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Background The pharmacokinetics of oral favipiravir and the relationships of plasma concentrations to antiviral effects are incompletely studied in influenza. Methods Serial plasma samples were collected from adults with uncomplicated influenza who were randomized to favipiravir (1800 mg twice a day on day 1, 800 mg twice a day on days 2 to 5; n = 827) or placebo (n = 419) in 2 phase 3 trials. Post hoc analyses assessed the frequency of reaching an average minimum concentration (Cmin) ≥20 µg/mL, its association with antiviral efficacy, and factors associated with reduced favipiravir exposure. Results Wide interindividual variability existed in favipiravir concentrations, and this regimen failed to reach an average Cmin > 20 µg/mL in 41%–43% of participants. Those attaining this threshold showed greater reductions in nasopharyngeal infectious virus titers on treatment days 2 and 3 and lower viral titer area under the curve compared to those who did not. Those with average Cmin <20 µg/mL had over 2-fold higher mean ratios of the metabolite T-705M1 to favipiravir, consistent with greater metabolism, and were more likely to weigh > 80 kg (61.5%–64%). Conclusions Higher favipiravir levels with average Cmin > 20 µg/mL were associated with larger antiviral effects and more rapid illness alleviation compared to placebo and to favipiravir recipients with lower average Cmin values in uncomplicated influenza. Clinical Trials Registration. NCT1068912 and NCT01728753. [ABSTRACT FROM AUTHOR]

Background: We conducted double-blind, placebo-controlled trials assessing the efficacy and tolerability of favipiravir in acute influenza.Methods: Otherwise healthy adults with influenza-like symptoms and fever of ≤48 hours were randomized to favipiravir (1800 mg twice daily [BID] on day 1, 800 mg BID on days 2-5) or placebo tablets (1:1 in US316; 3:1 in US317). The primary efficacy endpoint was the time to illness alleviation when 6 influenza symptoms were self-rated as absent or mild and fever was absent in the intention-to-treat, influenza-infected participants.Results: In US316 (301 favipiravir, 322 placebo), favipiravir was associated with a 14.4-hour reduction (median, 84.2 vs 98.6 hours; P = .004) in time to illness alleviation vs placebo. In US317 (526 favipiravir, 169 placebo), favipiravir did not significantly reduce time to alleviation (median, 77.8 vs 83.9 hours). In both trials favipiravir was associated with reduced viral titers, RNA load area under the curve over days 1-5, and median times to cessation of virus detection (P < .001). Aside from asymptomatic hyperuricemia, no important differences in adverse events were found.Conclusions: This favipiravir dosing regimen demonstrated significant antiviral efficacy but inconsistent illness alleviation in uncomplicated influenza. Studies of higher doses and antiviral combinations for treating serious influenza and other RNA viral infections are warranted. Clinical Trials Registration. NCT02026349; NCT02008344. [ABSTRACT FROM AUTHOR]

Prompt antiviral treatment has the potential to reduce influenza virus transmission to close contacts, but rigorous data on the magnitude of treatment effects on transmission are limited. Animal model data indicate that rapid reductions in viral replication after antiviral treatment reduce the risk of transmission. Observational and clinical trial data with oseltamivir and other neuraminidase inhibitors indicate that prompt treatment of household index patients seems to reduce the risk of illness in contacts, although the magnitude of the reported effects has varied widely across studies. In addition, the potential risk of transmitting drug-resistant variants exists with all approved classes of influenza antivirals. A controlled trial examining baloxavir treatment efficacy to reduce transmission, including the risk of transmitting virus with reduced baloxavir susceptibility, is currently in progress. If reduced transmission risk is confirmed, modeling studies indicate that early treatment could have major epidemiologic benefits in seasonal and pandemic influenza. [ABSTRACT FROM AUTHOR]

The NIH Virtual SARS-CoV-2 Antiviral Summit, held on 6 November 2020, was organized to provide an overview on the status and challenges in developing antiviral therapeutics for coronavirus disease 2019 (COVID-19), including combinations of antivirals. Scientific experts from the public and private sectors convened virtually during a live videocast to discuss severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) targets for drug discovery as well as the preclinical tools needed to develop and evaluate effective small-molecule antivirals. The goals of the Summit were to review the current state of the science, identify unmet research needs, share insights and lessons learned from treating other infectious diseases, identify opportunities for public-private partnerships, and assist the research community in designing and developing antiviral therapeutics. This report includes an overview of therapeutic approaches, individual panel summaries, and a summary of the discussions and perspectives on the challenges ahead for antiviral development. [ABSTRACT FROM AUTHOR]

Background Baloxavir marboxil has demonstrated safety and efficacy in treating adult and adolescent outpatients with acute influenza (CAPSTONE-1 trial). Here, we report a subgroup analysis of outcomes in adolescents from the trial. Methods CAPSTONE-1 was a randomized, double-blind, placebo-controlled study. Eligible adolescent outpatients (aged 12-17 years of age) were randomized in a ratio of 2:1 to a single dose of baloxavir 40/80 mg if less than/greater than or equal to 80 kg or placebo. The main outcomes were the time to alleviation of symptoms (TTAS), duration of infectious virus detection, and incidence of adverse events (AEs). Results Among 117 adolescent patients, 90 (77%) comprised the intent-to-treat infected population (63 baloxavir and 27 placebo; 88.9% A(H3N2)). The median TTAS was 38.6 hours shorter (95% confidence interval: −2.6, 68.4) in the baloxavir group compared with placebo (median TTAS, 54.1 hours vs 92.7 hours, P =.0055). The median time to sustained cessation of infectious virus detection was 72.0 hours for baloxavir compared with 120.0 hours for placebo recipients (P <.0001). Treatment-emergent PA/I38X-substituted viruses were detected in 5 of the 51 (9.8%) baloxavir recipients. In the safety population (76 baloxavir and 41 placebo), AEs were less common in baloxavir than placebo recipients (17.1% vs 34.1%; P =.0421). In the baloxavir group, no AEs except for diarrhea were reported in 2 or more patients. Conclusions Baloxavir demonstrated clinical and virologic efficacy in the otherwise healthy adolescents with acute influenza compared with placebo. There were no safety concerns identified. These results were similar to the adult population in CAPSTONE-1 and support baloxavir as a treatment option in adolescents. [ABSTRACT FROM AUTHOR]

