Influenza Virus Pneumonia Research Articles

Study of antivirus, antibacteria and immune functions of Gaoreqing freeze-dried powder

Gaoreqing freeze-dried powder was effective fraction extracted from Lonicera japonica Thunb.,Scutellaria baicalensis Georgi and Forsythia suspense (Thunb) Vahl. It was confirmed to have certain anti-virus, anti-bacterial effects and immuno-enhancing activities. Cell culture and influenza viral pneumonia model of mouse were used to study its antiviral effect. Plate culture and pathogenic bacteria-infected model in mouse were established to examine its anti-bacterial effect. Carbon particle clearance test and determination of serum hemolysin were done to observe its immune-enhancing effect. The results showed that Gaoreqing had significant effect on inhibiting cytopathic effect induced by various viruses. Compared with virus control group, high and middle dosage groups could significantly decrease the pulmonary index, pulmonary virus hemagglitination titer in influenza viral pneumonia model of mouse (P < 0.01). It showed obvious inhibitory effects on Streptococcus pyogenes,Staphylococcus aureus, pneumococcus and so on. Gaoreqing also had obvious protective effect on mice infected by S. aureus and pneumococcus. In addition, phagocytosis and 50% hemolyzing concentration of mice were obviously reinforced by Gaoreqing (P < 0.05 to 0.01). The results obtained here demonstrated that Gaoreqing had obvious anti-virus and anti-bacterial effects and enhanced immune function in mice. Key words: Gaoreqing freeze-dried powder, anti-virus, anti-bacterial, immune function.

Imunização anti-influenza: universal ou selecionada?

Dear Editor, Our recently published article in the Brazilian Archives of Cardiologia1 aimed to evaluate the implementation of vaccination against influenza (INF) and Pneumococcus virus (pneumonia) in a specific subgroup of patients with heart failure (HF), due to consensus recommendation of the NorthAmerican, European and Brazilian guidelines on HF. The increased susceptibility to respiratory infections in patients with heart failure is attributed to pulmonary congestion. Dear Editor, Martins et al1 recommend measures for increasing influenza and pneumococcal immunization based on the reduced rates detected in patients with heart failure in the city of Teresopolis. We understand that, in spite of the benefit of this strategy at the population level to prevent infections and complications, we must evaluate mass vaccination and immunization extended to special groups such as immunologically susceptible individuals and those with comorbidities2. Even vaccines made from inactivated agents may trigger important and unpredictable reactions, such as, for instance, Guillain-Barre syndrome. We recently reported a case series of symptomatic pericardial effusion with increased incidence in patients who received influenza vaccine. The patients, mostly elderly and individuals with compensated diseases, showed viral symptoms, increased incidence in the peri-immunization period and resolution of the clinical draw with anti-inflammatory drug use3. Post-vaccination myopericarditis has been reported and may be underdiagnosed and sub-notified4,5.

Clinical experience in adults and children treated with intravenous peramivir for 2009 influenza A (H1N1) under an Emergency IND program in the United States.

Peramivir, an investigational intravenous neuraminidase inhibitor in Phase 3 trials for hospitalized patients, was made available during the 2009 H1N1 influenza pandemic under the Emergency Investigational New Drug (eIND) regulations. We describe the clinical characteristics and outcomes of all patients for whom peramivir was requested under the eIND. After obtaining eIND approval from the Food and Drug Administration and local institutional review board approval, clinicians caring for hospitalized patients with influenza administered intravenous peramivir and collected information on demographic characteristics, clinical characteristics, and outcomes. From April through October 2009, peramivir was requested for 42 patients and administered to 20 adults and 11 children. At hospitalization, all patients had rapidly progressing, radiographically confirmed viral pneumonia with respiratory failure, and all but 1 patient required mechanical ventilation. In most patients, including 1 person with documented oseltamivir-resistant infection, the illness had progressed despite oseltamivir treatment. Peramivir was administered for 1-14 days (median duration, 10 days). The 14-day, 28-day, and 56-day survival rates were 76.7%, 66.7%, and 59.0%, respectively. Peramivir was generally well tolerated. Intravenous peramivir was well tolerated and was associated with recovery in most patients hospitalized with severe 2009 H1N1 influenza viral pneumonia and treated under an eIND.

