Influenza virus and CNS manifestations.

Neurological involvement during influenza infection has been described during epidemics and is often consistent with serious sequelae or death. An increasing incidence of influenza-associated encephalitis/encephalopathy has been reported in Japan, mainly in children. A variety of other clinical CNS manifestations, such as Reye's syndrome, acute necrotising encephalopathy (ANE), and myelitis as well as autoimmune conditions, such as Guillain-Barre's syndrome, may occur during the course of influenza infection. Virological diagnosis is essential and based on virus isolation, antigen detection, RNA detection by PCR, and serological analyses. Neuroimaging with CT and MRI of the brain are of prognostic value. The pathogenic mechanisms behind the influenza CNS complications are unknown. The treatment is symptomatic, with control of vital functions in the intensive care unit, antiepileptic medication and treatment against brain oedema.     

Clinical features of influenza A and B in children and association with myositis.

Influenza virus is among the most common causes of respiratory illness, which may manifest as a range of conditions, from mild upper respiratory tract infection to bronchiolitis and pneumonia. Acute childhood myositis associated with influenza occurs mostly in influenza B infection. In this retrospective study, we analyzed the characteristics of 197 children with influenza virus treated from January 2000 to December 2001. Among them, 73 children had influenza A infection and 124 had influenza B infection. Influenza A virus outbreaks occurred in January 2000, July 2001, and December 2001, while influenza B virus outbreaks occurred from March 2000 to May 2000 and from December 2000 to February 2001. The most common clinical manifestations of influenza A and influenza B virus infection included fever, cough, and rhinorrhea. These infections also frequently manifested as laryngo-tracheobronchitis, pneumonia, and unexplained fever, which led to hospitalization. The most common clinical diagnosis was upper respiratory tract infection. The rates of benign acute childhood myositis in influenza A and influenza B were 5.5% and 33.9%, respectively. Creatine kinase levels were elevated in most myositis cases and boys were more commonly affected. Acute childhood myositis was more commonly seen in influenza B infection.     

Interference following dual inoculation with influenza A (H3N2) and (H1N1) viruses in ferrets and volunteers

The effects of simultaneous inoculation with two attenuated influenza A viruses was studied in ferrets and volunteers. Groups of ferrets were inoculated with an influenza A (H3N2) or (H1N1), virus or a combination of both viruses: The temperature response, serum and local antibody response, and the change in nasal wash protein concentration was determined. The results showed that both viruses were attenuated for ferrets, and that inoculation with both viruses together did not cause clinical reactions. Serological studies on paired serum samples obtained from ferrets showed that both viruses when given separately infected all the inoculated animals; however, dual infection resulted in all ferrets being infected with the influenza A (H3N2) virus strain, but this infection interfered with infection by the influenza A (H1N1) strain. Similar investigations were carried out in volunteers. Again, the clinical reactions and temperature response of volunteers to infection by one or other of the viruses showed both strains to be attenuated for man even when given together. In addition, no adverse clinical reactions were seen in volunteers inoculated with both viruses simultaneously. Serum antibody studies showed that infection by influenza A (H1N1) virus interfered with infection by the influenza A (H2N2) virus strain. These results show evidence of interference by influenza A viruses; however, the direction of interference was one-way, and differed for ferrets and for volunteers.     

Pandemic and seasonal human influenza virus infections in domestic cats: prevalence, association with respiratory disease, and seasonality patterns

Domestic cats have several features that make them ideal vehicles for interspecies transmission of influenza viruses; however, they have been largely overlooked as potential reservoirs or bridging hosts. In this study, we conducted serological surveillance to assess the prevalence of novel pandemic H1N1 as well as seasonal human influenza virus infections in domestic cats in Ohio. Four hundred serum samples collected from domestic cats (September 2009 to September 2010) were tested using a hemagglutination inhibition (HI) test. The seroprevalences of pandemic H1N1, seasonal H1N1, and H3N2 were 22.5%, 33%, and 43.5%, respectively. In addition, a significant association between clinical feline respiratory disease and influenza virus infection was documented. In this sample of cats, the prevalence of pandemic H1N1 did not follow the seasonality pattern of seasonal H1N1 or H3N2 influenza, similar to observations in humans. Pandemic H1N1 seroprevalence did not vary in relation to ambient temperature changes, while the seroprevalence of seasonal H3N2 and H1N1 influenza viruses increased with the decline of ambient temperature. Our results highlight the high prevalence of influenza virus infection in domestic cats, a seasonality pattern of influenza virus infection comparable to that in humans, and an association of infection with clinical respiratory disease.     

