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In December 2003, the largest outbreak of highly pathogenic avian influenza H5N1 occurred among poultry in 8 Asian countries. A limited number of human H5N1 infections have been reported from Vietnam and Thailand, with a mortality rate approaching 70%. Deaths have occurred in otherwise healthy young individuals, which is reminiscent of the 1918 Spanish influenza pandemic. The main presenting features were fever, pneumonitis, lymphopenia, and diarrhea. Notably, sore throat, conjunctivitis, and coryza were absent. The H5N1 strains are resistant to amantadine and rimantadine but are susceptible to neuraminidase inhibitors, which can be used for treatment and prophylaxis. The widespread epidemic of avian influenza in domestic birds increases the likelihood for mutational events and genetic reassortment. The threat of a future pandemic from avian influenza is real. Adequate surveillance, development of vaccines, outbreak preparedness, and pandemic influenza planning are important. This article summarizes the current knowledge on avian influenza, including the virology, epidemiology, diagnosis, and management of this emerging disease.
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PMID:Avian influenza: a new pandemic threat? 1506 17

A pharmacoeconomic evaluation was made of prophylaxis against influenza using the oral neuraminidase inhibitor oseltamivir. Two patterns consisting of administration for 7 days as postcontact prophylaxis (7 day model) and seasonal administration for 6 weeks (6 week model) were examined. Decision analysis models were created on the basis of reports of clinical studies and epidemiologic studies relating to the drug and vaccination, and cost-effectiveness analyses were conducted based on the number of persons who had influenza and pneumonia as health outcomes. Costs were estimated with respect to health expenditures from the societal perspective as well as productivity costs. In the case of administration for 1-week postcontact prophylaxis, the health outcomes improved and costs were reduced in comparison with nontreatment, thus making this administration schedule the dominant choice. With administration for 6 weeks during the infectious period, vaccination involved lower costs and was superior in terms of health outcomes.
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PMID:[Pharmacoeconomic evaluation of oseltamivir as prophylaxis against influenza infection]. 1506 84

Influenza infection can be severe in bone marrow transplant (BMT) recipients. Although yearly epidemics occur worldwide, and a higher risk of complication is expected in these patients, few studies have addressed the impact of the new neuraminidase inhibitors in the prognosis of influenza after BMT. Influenza A or B infections were found in 39 of the 66 patients (59%) showing a positive nasal wash by DFA. Influenza A was diagnosed in 18 patients and influenza B in 23 patients; two patients were infected by influenza A and B with 84- and 90-day intervals between episodes, respectively. Of the 41 episodes (61%) of influenza A or B, 25 infections occurred during the spring and summer months. Oseltamivir was introduced within 48 h of symptoms appearing. Only two patients (5.1%) developed influenza pneumonia, and no patient died of influenza. A total of 22 patients (56.4%) acquired influenza before day +180 when preventive vaccination strategies are precluded owing to poor immunogenicity of the vaccine during this period. Oseltamivir proved to be safe and appears to have played an important role in the outcome of influenza infection in this population. The therapeutic and/or prophylactic benefits of Oseltamivir in BMT recipients remain to be demonstrated in randomized, prospective trials.
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PMID:Use of Oseltamivir to control influenza complications after bone marrow transplantation. 1509 55

Secondary bacterial pneumonia is an important cause of influenza-associated death. Although antibacterial therapy is standard, antiviral therapy has been ignored because viral infections usually resolve by the time bacterial pneumonia presents. In the present study, antiviral compounds were tested in a mouse model of secondary pneumococcal pneumonia after influenza. Treatment with oseltamivir improved survival in mice from 0% to 75%, even when therapy was delayed for up to 5 days after infection with influenza virus. In mice, treatment with rimantadine had no effect on survival. Treatment with ampicillin cleared infection but, in the absence of treatment with oseltamivir, did not improve survival. Pneumonia developed in only 7 of the 22 mice receiving oseltamivir, and subsequent treatment with ampicillin resulted in cure (100% survival). Treatment of the predisposing influenza-virus infection with inhibitors specific for the viral neuraminidase may improve the efficacy of antibiotics and increase survival in persons who are at high risk for complications and mortality during influenza.
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PMID:Effect of antiviral treatment on the outcome of secondary bacterial pneumonia after influenza. 1524 27