Angioembolisation of Pulmonary Artery Pseudoaneurysm Arising in H1N1 Influenza Viral Pneumonia

A 51 year-old Aboriginal woman was diagnosed with H1N1 influenza virus and methicillin-resistant Staphylococcus aureus. Contrasted CT of the pulmonary and bronchial vasculature undertaken for investigation for of haemoptysis revealed an 11 mm left upper lobe pulmonary artery pseudoaneurysm (PAP). The PAP was successfully treated with angioembolisation of the parent artery with two platinum coils. Pulmonary artery pseudoaneurysms are uncommon but potentially life-threatening and have not previously been reported in association with H1N1 influenza viral pneumonia, which has been prominent in recent times in both medical literature and popular press.

Clinical characteristics and computed tomography findings in children with 2009 pandemic influenza A (H1N1) viral pneumonia

In this article we review the clinical characteristics and computed tomography (CT) findings in children with 2009 pandemic H1N1 influenza viral pneumonia. The medical charts of 88 children with pandemic H1N1 influenza virus infection, admitted to our hospital in Japan from 10 August to 28 December 2009, were reviewed; we compared the clinical features of these children with those of 61 children admitted with seasonal influenza A during the previous 3 seasons. Of 88 patients, 53 (60%) had radiographic findings consistent with pneumonia and 34 patients underwent a chest computed tomography (CT) scan. Pneumonia was a more frequent complication in children with pandemic H1N1 influenza compared with those with seasonal influenza (60% vs 11%; p < 0.001). The predominant CT findings were unilateral or bilateral multifocal consolidation (15/34; 44%) associated with ground-glass opacities in the peribronchovascular region. The second most common CT finding was unilateral diffuse consolidation or atelectasis in 1 or more lung zones (12/34; 35%). The chest CT findings of unilateral or bilateral multifocal consolidation often associated with ground-glass opacities were commonly seen in children with pandemic H1N1 influenza viral pneumonia. Atelectasis was seen in patients who required oxygen administration.

A new therapeutic strategy for lung tissue injury induced by influenza with CR2 targeting complement inhibitior

BackgroundInfluenza is a respiratory disease that seriously threatens human health. In fact, influenza virus itself does not make critical contribution to mortality induced by influenza, but "cytokine storm" produced by the excessive immune response triggered by the virus can result in inflammatory reaction of lung tissues and fatal lung tissue injury, and thus increase influenza mortality. Therefore, besides antiviral drugs, immunosuppression drugs should also be included in infection treatment.Presentation of the hypothesisComplement is the center of inflammatory reaction. If complement system is over activated, the body will have strong inflammatory reaction or tissue injury, resulting in pathological process. Many studies have proved that, inflammatory injury of lung tissues caused by influenza virus is closely related to complement activation. Therefore, inhibiting complement activation can significantly reduce inflammatory injury in lung tissues. As complement is both a physiological defense and pathological damage medium, systematic inhibition may result in side effects including infection. Therefore, we design targeting complement inhibitors for complement activation sites, i.e. with CR2 as targeting vector, complement inhibitors like CD59 and Crry are targeted to inflammatory sites to specially inhibit the complement activation in local injury, thus local inflammatory reaction is inhibited.Testing the hypothesisCR2-CD59 and CR2-Crry targeting complement inhibitors are fusion-expressed, and their biological activity is examined via in vivo and in vitro tests. CR2 targeting complement inhibitors are used to treat mouse influenza viral pneumonia model, with PBS treatment group as the control. The survival and lung tissue injury of the mice is observed and the effect of CR2 targeting complement inhibitors on pneumonia induced by influenza virus is evaluated.Implications of the hypothesisCR2 targeting complement inhibitors are expected to be ideal drugs for viral pneumonia.