Quelling the storm: utilization of sphingosine-1-phosphate receptor signaling to ameliorate influenza virus-induced cytokine storm

Initial and early tissue injury associated with severe influenza virus infection is the result of both virus-mediated lysis of infected pulmonary cells coupled with an exuberant immune response generated against the virus. The excessive host immune response associated with influenza virus infection has been termed “cytokine storm.” Therapies that target virus replication are available; however, the selective pressure by such antiviral drugs on the virus often results in mutation and the escape of virus progeny now resistant to the antiviral regimen, thereby rendering such treatments ineffective. This event highlights the necessity for developing novel methods to combat morbidity and mortality caused by influenza virus infection. One potential method is restricting the host’s immune response. However, prior treatment regimens employing drugs like corticosteroids that globally suppress the host’s immune response were found unsatisfactory in large part because they disrupted the host’s ability to control virus replication. Here, we discuss a novel therapy that utilizes sphingosine-1-phosphate (S1P) receptor signaling that has the ability to significantly limit immunopathologic injury caused by the host’s innate and adaptive immune response, thereby significantly aborting morbidity and mortality associated with influenza virus infection. Moreover, S1P analog therapy allows for sufficient anti-influenza T cell and antibody formation to control infection. We review the anti-inflammatory effects of S1P signaling pathways and how modulation of these pathways during influenza virus infection restricts immunopathology. Finally, we discuss that combinatorial administration of S1P simultaneously with a current antiviral enhances the treatment efficacy for virulent influenza virus infections above that of either drug treatment alone. Interestingly, the scope of S1P receptor therapy reported here is likely to extend beyond influenza virus infection and could prove useful for the treatment of multiple maladies like other viral infections and autoimmune diseases where the host’s inflammatory response is a major component in the disease process.     

Decreased leukocytes and other characteristics of laboratory findings of influenza virus infections in children

BACKGROUND AND PURPOSE: An outbreak of influenza A and influenza B appeared at the beginning and end of 2006 in southern Taiwan. We conducted this study to test whether laboratory findings could differentiate influenza A from influenza B infection. METHODS: All children aged 16 years or less, who had nasal and/or throat swabs sent from inpatient or outpatient settings at National Cheng Kung University Hospital for the diagnosis of influenza infection from January 2005 to February 2007, were considered eligible subjects. Retrospective chart review of clinical and laboratory data was performed. RESULTS: 274 patients were enrolled, 151 with influenza A and 123 with influenza B, of whom 127 (46.4%) received laboratory examinations. The peak month of influenza A and influenza B infections was January 2006 and January 2007, respectively. Children with influenza B infections were older than those with influenza A infections (p<0.001). Influenza B-infected patients were more likely to have myalgia (p=0.004) than those with influenza A infections. Furthermore, children with influenza B infections tended to have lower leukocyte counts (6383 +/- 3970/mm(3) vs 7639 +/- 3476/mm(3), p=0.004), and higher serum creatine kinase level (p=0.002) than those with influenza A infections. The clinical outcomes were usually favorable. CONCLUSIONS: The clinical features of influenza B and influenza A infections are similar. However, decreased leukocytes and increased serum creatine kinase can be used as adjunctive criteria for diagnosis of influenza B infection before viral culture results are available.     