Antivirals, respiratory syncytial virus, therapeutics. [Extracted from the article]

Background: A synergistic effect of combination therapy with favipiravir and oseltamivir has been reported in preclinical models of influenza. However, no data are available on the clinical effectiveness of combination therapy in severe influenza.Methods: Data from 2 separate prospective studies of influenza adults were used to compare outcomes between combination and oseltamivir monotherapy. Outcomes included rate of clinical improvement (defined as a decrease of 2 categories on a 7-category ordinal scale) and viral RNA detectability over time. Subhazard ratios (sHRs) were estimated by the Fine and Gray model for competing risks.Results: In total, 40 patients were treated with combination therapy and 128 with oseltamivir alone. Clinical improvement on day 14 in the combination group was higher than in the monotherapy group (62.5% vs 42.2%; P = .0247). The adjusted sHR for combination therapy was 2.06 (95% confidence interval, 1.30-3.26). The proportion of undetectable viral RNA at day 10 was higher in the combination group than the oseltamivir group (67.5% vs 21.9%; P < .01). No significant differences were observed in mortality or other outcomes.Conclusions: Favipiravir and oseltamivir combination therapy may accelerate clinical recovery compared to oseltamivir monotherapy in severe influenza, and this strategy should be formally evaluated in a randomized controlled trial. [ABSTRACT FROM AUTHOR]

Background: Single-dose baloxavir rapidly reduces influenza virus titers and symptoms in patients with uncomplicated influenza, but viruses with reduced in vitro susceptibility due to amino acid substitutions at position 38 of polymerase acidic protein (PA/I38X) sometimes emerge.Methods: We evaluated the kinetics, risk factors, and effects on clinical and virologic outcomes of emergence of PA/I38X-substituted viruses.Results: Viruses containing PA/I38X substitutions were identified 3-9 days after baloxavir treatment in 9.7% (36/370) of patients, of whom 85.3% had transient virus titer rises. Median time to sustained cessation of infectious virus detection was 192, 48, and 96 hours in the baloxavir recipients with PA/I38X-substituted viruses, without PA/I38X-substituted viruses, and placebo recipients, respectively. The corresponding median times to alleviation of symptoms were 63.1, 51.0, and 80.2 hours, respectively. After day 5, symptom increases occurred in 11.5%, 8.0%, and 13.0%, respectively, and in 8.9% of oseltamivir recipients. Variant virus emergence was associated with lower baseline neutralizing antibody titers.Conclusions: The emergence of viruses with PA/I38X substitutions following baloxavir treatment was associated with transient rises in infectious virus titers, prolongation of virus detectability, initial delay in symptom alleviation, and uncommonly with symptom rebound. The potential transmissibility of PA/I38X-substituted viruses requires careful study.Clinical Trial Registration: NCT02954354. [ABSTRACT FROM AUTHOR]

The article focuses on experimental therapies that are used in the treatment of Ebola virus disease (EVD). Various topics discussed include mortality rate of EVD, supportive care offered to patients suffering from EVD, child's survival through these therapies and use of antiviral agents in the treatment.

Emergence of resistance is a major concern in influenza antiviral treatment and prophylaxis. Combination antiviral therapy might overcome this problem. Here, we estimate that all possible single mutants and a sizeable fraction of double mutants are generated during an uncomplicated influenza infection. While most of them may sustain a fitness cost, some variants may confer drug resistance and be selected during therapy. We argue that a triple combination regimen would markedly reduce the risk of antiviral resistance emergence in seasonal and pandemic influenza viruses, especially in seriously ill or immunocompromised hosts. [ABSTRACT FROM AUTHOR]

Influenza infection results in substantial morbidity and mortality in hospitalized patients, including those who are immunocompromised or pregnant. Antiviral therapy likely provides considerable benefit to these patients, but few studies have been successfully conducted in these high-risk populations, and no drugs are specifically licensed for treating these subgroups. One of the key challenges facing novel antiviral drug development for influenza is determining the appropriate efficacy end points that would enable rapid regulatory approval for drug use in seriously ill patients, for whom risk-benefit assessments differ from those with uncomplicated illness. All available antiviral drugs currently affect viral replication, and respiratory tract viral titers correlate with both symptoms and measures of host inflammatory responses, including cytokine and chemokine expression that are likely responsible for many of the clinical symptoms. Consequently, we outline the evidence to support the use of primary virological end points in studies of antiviral agents involving patients who are hospitalized with severe influenza or those who are at high risk of severe and life-threatening disease. [ABSTRACT FROM AUTHOR]

The author discusses the gain-of-function (GOF) research with potential pandemic pathogens and the Infectious Diseases Society of America (IDSA). He discusses the importance of clinician perspective for risk-benefit assessment (RBA) of GOF research. The author mentioned the recommendations from the National Science Advisory Board for Biosecurity (NSABB) on the dual use and biosecurity of GOF.