Most clinical isolates of Streptococcus pneumoniae consist of heterogeneous populations of at least two colony phenotypes, opaque and transparent, selected for in the bloodstream and nasopharynx, respectively. Microarray analysis revealed 24 orfs that demonstrated differences in expression greater than twofold between variants of independent strains. Twenty-one of these showed increased expression in the transparent variants, including 11 predicted to be involved in sugar metabolism. A single genomic region contains seven of these loci including the gene that encodes the neuraminidase, NanA. In contrast to previous studies, there was no contribution of NanA to adherence of S. pneumoniae to epithelial cells or colonization in an animal model. However, we observed NanA-dependent desialylation of human airway components that bind to the organism and may mediate bacterial clearance. Targets of desialylation included human lactoferrin, secretory component, and IgA2 that were shown to be present on the surface of the pneumococcus in vivo during pneumococcal pneumonia. The efficiency of desialylation was increased in the transparent variants and enhanced for host proteins binding to the surface of S. pneumoniae. Because deglycosylation affects the function of many host proteins, NanA may contribute to a protease-independent mechanism to modify bound targets and facilitate enhanced survival of the bacterium.
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PMID:Phase variable desialylation of host proteins that bind to Streptococcus pneumoniae in vivo and protect the airway. 1545 13

Streptococcus pneumoniae has been recognised as a major cause of pneumonia since the time of Sir William Osler. Drug-resistant S. pneumoniae (DRSP), which have gradually become resistant to penicillins as well as more recently developed macrolides and fluoroquinolones, have emerged as a consequence of indiscriminate use of antibacterials coupled with the ability of the pneumococcus to adapt to a changing antibacterial milieu. Pneumococci use cell wall choline components to bind platelet-activating factor receptors, colonise mucosal surfaces and evade innate immune defenses. Numerous virulence factors that include hyaluronidase, neuraminidase, iron-binding proteins, pneumolysin and autolysin then facilitate cytolysis of host cells and allow tissue invasion and bloodstream dissemination. Changes in pneumococcal cell wall penicillin-binding proteins account for resistance to penicillins, mutations in the ermB gene cause high-level macrolide resistance and mutations in topoisomerase IV genes coupled with GyrA gene mutations alter DNA gyrase and lead to high-level fluoroquinolone resistance. Risk factors for lower respiratory tract infections in the elderly include age-associated changes in oral clearance, mucociliary clearance and immune function. Other risks for developing pneumonia include poor nutrition, hypoalbuminaemia, bedridden status, aspiration, recent viral infection, the presence of chronic organ dysfunction syndromes including parenchymal lung disease and recent antibacterial therapy. Although the incidence of infections caused by DRSP is rising, the effect of an increase in the prevalence of resistant pneumococci on mortality is not clear. When respiratory infections occur, rapid diagnosis and prompt, empirical administration of appropriate antibacterial therapy that ensures adequate coverage of DRSP is likely to increase the probability of a successful outcome when treating community-acquired pneumonia in elderly patients, particularly those with multiple risk factors for DRSP. A chest x-ray is recommended for all patients, but other testing such as obtaining a sputum Gram's smear is not necessary and should not prolong the time gap between clinical suspicion of pneumonia and antibacterial administration. The selection of antibacterials should be based upon local resistance patterns of suspected organisms and the bactericidal efficacy of the chosen drugs. If time-dependent agents are chosen and DRSP are possible pathogens, dosing should keep drug concentrations above the minimal inhibitory concentration that is effective for DRSP. Treatment guidelines and recent studies suggest that combination therapy with a beta-lactam and macrolide may be associated with a better outcome in hospitalised patients, and overuse of fluoroquinolones as a single agent may promote quinolone resistance. The ketolides represent a new class of macrolide-like antibacterials that are highly effective in vitro against macrolide- and azalide-resistant pneumococci. Pneumococcal vaccination with the currently available polysaccharide vaccine is thought to confer some preventive benefit (preventing invasive pneumococcal disease), but more effective vaccines, such as nonconjugate protein vaccines, need to be developed that provide broad protection against pneumococcal infection.
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PMID:Drug treatment of pneumococcal pneumonia in the elderly. 1549 50