Study of influenza C virus infection in France

From November 2004 to April 2007, specimens were obtained from 2,281 patients with acute respiratory tract illness in Normandy, France. Eighteen strains of influenza C virus were detected in these samples using a combined tissue culture/RT-PCR diagnostic method. Most patients with influenza C virus infection (13/18) were infants or young children (<2 years of age). The most frequent symptoms were fever and cough, and the clinical presentation of influenza C virus infection was similar to that of other respiratory viruses. Thirteen of the 18 infected patients were hospitalized; 3 presented with a severe lower respiratory infection. The hemagglutinin-esterase (HE) gene of 10 isolates was sequenced to determine the lineages of the circulating influenza C viruses. Phylogenetic analysis revealed that most of the isolated strains had an HE gene belonging to the C/Yamagata/26/81-related lineage. These results show that influenza C virus regularly circulates in Normandy and generally causes a mild upper respiratory infection. Because the differential clinical diagnosis of influenza C virus infection is not always easy, it is important to identify viral strains for both patient management and epidemiological purposes.     

Assessment of Markers of the Cell-Mediated Immune Response after Influenza Virus Infection in Frail Older Adults

The purpose of this study was to determine whether measures of the cell-mediated immune response to influenza virus could be used as markers of influenza virus infection. We studied 23 subjects who developed upper respiratory, lower respiratory, or systemic symptoms during a small outbreak of influenza in a nursing home population. Influenza virus culture from nasopharyngeal swabs yielded influenza virus isolates from 7 of the 23 subjects. Only three of the subjects had a fourfold rise in antibody titer to the influenza virus antigen positivity after the infection. Granzyme B and cytokine levels were measured in peripheral blood mononuclear cells (PBMC) obtained from all subjects and stimulated with live influenza virus. Elevated granzyme B levels in virus-stimulated PBMC in combination with lower respiratory tract or systemic symptoms in study subjects was a significant predictor of culture-confirmed influenza virus infection compared to those from whom influenza virus could not be identified. Cytokine levels did not distinguish between the two groups in a similar type of analysis. Granzyme B in combination with the clinical profile of symptoms may be a useful retrospective marker for influenza virus infection.     

Influenza and HIV: Lessons from the 2009 H1N1 Influenza Pandemic

Influenza is a common respiratory disease in adults, including those infected with HIV. In the spring of 2009, a pandemic influenza A (H1N1) virus (pH1N1) emerged. In this article, we review the existing literature regarding pH1N1 virus infection in HIV-infected adults, which suggests that susceptibility to pH1N1 virus infection and severity of influenza illness are likely not increased in HIV-infected adults without advanced immunosuppression or comorbid conditions. The risk of influenza-related complications, however, may be increased in those with advanced immunosuppression or high-risk comorbid conditions. Prevention and treatment of high-risk comorbid conditions and annual influenza vaccination should continue to be part of HIV clinical care to help prevent influenza illness and complications. Additional information about pH1N1 vaccine immunogenicity and efficacy in HIV-infected patients would be useful to guide strategies to prevent influenza virus infection in this population.     

A case of benign acute childhood myositis associated with influenza A (HINI) virus infection

Benign acute childhood myositis (BACM) is a rare transient condition usually occurring at the early convalescent phase of a viral upper respiratory tract illness, normally influenza A, and, more frequently, influenza B infection. It is characterized by acute-onset difficulty in walking as a result of severe bilateral calf pain and by elevated muscle enzymes including creatinine kinase. It is self-limiting because there is rapid full recovery usually within 1 week. We describe the first case of BACM in association with the new pandemic influenza A (HINI) virus infection in an 11-year-old boy from Cyprus. The child had the typical clinical and laboratory characteristics of this clinical syndrome. Prompt diagnosis of this clinical entity is essential to prevent unnecessary investigations and therapeutic interventions and to reassure the patient and parents of the excellent prognosis.     

