between years, but no consistent pattern of differences was noted in relation to number of successive years of vaccination. These results suggest that the current recommendation for annual influenza vaccination of persons at special risk of serious disease and complications is appropriate, but that continued efforts to improve the effectiveness of our prophylactic measures against influenza are needed.

Cytotoxic T lymphocyte responses of infants after natural infection or immunization with live cold-recombinant or inactivated influenza A virus vaccine.

The cytotoxic T lymphocyte (CTL) response of infants after immunization with either inactivated trivalent subvirion vaccine (TIV) or bivalent attenuated cold-recombinant (CR) vaccine or occurrence of natural influenza virus infection were compared in a blinded, placebo-controlled study during the 1987-1988 and 1988-1989 influenza epidemic seasons. Healthy infants between 6 and 13 months of age were randomly assigned and administered a single dose of intranasal bivalent (A/H3N2/A/H1N1) CR vaccine, a two-dose regimen of TIV (A/H3N2/A/H1N1/B) influenza vaccine, or placebo. Peripheral blood lymphocytes were obtained prior to and 2-8 weeks after vaccination and at the end of the epidemic season and stimulated with virus in vitro for 6 or 7 days. Lysis of autologous virus-infected target cells was assessed in a 4 hr 51Cr release assay. MHC class I-restricted influenza A-specific CTL was stimulated following natural influenza A virus infection but not after immunization with CR influenza A virus vaccine or TIV. These results demonstrate for the first time induction of influenza virus-specific CTL activity in infants under 1 year of age.

Increasing doses of purified influenza virus hemagglutinin and subvirion vaccines enhance antibody responses in the elderly.

The reactogenicities and immunogenicities of two influenza virus vaccines were compared in a placebo-controlled clinical trial among healthy ambulatory persons > or = 65 years old (mean age, 72 years). Volunteers were assigned randomly to receive 15-, 45-, or 135-micrograms doses of monovalent influenza A/Taiwan (H1N1) hemagglutinin (HA) or subvirion (SV) vaccine intramuscularly or a placebo. Increasing doses of SV vaccine were associated with a higher rate of injection site discomfort (P < 0.05; chi-square test for linear trend), but all doses of both vaccines were well tolerated. Increasing the dose of the HA or the SV vaccine resulted in increasingly higher postimmunization levels of serum hemagglutination inhibition and neutralizing antibody levels (P < 0.001; multiple linear regression). Mean serum antibody titers at 1 month increased two- to threefold with a ninefold increase in dose; the frequencies of fourfold or greater rises in titer likewise increased. An increase in the dose of the HA or the SV vaccine also resulted in increased frequencies of rises in immunoglobulin A or G antibody titers in nasal wash specimens. The frequencies increased approximately twofold for each vaccine with a ninefold increase in the dose. These data suggest that increasing the HA vaccine dose is a promising approach to the development of improved influenza virus vaccines for use in elderly people.

Tuberculous meningitis among adults with and without HIV infection. Experience in an urban public hospital.

BACKGROUND: Tuberculous meningitis remains a frequently diagnosed entity in urban US hospitals, with the incidence increasing as a consequence of infection with the human immunodeficiency virus (HIV). OBJECTIVE: To describe the occurrence, characteristics, and therapeutic responses of tuberculous meningitis among adult patients of an urban public hospital, with special attention to the effects of HIV infection. DESIGN: Retrospective clinical review of all cases identified among adults over a 12-year interval, collecting demographic and clinical variables. SETTING: A 550-bed urban teaching hospital. MAIN OUTCOME MEASURE: Nine-month outcome stratified by survival. RESULTS: Among 31 adult patients identified as having definite or probable tuberculous meningitis, a majority (n = 20 [65%]) were infected with HIV. Cumulative rates of occurrence per 100 000 persons over the 12 years of the study were estimated at 1.72 for those without HIV infection and 400 for those with HIV infection. The most common symptoms at presentation were fever (83% [24/ 29]) and abnormal mental status (71% [20/28]). One or more abnormalities were present in the cerebrospinal fluid of 97% (30/31) of subjects, and 74% (23/31) had cerebrospinal fluid cultures positive for Mycobacterium tuberculosis. Neuroimaging of 28 patients revealed 1 or more abnormalities in 82% (n = 23). Among 30 patients with available outcome data at 9 months, 43% (n = 13) had died, 40% (n = 12) had survived without sequelae, and 17% (n = 5) had survived with morbidity. HIV infection had no discernible effect on findings. CONCLUSIONS: Tuberculous meningitis remains relatively common among indigent urban nonwhite populations. While HIV infection has contributed to the increased incidence of tuberculous meningitis, it has not significantly altered the presenting clinical, laboratory, or radiographic findings or the response to therapy of this disease. Parameters associated in a multivariate regression analysis with mortality at 9 months were black race and the absence of corticosteroid use.