In 2003, an outbreak of highly pathogenic avian influenza occurred in The Netherlands. The avian H7N7 virus causing the outbreak was also detected in 88 humans suffering from conjunctivitis or mild respiratory symptoms and one person who died of pneumonia and acute respiratory distress syndrome. Here we describe a mouse model for lethal infection with A/Netherlands/219/03 isolated from the fatal case. Because of the zoonotic and pathogenic potential of the H7N7 virus, a candidate vaccine carrying the avian hemagglutinin and neuraminidase proteins produced in the context of the high-throughput vaccine strain A/PR/8/34 was generated by reverse genetics and tested in the mouse model. The hemagglutinin gene of the recombinant vaccine strain was derived from a low-pathogenicity virus obtained prior to the outbreak from a wild mallard. The efficacy of a classical nonadjuvanted subunit vaccine and an immune stimulatory complex-adjuvanted vaccine was compared. Mice receiving the nonadjuvanted vaccine revealed low antibody titers, lack of clinical protection, high virus titers in the lungs, and presence of virus in the spleen, liver, kidneys, and brain. In contrast, mice receiving two doses of the immune stimulatory complex-adjuvanted vaccine revealed high antibody titers, clinical protection, approximately 1,000-fold reduction of virus titers in the lungs, and rare detection of the virus in other organs. This is the first report of an H7 vaccine candidate tested in a mammalian model. The data presented suggest that vaccine candidates based on low-pathogenicity avian influenza A viruses, which can be prepared ahead of pandemic threats, can be efficacious if an effective adjuvant is used.
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PMID:Protection of mice against lethal infection with highly pathogenic H7N7 influenza A virus by using a recombinant low-pathogenicity vaccine strain. 1616 Jan 67

Increasing evidence has linked the anaerobic bacteria forming periodontopathic biofilms with aspiration pneumonia in elderly persons. In experiments designed to eliminate the potent respiratory pathogens forming biofilms in the oral cavity, we have shown that the mechanical and chemical oral cleansing using povidone-iodine effectively reduced the detection rates and numbers of methicillin-sensitive Staphylococcus species, Streptococcus pneumoniae, and Haemophilus influenzae in patients scheduled to undergo oral surgery requiring endotracheal intubation. We confirmed the pathogenicity of periodontopathic anaerobic bacteria for aspiration pneumonia in an experimental mouse model. Based upon the finding of the coexistence of Porphyromonas gingivalis with Treponema denticola in chronic periodontitis lesions, we innoculated a mixed culture of P. gingivalis and T. denticola into the mouse trachea; the resulting infection induced inflammatory cytokine production and caused pneumonia. In another series of investigations, professional oral health care (POHC), mainly cleansing administered by dental hygienists once a week for 24 months to elderly persons requiring daily care, resulted in the reduction of the number of total anaerobes, Candida albicans, and Staphylococcus species and in the number of cases of fatal aspiration pneumonia. We also found that the POHC treatment of elderly persons for 6 months in the winter season reduced the salivary levels of protease, trypsin-like activity, and neuraminidase and also decreased the frequency of influenza cases.
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PMID:Involvement of periodontopathic anaerobes in aspiration pneumonia. 1627 88

Influenza pneumonia and influenza-associated severe exacerbation of pre-existing heart and lung disease are responsible for major complications that may require intensive care unit admission. Here, we report the case of a diabetic 70 year-old man hospitalised in the intensive care unit (ICU) of the University Medical Center of Reims (France) for a severe bilateral and alveolar pneumonia requiring mechanical ventilation. This patient had received a classical antibiotic treatment by amoxycillin (3 g/24 hours per os); 48 hours later, he was admitted in ICU for a respiratory failure that evolved rapidly towards an acute respiratory distress syndrome. Because of the context of a winter influenza outbreak, a nasal swabbing sample was tested for the presence of Influenzavirus nucleocapsid-antigens (Immunochromatographic test; BinaxNow Flu A & B, Binax, Portland, USA). This rapid assay revealed the presence of an Influenzavirus A respiratory infection five days after the beginning of the respiratory syndrome. This rapid viral diagnosis will be further confirmed in post mortem by the positive Influenza strain isolation onto lung tissues by classical cell culture techniques (Influenzavirus A strain, H3N2). Influenza pneumonia is a significant cause of morbidity and mortality, especially during influenza epidemics. The use of commercially available rapid diagnostic tests for influenza associated pneumonia, allows the potential use of new specific anti-neuraminidase drugs, which can be efficient during the 30 hours after the beginning of the clinical influenza syndrome.
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PMID:[A case of influenza A community-acquired pneumonia in an elderly subject hospitalised in intensive care unit]. 1633 Mar 85