TRAIL induction in lung macrophages is IFN-ß-dependent and results in alveolar epithelial apoptosis in IV pneumonia

Introduction: Influenza virus (IV) pneumonia is characterized by rapid progression to lung failure and high mortality. Although lung macrophages have been attributed a significant role in the host defense towards IV, they are as well contributing to alveolar epithelial cell damage and lung barrier dysfunction during IV pneumonia by the release pro-apoptotic mediators such as TNF-related apoptosis-inducing ligand (TRAIL). However, the molecular signals underlying the regulation of TRAIL expression in lung macrophages upon IV infection remain elusive. Results: PR/8 infection of wild-type alveolar macrophages in vitro resulted in a dose-dependent upregulation of TRAIL mRNA and enhanced surface-expression which was largely abrogated in PKR (Protein Kinase R)-deficient macrophages. IFN-ß was released from PR/8 infected wild-type but not from PKR-deficient alveolar macrophages. Additionally NF-κB activity was impaired in PKR-/- macrophages upon IV infection. Moreover, TRAIL mRNA was found highly upregulated in wild-type and as well in PKR-deficient alveolar macrophages upon IFN-ß stimulation. In addition, blockade of IFN-ß in the supernatant of PR/8 infected wild-type macrophages resulted in reduced TRAIL expression. Interestingly, TRAIL mRNA was upregulated on flow-sorted F4/80-positive alveolar macrophages in comparison to peripheral blood monocytes in PR/8 infected wild-type mice in vivo at day 8 post infection when PR/8 was largely cleared and type I IFN levels were increased in lung homogenates. Finally, abrogation of TRAIL signalling significantly reduced alveolar epithelial cell apoptosis in PR/8 infected mice. Conclusion: These data demonstrate that IFN-ß released from PR/8-infected alveolar macrophages in a PKR-dependent manner is an important auto-/paracrine inducer of macrophage TRAIL expression, contributing to alveolar epithelial damage during severe IV pneumonia.

Role of macrophage migration inhibitory factor in influenza H5N1 virus pneumonia

The severe and often fatal disease in humans and birds caused by H5N1 influenza viruses has been attributed to aberrant pulmonary inflammatory responses. We investigated the role of macrophage migration inhibitory factor (MIF), a proinflammatory cytokine and a pivotal regulator of innate immunity, in H5N1 influenza virus pneumonia in murine model. We found increased MIF mRNA levels in the lungs and MIF protein levels in the serum of infected mice. Although the inhibition of MIF action by isoxazolone-1 (ISO-1) did not render mice more resistant to the lethality of infection, it caused a significant reduction in pulmonary inflammatory cytokines interleukin-1 beta (IL-1beta), IL-6 and tumor necrosis factor alpha (TNF-alphalfa) and chemokine interferon-inducible protein-10 (IP-10). These results indicate the involvement of MIF in inflammatory responses to H5N1 influenza virus infections by induction of pulmonary inflammatory cytokines and chemokines, and suggest that pharmacotherapeutic approaches targeting MIF may hold promise for the treatment of H5N1 influenza virus pneumonia.

Experimental Study on the Antivirus Effect of Zhongsheng Pills on Influenza Virus H5N1

Abstract The present study reported the inhibitory effect of Zhongsheng Pills on avian influenza virus H5N1 in mice. Oseltamivir was used as the positive control group in order to observe the inhibitory effect and the death prevention effect of Zhongsheng Pills on influenza viral pneumonia in mice. Compared with the viral control group, Zhongsheng Pills reduced the lung index of avian influenza viral pneumonia, regulated the T lymphocyte subgroup, reduced the levels of TNF-α in sera, promoted the development of IFN-γ and IL-10, and weakened interstitial lung disease and inflammation of the alveolar walls. The low dose of Zhongsheng Pills decreased the pulmonary index of the mice infected with the avian influenza virus H5N1, and extended the survival time of the mice. The results showed that Zhongsheng Pills have inhibitory effects on the lung diseases caused by avian influenza virus H5N1.