Clinical and socio-economic impact of influenza and respiratory syncytial virus infection on healthy children and their households

This prospective study compared the clinical and socio-economic impact of laboratory-confirmed influenza and respiratory syncytial virus (RSV) infection on healthy children and their families. Among 1,520 otherwise healthy children aged< 15 years attending the Emergency Department for acute conditions other than trauma, influenza viruses and RSV were found in 234 (15.4%) and 116 (7.6%; p<0.0001) patients, respectively. The fact that influenza has a similar global clinical impact on the community to that of RSV infection, but represents a greater socio-economic burden, may contribute to broadening the acceptance of influenza vaccination.     

Signs and symptoms predicting influenza in children: a matched case–control analysis of prospectively collected clinical data

We aimed to determine whether there are signs or symptoms that could help clinicians to distinguish between influenza and other respiratory infections. The clinical data for this matched case-control analysis were derived from a 2-year prospective cohort study of respiratory infections among children aged≤13 years. At any signs of respiratory infection, the children were examined and nasal swabs were obtained for virologic analyses. Cases were 353 children with laboratory-confirmed influenza and controls were 353 children with respiratory symptoms who tested negative for influenza. Cases and controls were matched for gender, age, and timing of the visit. In the multivariate conditional logistic regression analyses, fever was the only sign that independently predicted influenza virus infection, with odds ratios ranging from 13.55 (95% confidence interval [CI], 6.90-26.63) to 50.10 (95% CI, 16.25-154.45), depending on the degree of fever. In all analyses, the predictive capability of fever increased with incremental elevations in the child's temperature. The likelihood ratio of fever≥40.0°C in predicting influenza was 6.00 (95% CI, 2.80-12.96). Among unselected children seen as outpatients during influenza outbreaks, fever is the only reliable predictor of influenza virus infection. The optimal use of influenza-specific antiviral drugs in children may require virologic confirmation.     

Comparison of four clinical specimen types for detection of influenza A and B viruses by optical immunoassay (FLU OIA test) and cell culture methods

Although laboratory diagnosis of respiratory viruses has been widely studied, there is a relative insufficiency of literature examining the impact of specimen type on the laboratory diagnosis of influenza A and B. In a clinical study comparing the FLU OIA test with 14-day cell culture, clinical specimens from nasopharyngeal swabs, throat swabs, nasal aspirates, and sputum were obtained from patients experiencing influenza-like symptoms. A total of 404 clinical specimens were collected from 184 patients. Patients were defined as influenza positive if the viral culture of a specimen from any sample site was positive. Patients were defined as influenza negative if the viral cultures of specimens from all sample sites were negative. By this gold standard, culture and FLU OIA test results for each sample type were compared. For each of the four specimen types, the viral culture and FLU OIA test demonstrated equal abilities to detect the presence of influenza A or B virus or viral antigen. Sputum and nasal aspirate samples were the most predictive of influenza virus infection. Throat swabs were the least predictive of influenza virus infection, with both tests failing to detect influenza virus in nearly 50% of the throat samples studied.     

Influenza vaccination in systemic lupus erythematosus: safe and protective?

Patients with systemic lupus erythematosus (SLE) show decreased immune responsiveness and are vulnerable for infectious diseases, due to the underlying disease and the frequent use of immunosuppressive drugs. Influenza has a high incidence in the population and is associated with increased morbidity and mortality in immunocompromised patients. Therefore, routine influenza vaccination of SLE patients seems indicated. However, there have been concerns about the safety of influenza vaccination in SLE as vaccination was thought to activate the autoimmune response. Safety of influenza vaccination has been studied, and, as far as SLE patients with quiescent disease are concerned, it is now generally accepted that influenza vaccination is safe. Another point of concern is vaccine efficacy. In immunocompromised patients, the immunogenicity of vaccines may be reduced. In the immune response to influenza (vaccination) both humoral and cell-mediated responses are involved. In SLE, research on the immune response to influenza vaccination has focused on humoral immune responses, demonstrating a blunted humoral response. Future research should focus on cell-mediated immune responses as well, as these are important for clearing of influenza infection and are expected to be impaired in SLE. Because of the decreased immunogenicity of the current influenza vaccine in SLE, new influenza vaccination strategies should be explored to improve vaccination efficacy.     