The availability of immunogenic, licensed H5N1 vaccines and the anticipated development of vaccines against "swine" influenza A(H1N1) have stimulated debate about the possible use of these vaccines for protection of those exposed to potential pandemic influenza viruses and for immunization or "priming" of populations in the so-called "prepandemic" (interpandemic) era. However, the safety of such vaccines is a critical issue in policy development for wide-scale application of vaccines in the interpandemic period. For example, wide-scale interpandemic use of H5N1 vaccines could lead to millions of persons receiving vaccines of uncertain efficacy potentially associated with rare severe adverse events and against a virus that may not cause a pandemic. Here, we first review aspects of the 1976 National Influenza Immunization Programme against "swine flu" and its well-documented association with Guillain-Barré syndrome as a case study illustration of a suspected vaccine-associated severe adverse event in a mass interpandemic immunization setting. This case study is especially timely, given the recent spread of a novel influenza A(H1N1) virus in humans in Mexico and beyond. Following this, we examine available safety data from clinical trials of H5N1 vaccines and briefly discuss how vaccine safety could be monitored in a postmarketing surveillance setting. [ABSTRACT FROM AUTHOR]

Guidelines for the treatment of persons with influenza virus infection were prepared by an Expert Panel of the Infectious Diseases Society of America. The evidence-based guidelines encompass diagnostic issues, treatment and chemoprophylaxis with antiviral medications, and issues related to institutional outbreak management for seasonal (interpandemic) influenza. They are intended for use by physicians in all medical specialties with direct patient care, because influenza virus infection is common in communities during influenza season and may be encountered by practitioners caring for a wide variety of patients. [ABSTRACT FROM AUTHOR]

Background. Respiratory syncytial virus (RSV) has been recognized recently as an important adult pathogen. Methods. This randomized, double-blind, placebo-controlled study was designed to compare humoral responses to licensed trivalent influenza vaccine given concomitantly with 1 of 2 RSV vaccine formulations in persons ⩾65 years old with cardiopulmonary disease. Hemagglutinin-inhibition assays and neutralization assays were used to measure levels of antibody to influenza and RSV, respectively. Subjects with respiratory illnesses during subsequent winters were tested for RSV and influenza by reverse-transcriptase polymerase chain reaction and serologic analysis. Results. Neither RSV vaccine formulation had an effect on the humoral response to influenza vaccination, and both RSV vaccines were well tolerated by 1169 participants. The immunogenicity of the nonadjuvanted vaccine was judged superior on the basis of mean postvaccination neutralizing antibody titers (12.5 vs. 12.1) and the percentage of subjects for whom ⩾4-fold increases in neutralizing titer were observed when acute-phase and convalescent-phase serum samples were compared (168 [44%] of 383 vs. 129 [33%] of 400). In year 1, the percentage of illnesses due to RSV was 7% (36 of 492 illnesses) and that due to influenza was 8%(40 of 492), compared with 6% (11 of 189) due to RSV and 11% (20 of 189) due to influenza in year 2. The incidence of RSV infection was not significantly different in the RSV vaccine and placebo groups. Conclusions. Although the safety and immunogenicity data of these RSV vaccines are encouraging, low rates of infection make it challenging to design efficacy trials. [ABSTRACT FROM AUTHOR]

The long history of influenza drug development has both contributed practical advances in antiviral chemotherapy and improved the understanding of influenza pathogenesis and epidemiology. The role played by these antivirals continues to grow with the dual threats of seasonal and pandemic influenza. The neuraminidase inhibitors are proven effective for the chemoprophylaxis and treatment of influenza A and B, although early therapy is essential for disease mitigation. Studies of topically applied zanamivir have demonstrated the importance of viral replication in the lower respiratory tract, even in uncomplicated influenza. Antiviral resistance, especially to the M2 ion channel inhibitors, sometimes limits clinical utility. Oseltamivir-resistant variants may emerge during treatment but have not yet circulated widely and are usually less fit than wild-type virus; most retain susceptibility to zanamivir. The transmission fitness cost of these resistant variants is drug-, neuraminidase subtype-, and mutation-specific. Continued vigilance in drug resistance surveillance is imperative, as is research into the development of new agents that will provide the potential for alternative and combination antiviral therapy. [ABSTRACT FROM AUTHOR]

The goals of antiviral treatment for influenza are to decrease symptoms and functional disability and, more important, to decrease associated complications, hospitalizations, and mortality. Four drugs have been approved for treatment of and prophylaxis against influenza in the United States, but they are underutilized. The M2 ion channel inhibitors amantadine and rimantadine are effective for prophylaxis, and they decrease the duration of symptoms if they are used for early treatment of influenza A. The rapid emergence of resistance during therapy and, recently, the circulation of resistant H3N2 viruses in the community have decreased the usefulness of these M2 ion channel inhibitors. Early therapy with neuraminidase (NA) inhibitors, either oseltamivir or zanamivir, reduces the duration of symptoms, the duration of disability, and the risk of lower respiratory tract complications. Oseltamivir has been shown to decrease antibiotic use, the number of hospitalizations, and, probably, the risk of death after influenza. NA inhibitors might provide substantial benefits in the treatment of pandemic influenza, with reductions in the numbers of hospitalizations and deaths occurring if such treatment (1) is made available in sufficient time, through rapid distribution, and (2) is available in sufficient quantities as a result of stockpiling. Both of the aforementioned NA inhibitors are highly effective for prophylaxis. Geographically targeted mass chemoprophylaxis might contain the spread of a pandemic virus, but multiple hurdles to successful implementation exist. Resistance to oseltamivir occurs with the H274Y variant in viruses that contain N1; however, to date, such variants have been less fit, have not been transmitted from person to person, and have retained susceptibility to zanamivir. Alternative agents and approaches, including parenteral and combination therapy, for the treatment of influenza are needed in the near and long term. [ABSTRACT FROM AUTHOR]