Morbidity and Mortality Associated With Nosocomial Transmission of Oseltamivir- Resistant Influenza A(H1N1) Virus

The sudden emergence and rapid spread of oseltamivir-resistant influenza A(H1N1) viruses with neuraminidase (NA) gene H274Y amino acid substitution is the hallmark of global seasonal influenza since January 2008. Viruses carrying this mutation are widely presumed to exhibit attenuated pathogenicity, compromised transmission, and reduced lethality. To investigate nosocomial viral transmission in a cluster of patients with influenza A(H1N1) virus infection. Descriptive outbreak investigation of 2 hematopoietic stem cell transplant recipients and an elderly patient who developed hospital-acquired influenza A virus infection following exposure to an index patient with community-acquired H274Y-mutated influenza A(H1N1) virus infection in a medical ward at a Dutch university hospital in February 2008. The investigation included a review of the medical records, influenza virus polymerase chain reaction and culture, phenotypic oseltamivir and zanamivir susceptibility determination, and hemagglutinin chain 1 (HA(1)) gene and NA gene sequence analysis. Phylogenetic relationship of patient cluster influenza A(H1N1) viruses and other 2007-2008 seasonal influenza A(H1N1) viruses. Viral HA(1) and NA gene sequence analysis from the 4 patients revealed indistinguishable nucleotide sequences and phylogenetic clustering of H274Y-mutated, oseltamivir-resistant influenza A(H1N1) virus, confirming nosocomial transmission. Influenza virus pneumonia (3 patients) and attributable mortality (2 patients) during active infection was observed in patients with lymphocytopenia at onset. Seasonal oseltamivir-resistant influenza A(H1N1) viruses with NA gene H274Y mutation are transmitted and retain significant pathogenicity and lethality in high-risk patients.

Clinical review: Primary influenza viral pneumonia

Primary influenza pneumonia has a high mortality rate during pandemics, not only in immunocompromised individuals and patients with underlying comorbid conditions, but also in young healthy adults. Clinicians should maintain a high index of suspicion for this diagnosis in patients presenting with influenza-like symptoms that progress quickly (2 to 5 days) to respiratory distress and extensive pulmonary involvement. The sensitivity of rapid diagnostic techniques in identifying infections with the pandemic 2009 H1N1v influenza strain is currently suboptimal. The most reliable real-time reverse transcriptase-polymerase chain reaction molecular testing is available in limited clinical settings. Despite 6 months of pandemic circulation, most novel H1N1v pandemic strains remain susceptible to oseltamivir. Ensuring an appropriate oxygenation and ventilation strategy, as well as prompt initiation of antiviral therapy, is essential in management.

Regulation of Influenza Virus-Caused Oxidative Stress by Kegan Liyan Oral Prescription, as Monitored by Ascorbyl Radical ESR Signals

To study the oxidative stress level of the influenza virus A FM1 subset-infected mouse in intranasal inhalation as a model, we employ an ascorbyl radical's ESR (electron spin resonance) spectrum as an oxidative stress biomarker. These infected mice were pretreated with Ribavirin, ascorbic acid, superoxide dismutase (SOD) or Kegan Liyan oral prescription (KGLY, proprietary Chinese medicine for influenza and common cold) in the stomach tube for 3 days, and then followed by the virus-infecting for 4 days. On the 4th day, samples were collected. It is recognized the strength of ascorbyl radical's ESR signal (A(-.)) (a(H4 = 0.177) Gauss, g = 2.00517) denotes oxidative stress level in vivo and in vitro. The magnitude of ESR spectrum (28.65 +/- 10.71 AU) in mice infected with influenza virus was significantly higher than those of healthy control mice (19.10 +/- 3.61 AU). Serum A(-.) in mice treated with Ribavirin, ascorbic acid, SOD and KGLY declined to 19.70 +/- 6.05, 18.50 +/- 2.93 and 16.25 +/- 3.59, 18.40 +/- 2.14 AU respectively. It is close to A(-.) signal height in healthy controls via down-regulation of the influenza virus-caused oxidative stress level getting decline in the lung index of pneumonia as compare to those of untreated healthy and the influenza virus infected mice pneumonia. It is well known that SOD can prevent the influenza virus pneumonia enhancing mouse survival rate; Ribavirin can treat viral diseases. Data from this study suggested that KGLY may indirectly relieve influenza virus-infected pneumonia via down- regulation of virus caused oxidative stress coupled with a redox reaction cascade as ribavirin, ascorbic acid and SOD.