(1) Influenza is a common acute respiratory disease due to a virus that causes annual seasonal epidemics. Three major pandemics occurred in the 20th century, in 1918-1919, 1957 and 1968, mainly due to genetic variants of type A influenza virus. (2) In temperate regions the incidence of hospitalisation increases during annual influenza epidemics. More than 90% of deaths linked to influenza involve people over 65 years of age. (3) The clinical manifestations of influenza virus infection are non specific. The main complications are secondary bacterial respiratory tract infections (especially pneumonia); those most at risk are people over 65, infants less than one year old, and people with underlying chronic disorders (pulmonary, cardiac, renal or metabolic) or immune deficiencies. (4) Vaccination is the main preventive measure. During most years the vaccine strain closely matches the epidemic strain. In relative terms, vaccination of people over 65 reduces the number of deaths linked to influenza by about 80%, hospitalisation and pneumonia by about 50%, and symptomatic influenza by about 30%. Yearly vaccination is recommended for younger people with serious chronic disease. (5) Three antiviral drugs are currently approved in France for prevention or treatment of influenza: amantadine and the neuraminidase inhibitors zanamivir and oseltamivir. (6) Efficacy of antiviral drugs has not been evaluated in comparative randomised trials in which death and influenza complications were the primary outcome measures. (7) A systematic review of 20 comparative randomised trials involving about 2500 healthy people showed that amantadine reduced the frequency of flu-like syndromes by about 7% in absolute terms (26.3% versus 33.1% with placebo). Zanamivir and oseltamivir have only been shown to reduce the frequency of serologically confirmed episodes of influenza (0.4% to 2.5%, compared to 4.4% to 14.9% with placebo). (8) In a randomised placebo-controlled trial of oseltamivir, involving 548 institutionalised subjects over 65 years of age, more than 80% of whom had been vaccinated, respiratory tract infections were less frequent in the oseltamivir group, but the relevance of this result is undermined by the small number of observed cases. (9) Efficacy of antiviral drugs on avian influenza (bird flu) was studied during a 2003 Dutch outbreak due to a type A/H7N7 virus. Among the 38 exposed persons who were treated, about 3% developed symptoms, compared with about 10% of 52 exposed persons who refused treatment (p = 0.38). The low statistical power and the lack of randomisation rule out any firm conclusions on preventive effects. (10) The three antiviral drugs have different profiles of adverse effects and drug interactions. Amantadine carries a risk of neuropsychological, atropinic and dopaminergic adverse effects, and can interact with drugs that have similar effects. Zanamivir carries a risk of life-threatening bronchospasm. Oseltamivir was approved relatively recently and its full spectrum of adverse effects is not yet known; its main adverse effects appear to be mild gastrointestinal disturbances, although a few cases of serious cutaneous reactions have been reported. (11) In vitro resistance to the three drugs has been demonstrated, but the possible clinical and epidemiological consequences are unclear. (12) In situations warranting antiviral therapy for the prevention of influenza, oseltamivir, at a dose of 75 mg/day for 10 days, is the drug with the best risk-benefit balance. Its use should be limited to situations where a major potential benefit exists in order to avoid selection for resistant strains. (13) Testing of oseltamivir in children is limited. Oseltamivir should be avoided during pregnancy, because of evidence that it may harm the unborn child. (14) In practice, the use of antiviral drugs in otherwise healthy adults and children is not generally recommended. (15) Despite the lack of convincing data regarding the efficacy of oseltamivir in preventing complications of influenza, its effect on documented infections suggests it may be useful for unvaccinated individuals who are at high risk of infection and severe complications. Under these conditions, treatment should be started within 48 hours after contact with a person who has flu-like symptoms during a seasonal epidemic; residents in institutions in which influenza cases occur may also qualify for preventive treatment. Other preventive measures should also be used, including immediate vaccination, case isolation, use of face masks, and more frequent hand washing. (16) During seasonal influenza epidemics due to viral strains against which the current vaccine is of limited effectiveness, the utility, target populations and optimal duration of preventive antiviral treatment must be determined by examining the groups most at risk and the severity of complications. (17) Most flu-like syndromes are not due to the influenza virus, and the preventive effect of antiviral drugs on complications in persons at risk has not yet been demonstrated. (18) In practice, antiviral drugs are not an alternative to influenza vaccination, but may be a useful adjunct in some situations. It is best to limit their use to short-term prophylaxis of vulnerable persons in situations where the risk of contracting influenza virus infection is high.
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PMID:Antiviral drugs in influenza: an adjunct to vaccination in some situations. 1654 14

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