There is a continued need to improve the state of preparedness for a potential influenza pandemic in the United States despite the publication of a pandemic influenza plan by the Department of Health and Human Services. Of particular importance are the sense of urgency for a coordinated response plan, an allocation of adequate funds to deal with this issue, and the need for a national leader to coordinate the development and execution of a national plan, including its relationship to the control of seasonal influenza. In addition, an infrastructure needs to be established in the United States to enable the rapid development and large-scale production of a safe and effective vaccine for new influenza strains; methods to treat influenza pneumonia need to be evaluated; a coordinated public health response needs to be defined; a nationally developed blueprint to deal with logistics of pandemic prevention is required; and there is a need to establish reliable communication systems on a national and local basis, to provide accurate information to the lay public, health care workers, and the agricultural sector. [ABSTRACT FROM AUTHOR]

Background. Staphylococcus aureus is among the most important pathogens in today's hospital setting. Methods. The effects of sneezing on the airborne dispersal of S. aureus and other bacteria were assessed in 11 healthy nasal S. aureus carriers with experimentally induced rhinovirus colds. Airborne dispersal was studied by volumetric air sampling in 2 chamber sessions with and without histamine-induced sneezing. After 2 days of preexposure measurements, volunteers were inoculated with a rhinovirus and monitored for 14 days. Daily quantitative nasal- and skin-culture samples for bacteria and nasal-culture samples for rhinovirus were obtained, cold symptoms were assessed, and volunteer activities were recorded during sessions. Results. All participants developed a cold. Sneezing caused a 4.7-fold increase in the airborne dispersal of S. aureus, a 1.4-fold increase in coagulase-negative staphylococci (CoNS), and a 3.9-fold increase in other bacteria (P < .001). An additional 2.83 colony forming units (cfu) of S. aureus/m³/min, 3.24 cfu of CoNS/m³/min, and 474.61 cfu of other bacteria/m³/min were released per sneeze. Rhinovirus exposure did not change the frequency of sneezing or airborne dispersal. Having respiratory allergies increased the spread of S. aureus by 3.8-fold during sneezing sessions (P < .001). Conclusion. Nasal S. aureus carriers disperse a significant amount of S. aureus into the air by sneezing. Experimental colds do not alter bacterial dispersal, but respiratory allergies multiply the effect of dispersing S. aureus. [ABSTRACT FROM AUTHOR]

We developed an immunocompromised murine model of influenza virus infection and demonstrated comparable efficacy of oral oseltamivir and A-322278 (both given at dosages of 10 mg/kg/day) in reducing viral replication, decreasing weight loss, and prolonging survival. Once the treatment was discontinued, severe combined immunodeficient (SCID) mice had progressive viral replication and clinical decline. Drug-resistant variants were detected in 4 (29%) of 14 and 2 (13%) of 15 mice (both BALB/c and SCID) treated with oseltamivir or A-322278, respectively; no resistant variants were detected in placebo-treated mice. Amino acid substitutions in the hemagglutinin receptor-binding site at aa 137 or 225 were detected in cloned resistant isolates. A substitution in the neuraminidase (NA) active site (Arg292Lys) was detected in the cloned virus recovered from an oseltamivir-treated mouse. This model would be useful for elucidation of the molecular mechanisms of resistance to NA inhibitors and for testing of anti-influenza therapy options that might prevent the emergence of resistant variants. [ABSTRACT FROM AUTHOR]

Influenza virus with resistance to antiviral drugs emerges with increased frequency in immunocompromised patients and can limit the benefit of M2 and neuraminidase (NA) inhibitors. We document 3 cases of influenza in severely immunocompromised patients from whom virus variants with molecular markers of resistance to anti-influenza drugs were recovered. Virus variants recovered from 2 patients had mutations in the M2, NA (with a previously recognized Glu119Val NA substitution), and hemagglutinin genes. We describe a novel Asp198Asn NA mutation in an influenza B virus and its decreased susceptibility to both oseltamivir and zanamivir. [ABSTRACT FROM AUTHOR]

Background. Previous studies have reported abnormal cardiac findings in up to 43% of ambulatory adults with influenza. This study was conducted to determine the frequency, magnitude, and duration of myocardial dysfunction in such persons. Methods. We enrolled 30 previously healthy young adults without known cardiovascular disease who presented to the clinic &les;72 h after onset of influenza symptoms and had a positive influenza antigen test. Most patients received antiviral therapy, and all underwent serial electrocardiography and had blood specimens collected on days 1, 4, 11, and 28 after presentation for measurement of total creatine kinase (CK) level, CK isoenzyme MB (CK- MB) level, troponin I level, and selected cytokine levels. Echocardiography was performed on days 4, 11, and 28. Results. None of the patients had an elevated CK-MB index or troponin I level. Abnormal electrocardiogram findings were noted in 53%, 33%, 27%, and 23% of patients on days 1, 4, 11, and 28, respectively, but none of the findings were considered to be clinically significant. No patient had significant changes in the ejection fraction or abnormal wall motions. Conclusions. Most ambulatory young adults with acute influenza have clinically insignificant abnormal electrocardiogram findings early during the illness. These abnormalities resolve promptly and are not associated with changes in cardiac markers or echocardiogram findings. [ABSTRACT FROM AUTHOR]