Human immunodeficiency virus-associated atypical mycobacterial skeletal infections.

The clinical and laboratory features of six human immunodeficiency virus (HIV)-positive patients with atypical mycobacterial skeletal infections, seen at a county outpatient HIV facility or university outpatient clinic, are reviewed and compared with other reported cases. Atypical mycobacterial skeletal infections are a manifestation of advanced HIV disease, with most cases having CD4 counts < 100/mm3 at the time these infections become clinically apparent. Multiple sites are frequently involved, and concomitant skin infection with the same organism is common, especially with Mycobacterium haemophilum. The incidence of atypical mycobacterial skeletal infection in HIV-infected individuals was significantly higher than in the general county hospital district patient population, whereas the frequency of Myobacterium tuberculosis skeletal infection did not differ significantly between the two populations. The clinician therefore should maintain a high index of suspicion for atypical mycobacteria in a patient presenting with skeletal infection in the setting of a markedly depressed CD4 count.

Purified influenza A virus N2 neuraminidase vaccine is immunogenic and non-toxic in humans.

The immunogenicity and toxicity of a purified influenza virus (N2) neuraminidase vaccine (NAV) were investigated in 88 human subjects aged 18-40, and compared to response to a conventional trivalent influenza vaccine, Fluogen (Parke-Davis). NAV doses ranged from 2.6 to 69.9 micrograms and were given intramuscularly. Serologic neuraminidase-inhibiting (NI) and neuraminidase-specific ELISA responses in this N2-primed population were roughly proportional to the dose administered. Maximal response was seen in 14-21 days and NI antibody titers persisted unabated for the 6-month post-vaccination follow-up period. All doses were well tolerated with respect to local and systemic reactions. NI tests performed with the putative (1975) priming N2 antigen demonstrated anamnestic response but did not reveal responses not already shown with the homologous (1992) antigen. Response to this purified, non-adjuvanted preparation encourages continuing investigation of the induction of infection-permissive immunity with influenza virus neuraminidase.

Comparison of trivalent cold-adapted recombinant (CR) influenza virus vaccine with monovalent CR vaccines in healthy unselected adults.

A trivalent cold-adapted recombinant (CR) influenza virus vaccine containing types A and B viruses was compared with monovalent vaccines of each virus in a double-blind, placebo-controlled trial. Adults with a wide range of preexisting antibody titers received one 0.5-mL dose intranasally of trivalent vaccine; monovalent A/H1N1, A/H3N2, or B vaccine; or placebo. All vaccines were well tolerated. Serum antibody response frequencies and postvaccination geometric mean antibody titers were similar for recipients of trivalent or the corresponding monovalent vaccine for each of the vaccine components. Stepwise logistic regression analysis of the antibody responses of trivalent vaccine recipients demonstrated that response to one vaccine virus did not adversely affect the likelihood of response to the other viruses. This study failed to find serologic evidence of interference between vaccine viruses, suggesting that trivalent CR influenza virus vaccine may be useful for preventing influenza in adult populations.

Influenza A subtype cross-protection after immunization of outbred mice with a purified chimeric NS1/HA2 influenza virus protein.

Influenza A/PR/8/34-derived chimeric (D) protein (SK&F 106160) composed of the first 81 amino acids (aa) of NS1 fused to the conserved 157 C-terminal aa of HA2 (NS1 1-81-HA2 65-222) was previously shown to induce H-2d-restricted protective cytotoxic T-lymphocyte (CTL) immunity in inbred mice. However, D protein, like other small peptides, exhibited haplotype dependence and was not immunogenic in H-2b and H-2K mice. A potential use of this antigen in humans and the role of T cells in any protection were evaluated in outbred Swiss and inbred CBF6F1 (H-2d/b) mice. Mice immunized with D protein and challenged by small-particle aerosol with a lethal dose of influenza virus were significantly protected against mortality from influenza A/H1N1 and A/H2N2 (p < 0.05-< 0.0000001), but not from A/H3N2 and influenza B viruses when compared with control mice. D protein did not induce serum virus-neutralizing antibody but caused virus to be cleared faster in immunized mice. Protection was long-lasting. In vivo depletion of either Lyt2 (CD8+) or L3T4 (CD4+) T cells with monoclonal antibodies led to abrogation of in vitro-generated CTL activity in CF6F1 mice and significant reduction in the protective efficacy of D protein against virus challenge in both Swiss and CF6F1 mice. These results suggest that protection was mediated by CD8+ and/or CD4+ cells and not antibody. Thus D protein, via a conserved sequence on the HA2 polypeptide, has the potential to induce partially cross-reactive CTL that may protect against influenza virus disease in humans.