Lung epithelial apoptosis in influenza virus pneumonia: the role of macrophage-expressed TNF-related apoptosis-inducing ligand

Mononuclear phagocytes have been attributed a crucial role in the host defense toward influenza virus (IV), but their contribution to influenza-induced lung failure is incompletely understood. We demonstrate for the first time that lung-recruited “exudate” macrophages significantly contribute to alveolar epithelial cell (AEC) apoptosis by the release of tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) in a murine model of influenza-induced pneumonia. Using CC-chemokine receptor 2–deficient (CCR2−/−) mice characterized by defective inflammatory macrophage recruitment, and blocking anti-CCR2 antibodies, we show that exudate macrophage accumulation in the lungs of influenza-infected mice is associated with pronounced AEC apoptosis and increased lung leakage and mortality. Among several proapoptotic mediators analyzed, TRAIL messenger RNA was found to be markedly up-regulated in alveolar exudate macrophages as compared with peripheral blood monocytes. Moreover, among the different alveolar-recruited leukocyte subsets, TRAIL protein was predominantly expressed on macrophages. Finally, abrogation of TRAIL signaling in exudate macrophages resulted in significantly reduced AEC apoptosis, attenuated lung leakage, and increased survival upon IV infection. Collectively, these findings demonstrate a key role for exudate macrophages in the induction of alveolar leakage and mortality in IV pneumonia. Epithelial cell apoptosis induced by TRAIL-expressing macrophages is identified as a major underlying mechanism.

P75. Guanine nitration and host defense during influenza virus pneumonia

P75. Guanine nitration and host defense during influenza virus pneumonia

Chest CT findings of influenza virus‐associated pneumonia in 12 adult patients

Objective In this study, we describe the chest computed tomography findings of influenza virus‐associated pneumonia in adult patients. Methods Our retrospective study included 12 adult patients who had proven influenza virus ‐ associated pneumonia. Results Out of 12 patients, six were diagnosed as having pure influenza virus pneumonia, five as having bronchopneumonia caused by bacteria associated with influenza A infection, and one as having a cryptogenic organizing pneumonia associated with influenza A infection. Conclusion Radiographic findings of influenza virus pneumonia in adult patients consist of ground‐glass attenuation. Localized patchy consolidations were observed in cases of bronchopneumonia.

Natural antibody and complement mediate neutralization of influenza virus in the absence of prior immunity.

Early control of virus replication by the innate immune response is essential to allow time for the generation of a more effective adaptive immune response. As an important component of innate immunity, complement has been shown to be necessary for protection against numerous microbial infections. This study was undertaken to investigate the role of complement in neutralizing influenza virus. Results demonstrated that the classical pathway of complement mediated serum neutralization of influenza virus. Although nonimmune serum neutralized influenza virus, the mechanism of virus neutralization (VN) required antibody, as sera from RAG1-deficient mice lacked VN activity; moreover, purified natural immunoglobulin M (IgM) restored VN activity to antibody-deficient sera. The mechanism of VN by natural IgM and complement was associated with virion aggregation and coating of the viral hemagglutinin receptor; however, viral lysis did not significantly contribute to VN. Additionally, reconstitution of RAG1-deficient mice with natural IgM resulted in delayed morbidity during influenza virus infection. Collectively, these results provide evidence that natural IgM and the early components of the classical pathway of complement work in concert to neutralize influenza virus and that this interaction may have a significant impact on the course of influenza viral pneumonia.