We determined the efficacy of postexposure prophylaxis (PEP) and treatment of ill index cases with oseltamivir, in an attempt to prevent influenza transmission in households, in a study conducted in 277 households with 298 index cases (62% with laboratory-confirmed influenza) and 812 contacts aged ≥1 year. Contacts were randomized by household to receive treatment (5 days; n = 402), if illness developed, or PEP for 10 days (n = 410), and the number of households with at least 1 contact developing laboratory-confirmed influenza was measured. PEP provided a protective efficacy of 58.5% (95% confidence interval [CI], 15.6%–79.6%; (P = .0114) for households against proven influenza and 68.0% (95% CI, 34.9%–84.2%;) for individual contacts, compared with treatment of index cases alone. No oseltamivir-resistant variants were detected in treated index cases or contacts. PEP of household contacts of those with influenza reduces the secondary spread of influenza in families when the initial household case is treated. [ABSTRACT FROM AUTHOR]

The novel capsid-binding antiviral pleconaril inhibits in vitro replication of most rhinoviruses and entero-viruses. Oral pleconaril treatment was studied in 2 parallel randomized, double-blind, placebo-controlledtrials. Among 1363 picornavirus-infected participants (65%) in the studies combined, the median time to alleviation of illness was 1 day shorter for pleconaril recipients than for placebo recipients (P < .001). Cold symptom scores and frequency of picornavirus cultured from nasal mucus specimens were lower among pleconaril recipients by day 2 of treatment. No treatment effects were seen in those without picornavirus infection. Pleconaril was associated with a higher incidence of nausea (6% vs. 4%) and diarrhea (9% vs. 7%) and with small increases in mean serum cholesterol levels and platelet counts, compared with baseline measurements. A subsequent 6-week prophylaxis study found that pleconaril induces cytochrome P-450 3A enzymes, which metabolize a variety of drugs, including ethinyl estradiol. Early pleconaril treatment was well tolerated and significantly reduced the duration and severity of colds due to picornaviruses in adults. [ABSTRACT FROM AUTHOR]

Little is known about the impact of human rhinovirus (HRV) and coronavirus infections in hematopoietic stem cell transplant (HSCT) recipients. We tested bronchoalveolar lavage (BAL) samples obtained from HSCT recipients with acute pulmonary infiltrates for HRV (n = 122) and coronavirus (n = 46) by reverse-transcriptase polymerase chain reaction. HRV RNA was detected in 6 (8) of 77 patients, and coronavirus RNA was detected in 0 of 46 of BAL samples from HSCT recipients. The fatality rate in HRV-infected patients was high (83), but all patients had significant coinfections, and the overall mortality rate was not different from that of patients who were negative for HRV in BAL samples. These results suggest that HRV may be a cause of lower respiratory tract infections in HSCT recipients and that its detection in BAL samples is associated with frequent copathogens. Whether the poor prognosis is due to HRV or the copathogen is not clear. [ABSTRACT FROM AUTHOR]

The relationship between Kaposi sarcoma--associated herpesvirus (KSHV) viremia and KS disease was investigated in 500 subjects who received treatment in Harare, Zimbabwe. Subjects were grouped by results of human immunodeficiency virus (HIV) type 1 serological tests, KS diagnosis, and KS clinical stage. The plasma KSHV DNA concentration was associated with concomitant KS and HIV-1 infection (AIDS-KS; P < .001) and AIDS-KS clinical stage (P = .01). Plasma KSHV DNA levels were greater in AIDS-KS than in matched HIV-1-seronegative KS (P = .04). The plasma KSHV DNA level was not associated with age, sex, systemic symptoms, or CD4[SUP+] lymphocyte count. Plasma and peripheral blood mononuclear cell KSHV DNA concentrations were linearly related (r[SUP2] = .44; P < .001), and the nucleotide sequence of the K1 gene highly variable region was identical in both compartments. These findings provide evidence that KSHV viremia is common in advanced AIDS-KS in Zimbabwe and suggest a relationship between KSHV lytic replication and untreated HIV-1 infection. [ABSTRACT FROM AUTHOR]

To examine the molecular epidemiology of influenza virus transmission, the nucleotide sequences of the HA1 domain of the hemagglutinin (HA) gene of 57 influenza A and 24 influenza B viruses recovered in a single season were analyzed. No nucleotide sequence differences were found among the 10 viruses that were recovered twice from the same patient. The nucleotide sequences of influenza A viruses were identical within each family but varied among the 14 families included in the study. The sequences of influenza A viruses recovered from 18 residents of the same community showed that 83% of the viruses differed from the others by at least 1 nucleotide residue. These findings indicate that most cases of influenza in households in which 1 family member has been infected are the result of secondary transmission from the index patient and not of acquisition from other community sources. Substantial genetic conservation during virus transmission within households is indicated. [ABSTRACT FROM AUTHOR]

Rhinoviruses and coronaviruses are recognized as the major causes of the common cold syndrome. The role of these viruses in more serious respiratory illnesses resulting in hospitalization is less well defined. During a winter when influenza A infection was prevalent, 100 elderly adults hospitalized because of cardiopulmonary illnesses were evaluated for rhinovirus and coronavirus infection. Patients who tested negative for influenza or respiratory syncytial virus had nasal swab samples tested for rhinovirus, coronavirus OC43, and coronavirus 229E by reverse-transcription polymerase chain reaction and for coronaviruses by serologic testing. Twelve percent of patients had rhinovirus or coronavirus identified (rhinovirus, 4 patients; coronavirus 229E, 4 patients; coronavirus OC43, 3 patients; and mixed rhinovirus/coronavirus 229E infection, 1 patient). All patients had significant underlying diseases. Although all patients recovered, the mean length of stay was 8 days; 4 persons had pneumonia, and 1 required ventilator support. These data suggest that rhinoviruses and coronaviruses may be associated with serious respiratory illnesses in frail older adults. [ABSTRACT FROM AUTHOR]