High doses of purified influenza A virus hemagglutinin significantly augment serum and nasal secretion antibody responses in healthy young adults.

The reactogenicity and immunogenicity of purified influenza virus hemagglutinin (HA) vaccines administered intramuscularly were evaluated in two placebo-controlled clinical trials. A total of 139 healthy young adults were randomized to receive increasing doses of monovalent influenza A/Taiwan/1/86 (H1N1) virus HA (range, 0 to 405 micrograms per dose [study 1]). An additional 139 subjects were given increasing doses of a trivalent HA vaccine containing equal amounts of A/H1N1 virus, A/Shanghai/16/89 (H3N2) virus, and influenza B/Yamagata/16/88 virus HA (range, 0 to 135 micrograms of HA per strain, 0 to 405 micrograms per dose) or a standard dose of commercial influenza vaccine (study 2). Increasing doses of HA were associated with increasing frequencies of symptoms at the vaccination site early after vaccination, but all doses were well tolerated. Occurrence of systemic symptoms was unrelated to dose. Increasing the dose of HA resulted in increasingly higher postimmunization levels of serum hemagglutination inhibiting and neutralizing antibody levels versus influenza A/H1N1 virus in study 1 (P < 0.05); these enhanced responses persisted for up to 6 months. Nasal secretory immunoglobulin A and G antibody responses were assessed 2 weeks after immunization with monovalent H1N1 virus HA; the frequencies of significant responses also increased in a dose-related fashion. Similar increases in serum antibody levels were noted for both A/H1N1 and A/H3N2 viruses in study 2. These data provide a basis for proceeding with the evaluation of high doses of purified HA in the elderly.

Developing and implementing guidelines to promote appropriate use of fluconazole therapy in an AIDS clinic.

A retrospective and concurrent drug use evaluation for fluconazole in an outpatient AIDS clinic is described. Eighty-eight patient charts were reviewed in the evaluation during an 8-week period, and 72 patients were studied in the concurrent evaluation for a period of 5 weeks. A set of preestablished fluconazole usage and dosing guidelines was developed by the clinical pharmacist and the chairman of the antimicrobial subcommittee/chief of infectious disease and approved by the pharmacy and therapeutics committee. Patients who did not meet these guidelines were those being treated for oropharyngeal and esophageal candidiasis. The use of fluconazole was not indicated in 43 of 54 (80%) patients in retrospective evaluation and 31 of 39 (79.5%) patients before clinical pharmacist intervention in concurrent study. If guidelines had been followed during the retrospective evaluation, cost savings would have been $295 per day, which adds up to $16,520 for 8 weeks. In the actual evaluation, the cost savings with pharmacist intervention for 5 weeks was $5,460, which can be extrapolated to annual cost savings of $65,520.

Concurrent ceftazidime DUE with clinical pharmacy intervention.

Ceftazidime use at our institution, a 580-bed county teaching hospital, has steadily increased since its addition to the formulary in 1986. In response to this increased use and because the institutional antibiogram showed increased resistance by Pseudomonas aeruginosa (from 10 to 28% resistant), the P & T Committee requested that a drug use evaluation (DUE) of ceftazidime be conducted. Analysis of this retrospective pilot study showed that 87% of ceftazidime use was inappropriate. To further evaluate ceftazidime use, to identify problems not assessed during retrospective review, and to correct problems while patients were receiving the drug, a concurrent ceftazidime use evaluation was conducted. The methods and results of the concurrent review are presented below.

In situ hybridization and immunohistochemical analysis of cytomegalovirus-associated ileal perforation.

A patient with the acquired immunodeficiency syndrome (AIDS) with a cytomegalovirus (CMV) infection localized in the area of an ileal Kaposi sarcoma resulting in perforation is described. Because only one case of such an association of Kaposi sarcoma with CMV leading to perforation has been reported, the presence and distribution of CMV-related nucleic acids and proteins in the affected segment of intestine were evaluated. By using in situ hybridization and immunocytochemical analyses the presence of CMV was shown within epithelial, endothelial, smooth muscle, and inflammatory cells at the site of perforation. This study not only confirmed that CMV can be detected in virtually all components of the intestinal wall despite the absence of distinctive cytomegalic changes, but also generated critical information that illustrates the usefulness of immunohistochemistry and in situ hybridization in elucidating the pathogenesis of CMV-associated lesions. These findings lend further support to the concept that CMV plays a pivotal role in the pathogenesis of intestinal perforation and emphasize the critical importance of in situ hybridization in gaining insight into the mechanisms of CMV-induced injury.