Laparoscopic hand-assisted living donor nephrectomy: the Calgary experience

Laparoscopic techniques, such as hand-assisted live donor nephrectomy (HALDN), have the potential to increase the number of living kidney donors. For these techniques to be acceptable, however, the standards for donor, recipient, and graft survival achieved by the open technique need to be matched. In this study we present the results of the first 20 HALDN procedures at our center. The 20 donors included nine men and 11 women of mean (±SD) donor age 41 (±10) years and mean donor weight 78 (±13) kg. Mean operative time was 174 (±32) minutes. Only one patient required an open conversion to procedure because of venous bleeding. All kidneys were successfully implanted; there were no episodes of primary nonfunction or delayed graft function. There were no surgical complications, either in the donor or the recipient. The range of postoperative stay was 3 to 5 days. One recipient died 62 days after transplant from influenza virus pneumonia. There were no other causes of graft loss. Our preliminary results suggest that HALDN is safe and is associated with short-term donor, recipient, and graft outcomes that are at least comparable to the standard open technique.

Radiographic and high-resolution CT findings of influenza virus pneumonia in patients with hematologic malignancies.

We sought to describe the radiographic and high-resolution CT findings of influenza virus pneumonia in patients with hematologic malignancies. Radiologic findings of influenza virus pneumonia in immunocompromised patients consist of patchy or confluent consolidation and nodular opacities on chest radiography and ground-glass attenuation, consolidation, centrilobular nodules, and branching linear opacities on high-resolution CT.

Pathology of human influenza A (H5N1) virus infection in cynomolgus macaques (Macaca fascicularis).

Infection with influenza A (H5N1) virus, which has not been associated with respiratory disease in humans previously, caused clinical signs of acute respiratory distress syndrome and multiple-organ dysfunction syndrome with high mortality in humans in Hong Kong in 1997. To study the pathogenesis of this disease, we infected four cynomolgus monkeys (Macaca fascicularis) with 2.5 x 104 median tissue culture infectious dose (TCID50) of influenza virus A/Hong Kong/156/97 (H5N1) and euthanatized them 4 or 7 days after infection. The main lesion was a necrotizing broncho-interstitial pneumonia (4/4) similar to those found in primary influenza virus pneumonia in humans, with desquamation of respiratory epithelium (4/4), intra-alveolar hemorrhage (4/4), hyaline membrane formation (2/4), and infiltration with neutrophils and macrophages (4/4). Lesions in other organs consisted of a suppurative tonsillitis (2/4) and necrosis in lymphoid organs (1/4), kidney (1/4), and liver (1/4). By immunohistochemistry, influenza virus antigen was limited to pulmonary tissue (4/4) and tonsils (2/4). Based on these results, we suggest that the cynomolgus monkey is a suitable animal model for studying the pathogenesis of human H5N1 virus infection and that multiple-organ dysfunction syndrome in this disease may be caused by diffuse alveolar damage from virus replication in the lungs alone.

Effective prophylaxis of influenza A virus pneumonia in mice by topical passive immunotherapy with polyvalent human immunoglobulins or F(ab')2 fragments.

The effectiveness of polyvalent plasma-derived human immunoglobulins (IVIG) in passive immunotherapy of influenza virus pneumonia was assessed, using the Strain Scotland (A/Scotland/74 (H3N2)) adapted to BALB/c mice by repeated lung passages. Haemagglutinin antibodies in two batches of IVIG at 10 mg/ml had a titre of 1/16. Intravenous injection of 1000-5000 microg of IVIG, 3 h after infection, gave 60-70% protection, whereas intranasal injection of 25-50 microg protected 90% of mice infected with a lethal dose of influenza virus. F(ab')2 fragments were at least as protective as intact IVIG, suggesting that complement or Fcgamma receptor-bearing cells were not required. Topical passive immunotherapy with IVIG or F(ab')2 gave protection up to 8 h after infection, but not at 24 h, suggesting that anti-influenza A antibodies in IVIG, delivered locally, are only effective at early stages of the infectious process. The potential value of topical administration of IVIG or F(ab')2 fragments for influenza A pneumonia prophylaxis was further demonstrated by the protective effects of their intranasal administration 24 h before challenge.