With the use of neuraminidase (NA) inhibitors (BCX-1812, oseltamivir, or zanamivir), drugresistant variants of influenza A viruses were generated that lacked characteristic markers of resistance, such as substitutions in the NA active center or in the hemagglutinin. Drug resistance was associated with the accumulation of defective (A) RNA segments encoding NA. This phenomenon could be explained by reduced dependence of the virus on its NA activity. Analysis of the last isolates recovered from 11 volunteers, experimentally infected with influenza virus and treated with BCX-1812, revealed that they maintained full susceptibility to the drug in the NA inhibition assay (50 % inhibitory concentration, 0.35-0.5 nM). The presence of ARNA segments was detected in 1 of these isolates but was not found in the isolates recovered from placebo recipients (n = 8). Because of a lack of cell culture-based assays for susceptibility testing of human influenza viruses, detection of ARNA segments should be considered an additional assay for monitoring of NA inhibitor resistance. [ABSTRACT FROM AUTHOR]

Features a study on the potential for the emergence of oseltamivir-resistant variants in human volunteers treated with neuraminidase inhibitor, after experimental infection with an influenza A virus. Inhibitors of influenza virus NA; Methodology; Results.

Studies correlates of immune protection induced by live, attenuated, cold-adapted, trivalent, intranasal influenza virus vaccine. Safety and efficacy against virus shedding; Correlation between the presence of either serum antibody or nasal wash immunoglobulin A and protection from infection by influenza strain H1N1.

Characterizes the local immune response to influenza virus infection through the determination of cytokine and chemokine levels in serial nasal lavate fluid samples from volunteers experimentally infected with influenza A. Effect of the inhibitor zanamivir on the clinical symptoms of influenza infection; Roles played cytokines and chemokines in the development of symptoms and resolution of influenza.

We monitored the responses of solid organ transplant recipients (SOTs) to influenza vaccine during consecutive influenza seasons. Standard 1993–1994 trivalent influenza vaccine was given to 68 SOTs and 29 healthy young adults) and hemagglutination-inhibition (HI) antibody titers were determined pre- and post-immunization. Significant rises in geometric mean antibody titers occurred post-immunization for all three antigens in both groups. However) the magnitude of the rise was lower in SOTs (1.5–2.3-fold vs. 8.7–10.4-fold, depending on the antigen) (P < .05), and significantly fewer SOTs had protective HI titers (⩾1:40) for B/Panama/45190 antigens (50% of SOTs vs. 76% of healthy subjects) and for A/Texas/36/91 (H1Nl) antigens (60% vs. 90%). After exclusion of persons with high preimmunization titers, SOTs had significantly reduced frequencies of ⩾4-fold antibody responses compared with those of healthy subjects (23%–38% vs. 86%–100%) (P < .05 for each antigen). When a series of two injections of standard 1994–1995 vaccine was given to 23 SOTs, there was no significant improvement in vaccine response with the second dose. Some SOTs have deficient responses to inactivated influenza vaccines. [ABSTRACT FROM PUBLISHER]

The therapeutic efficacy of recombinant interferon-α2, (HuIFN-α2) in experimental infection with rhinovirus type 39 was assessed in two randomized, double-blind, placebo- controlled studies. Adult volunteers (serum neutralizing antibody titer, ⩽1:2) were given 9 × 106 international units of HuIFN-α2 three times a day for five days by intranasal spray (study 1) or drops (study 2) beginning 28 hr after rhinovirus inoculation. HuIFN-α2 did not prevent rhinovirus infection or colds in either study. Treatment by nasal drops and to a lesser extent by spray was associated with significant reductions in duration and quantity of viral shedding. Treatment by drops was associated with significant but modest effects on nasal symptom scores and trends toward reduced quantities of production of nasal mucus. Despite lower nasal wash concentrations of interferon, HuIFN-α2 drops appeared to have greater antiviral activity and therapeutic efficacy than did HuIFN-α2 spray. These findings suggest that HuIFN-α2 may not be therapeutically useful in treating naturally occurring rhinoviral colds. [ABSTRACT FROM PUBLISHER]

Fifty-two healthy adults were randomly assigned interferon-α2 (HuIFN-α2), 8.4 × 106 U/day, or placebo by intranasal spray for 28 days. Symptoms, nasal examinations, and histologic analysis of nasal biopsy specimens obtained three days before and one day after exposure were evaluated under blind conditions. HuIFN-α2 was associated with signs of mucosal irritation (dry mucous membranes, crusts, and friability) and/or symptoms (blood-tinged mucus) in 23% of recipients. Moderate or marked epithelial acute inflammation with ulceration occurred in 19% of HuIFN-α2 recipients. Pronounced submucosal lymphocytic and mononuclear cell infiltrates developed in 58%. These histopathologic abnormalities resolved within eight weeks of stopping exposure. These results indicate that long-term or indefinite intranasal administration of HuIFN-α2 at the dosages used in this study is not feasible strategy for prophylaxis of respiratory viral infections. [ABSTRACT FROM PUBLISHER]

In two placebo-controlled, double-blind studies, the prophylactic efficacy of recombinant DNA-produced interferon α2 (lFN-α2) against induced rhinovirus (RV) type 39 infection in susceptible volunteers was assessed. IFN-α2 was given by intranasal drops in either multiple treatments (11.4 × 106 IU four times per day for four days) or one treatment daily (42.8 × 106 IU once per day for five days) starting before RV type 39 challenge. The efficacy rates of multiple-dose IFN-α2 for preventing infection, virus shedding, and RV type 39-specific colds were 78%, 78%, and 100%, respectively. The corresponding rates for one daily treatment were 45%, 64%, and 75%, respectively. Both dosage regimens were associated with significant reductions in days of virus shedding and nasal mucus production. In the second study, three IFN-α2 recipients developed transient leukopenia (<4,000 leukocytes/rum3). The results suggest that intranasal IFN-α2 may prove to be a safe and effective method of preventing rhinovirus infection and illness. [ABSTRACT FROM PUBLISHER]

The effect of small-particle aerosol therapy with amantadine was assessed in a randomized, double-blind study of 20 patients with naturally acquired influenza A virus infection. Aerosol treatments of 20 min with either distilled water or with amantadine hydrochloride (1.0 g/100 ml of distilled water) were given three times a day for four days. The amantadine-treated patients experienced a significantly more rapid resolution of clinical signs and symptoms when compared with placebo-treated patients. The resolution of fever was similar for both groups. Aerosol delivery of amantadine did not affect the frequency of viral isolation from upper respiratory tract secretions but was associated with a trend toward reduced quantity of viral shedding. Serial pulmonary function tests found no important differences between the groups. Amantadine-treated patients experienced a greater frequency of mild local side effects (rhinorrhea, nasal irritation) during aerosol exposures, but aerosol treatments did not cause any apparent decline in pulmonary function. [ABSTRACT FROM PUBLISHER]

Susceptible adults (n = 105) were enrolled into a randomized double-blind study of rimantadine treatment of experimental influenza A infection. Subjects were cloistered for 8 days and challenged with a rimantadine-sensitive strain of influenza A H1N1 virus at the end of the first day. Fortyeight hours after challenge and for 8 days, 54 subjects received placebo and 51 received rimantadine (100 mg orally, twice a day). Symptoms, signs, and pathophysiologies were monitored. Nine subjects were not infected. Seventeen subjects (38%) in the rimantadine and 26 (53%) in the placebo group became ill. A beneficial effect of rimantadine was documented for virus shedding, symptom load, and sinus pain. Rimantadine had no effect on nasal patency, mucociliary clearance, nasal signs, or on symptoms and signs of otologic complications. These results do not support a preventive effect of rimantadine on the development of otologic manifestations of influenza A infection in adults. [ABSTRACT FROM PUBLISHER]

A model was developed for the emergence of drug-resistant influenza viruses during a closed population influenza epidemic that occurs in a single wave. The model was used to consider several treatment and chemoprophylaxis strategies and to determine their effects on the spread of the infection. The model predicts frequent emergence and transmission of drug-resistant viruses with certain treatment scenarios. According to the model, chemoprophylaxis of susceptible persons (without treatment of those who are symptomatic) may be the best way to reduce the force of an epidemic and to keep development of drug resistance low. The model predictions indicate that the relative transmissibility of resistant variants compared with wild type virus and the choice of the treatment or chemoprophylaxis strategy can be decisive for the spread of drug-resistant viruses, a feature that may be crucial in a pandemic. [ABSTRACT FROM PUBLISHER]

Middle ear pressure (MEP) abnormalities are frequently observed during influenza virus infection and may serve as surrogate markers for the risk of otitis media. MEP abnormalities were evaluated in adult volunteers who were inoculated with influenza A/Texas/36/91(H1N1) or B/Yamagata/88 virus and given the antiviral zanamivir (GG167) intranasally as prophylaxis or early treatment in randomized, double-blind, placebo-controlled trials. In the influenza A prophylaxis studies, 15% of 61 zanamivir recipients versus 61% of 33 placebo recipients showed significant MEP abnormalities (P < .01). In the influenza A early treatment trial, 32% of 31 infected zanamivir recipients versus 73% of 26 infected placebo recipients developed MEP abnormalities (P < .01). In the influenza B prophylaxis trial, 16% of 25 zanamivir versus 44% of 9 placebo recipients showed abnormalities (P < .09). These findings indicate that the neuraminidase inhibitor zanamivir, which is effective in reducing experimental influenza illness, provides protection against the development of MEP abnormalities. [ABSTRACT FROM PUBLISHER]

Consecutive A (H3N2) influenza virus isolates from 2 influenza virus-infected immunodeficient patients treated with amantadine were examined using a novel polymerase chain reaction (PCR)restriction analysis for resistance to this antiviral compound. The data indicate that immunodeficient patients may shed resistant viruses for prolonged periods and with different drug resistance mutations present at different times. This PCR-restriction technique allows rapid detection of amantadine- or rimantadine-resistant strains. [ABSTRACT FROM PUBLISHER]

To better understand the significanceof viral upper respiratory tract infections in the pathogenesis of acute otitis media (OM), 27 adults underwent intranasal inoculation with influenza A virus. Monitoring consisted of antibody titer determination, tympanometry, and otoscopy. Microbiologic analysis consisted of cultures and polymerase chain reaction (PCR)-based detection for influenza A virus, Streptococcus pneumoniae, Haemophilus infiuenzae, and Moraxella catarrhalis. All subjects became infected with the challenge virus. By day 4, 16 (59%) developed middle ear pressures of −100 mm H2O or below and 4 (25%) of them developed OM. One subject (4%) developed purulent OM requiring myringotomy for pain relief. Middle ear effusion cultures were negative. PCR analysis of that subject's middle ear effusion and nasal washes were positive for influenza A virus and S. pneumoniae. These findings support a causal role for viral upper respiratory tract infections in the pathogenesis of OM, possibly mediated by middle ear underpressures and viral and bacterial middle ear infection. [ABSTRACT FROM PUBLISHER]

To localize the sites and determine the extent of human rhinovirus (HRV) replication in the upper respiratory tract, biopsies of nasal and nasopharyngeal epithelia were collected from 26 HRV-or 7 sham-inoculated volunteers on days 1, 3, and 5 and on days 12, 20, or 33 after inoculation and analyzed by in situ hybridization. HRV-infected cells were detected on at least 1 day in 22 of the 23 HRV-infected subjects and in 1 of the 7 sham-inoculated subjects who developed a cold and had nasal secretions positive for a picornavirus by polymerase chain reaction. Low numbers of in situ hybridization-positive ciliated cells were present in nasal biopsies. In the nasopharynx, most HRV-infected cells were ciliated, but infected nonciliated epithelial cells were also detected. Our results indicate that HRV replicates in a very small proportion of cells in the nasal epithelium and in both ciliated and nonciliated cells in the nasopharynx of experimentally infected humans. [ABSTRACT FROM PUBLISHER]

To determine middle ear pressure (MEP) changes during natural rhinovirus colds, adults with illness for ⩽3 days were tested by digital tympanometer daily for 5 days (study 1) or every other day for 7 days (study 2). Abnormal MEPs <−50 or >+20 mm H20) were found in 72% of 36 patients in study 1 (P < .001, vs. baseline of 11%) and 76% of 55 patients in study 2 (P < .001, vs. 15% of 103 healthy controls). Major abnormalities (⩾+100 or ⩽−100 mm H20) were found in 61% ofpatients in study 1 (P < .001, vs. baseline of 0) and 47% in study 2 (P < .001, vs. control of 5%). MEP abnormalities usually resolved by day 14. Only 1 subject developed clinically apparent otitis media. Earache or respiratory symptom scores did not correlate with MEP abnormalities. These results indicate that natural rhinovirus colds in adults are frequently associated with marked but transient MEP abnormalities. [ABSTRACT FROM PUBLISHER]

Epidemic keratoconjunctivitis (EKC) due to adenovirus type 8 affected 126 (7%) of 1870 ophthalmology clinic patients during an outbreak. Risk factors and mode of transmission were studied by comparing cases (n = 58) and controls (n = 200) for exposure to risk factors. Pneumotonometry (odds ratio [OR], 10.5; 95% confidence interval [CI], 4.0-27.7), multiple clinic visits (OR, 5.9; 95% CI, 3.3-10.6), and contact with an infected physician (OR, 3.3; 95% CI, 1.2-9.0) were significant risk factors for infection. The hands of 3 patients and 3 physicians with EKC were cultured before and after hand washing to assess adenovirus removal; 3 had hand cultures positive for adenovirus after hand washing. In conclusion, this outbreak appeared to be due to inadequate disinfection of instruments, especially pneumotonometers, and finger-to-eye transmission by health care workers. Hand washing did not reliably remove adenovirus from contaminated fingers. Gloving for exam of eyes with EKC may help prevent transmission. Ophthalmologists with EKC were a significant risk factor for patients and should be furloughed for the duration of communicability. [ABSTRACT FROM PUBLISHER]

The influence of rimantadine-resistance mutations on the virulence of human H3N2 viruses in ferrets was examined. The similarities in virulence of the drug-resistant mutants with single amino acid substitutions at three different locations, 27, 30, and 31, within the M2 sequence and their corresponding sensitive wild-type isolates contrasted with differences in virulence between the three pairs of viruses. These data provide further evidence that rimantadine-resistant viruses that emerge during treatment of patients with the drug are unaltered both in their growth characteristics and virulence. [ABSTRACT FROM PUBLISHER]

The morbidity of acute respiratory infections in young children and the role of respiratory viruses were evaluated in a 29-month household-based study in an impoverished urban population in Fortaleza, Brazil; subjects were 175 children <5 years of age in 63 families. Home visits were conducted three times weekly during which staff recorded the presence of respiratory and systemic symptoms and collected upper respiratory tract samples for viral isolation. A large and sustained burden of respiratory illness was observed, and respiratory viruses were isolated in 35% of the samples collected. Of the isolates, 45.6% were rhinoviruses, 16% parainfluenza viruses, 15.8% enteroviruses, 9.9% adenoviruses, 7.0% herpes simplex viruses, and 5.7% influenza viruses. The results indicate that poor children in northeast Brazil have a high prevalence of respiratory illness and that rhinovirus is the most frequent respiratory virus. [ABSTRACT FROM PUBLISHER]

The effects ofcombined intranasal and systemic glucocorticoid steroids on the local inflammatory response, and symptoms due to experimental rhinovirus infection were studied in 45 adults randomized to prophylaxis with either placebo or steroids. Intranasal beclomethasone (168 IJ.g twice a day) was begun 4 days before viral challenge and continued 5 days after challenge. Oral prednisone (30 mg twice daily) was given for 3 days beginning 1 day before challenge. During the first 48 h after viral inoculation, nasal obstruction, nasal mucus weights, and kinin concentrations in nasal lavages were lower in steroid recipients, but subsequent increases in these variables in the steroid group resulted in no significant cumulative differences between treatment groups. These data suggest that steroid prophylaxis may suppress nasal inflammation and cold symptoms during the first 2 days in experimental rhinovirus colds. [ABSTRACT FROM PUBLISHER]