Reduced incidence of pneumonia in influenza-vaccinated solid organ transplant recipients with influenza disease

Whether influenza vaccination influences the severity of illness in cases of clinical failure in solid organ transplant (SOT) recipients receiving influenza vaccine has not been extensively studied. Our goal was to evaluate the frequency of influenza vaccination among SOT recipients with influenza disease and its impact on the illness severity during the 2010–2011 season. Adult SOT recipients with confirmed influenza infection were included from December 2010 to April 2011. Follow-up data were recorded and antibody titres were determined using a microneutralization assay. Sixty-four SOT recipients were included in the study, ten (15.6%) with severe disease, requiring admission to intensive care units, of whom four (6.3%) died. In all, 34 (53.1%) received the 2010–2011 seasonal influenza vaccine and 32 (50.0%) received the 2009-H1N1 pandemic vaccine, and none had detectable antibodies against influenza at the time of diagnosis of influenza infection. Twenty-three (67.6%) of the patients that received the vaccine required hospital admission and presented less dyspnoea (10, 29.4% versus 14 (50.0%), p 0.09) and pneumonia (8, 23.8% versus 15, 50.0%, p 0.03, relative risk 0.3, 95% CI 0.1-0.9) than unvaccinated patients, with relative risk reductions of 60% and 70%, respectively. Although influenza vaccination confers protection on SOT recipients against developing influenza pneumonia, the rate of clinical failure is still high. New strategies to improve influenza immunization are needed for this group of patients.     

Pulse-oximetry accurately predicts lung pathology and the immune response during influenza infection

In animal models of influenza, systemic weight loss is the primary indicator of morbidity from infection, which does not assess local lung pathology or the immune response. Here, we used a mouse-adapted pulse-oximeter as a non-invasive clinical readout of lung function during influenza infection in mice, and found direct correlations between oxygen saturation levels and lung pathology, that reflected the morbidity and survival from influenza infection. We found blood oxygen levels to be a more accurate assessment than weight-loss morbidity in predicting lung pathology in hosts infected with different viral doses, and in assessing immune-mediated viral clearance in the lung.     

广州市甲型H1N1流感暴发疫点与监测人群病毒抗体检测

目的通过分析广州市甲型H1N1流感暴发疫点与监测人群病毒的抗体水平,了解甲型H1N1流感的流行趋势,为预防甲型H1N1流感疫情提供科学依据。方法应用红细胞血凝抑制（HI）方法检测流感甲型H1N1抗体,对比分析1570名疫区学生与1326名监测人群血清标本H1N1流感病毒的抗体水平。结果疫区学生甲型H1N1流感病毒感染率、流感罹患率分别为32.17%、22.23%,明显高于市区监测人群的22.62%、15.38%（P=0.000,P=0.000）。疫点学生与市区监测人群甲型H1N1流感隐性感染率分别为9.94%、7.24%,差异有统计学意义（P=0.012）。在已感染甲型H1N1流感病毒的疫点学生和市区监测人群中,甲型H1N1流感隐性感染率（30.89%、32.00%）差异无统计学意义（P=0.754）。疫点人群显性感染者的抗体滴度明显高于隐性感染者（t=4.701,P=0.000）,监测人群中显性感染与隐性感染者的抗体滴度无显著差异（t=0.248,P=0.804）。结论疫点学生甲型H1N1流感隐性感染率明显高于监测人群。提示隐性感染人群具有潜在的传染力,应加强隐性感染者的监测。     

Influenza vaccination of patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA)

The role of influenza vaccination in patients suffering from autoimmune diseases, including systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), has long been a subject of discussion. The risk of exacerbation of the main disease following vaccination is of particular concern, and needs to be carefully evaluated against the risk of disease flares as a result of infections. Our study included 69 SLE patients and 54 RA patients, all in stable condition. We split the groups into two subgroups each: patients in SLE1 (23 patients) and RA1 (23 patients) received the flu vaccine ("Vaxigrip", Aventis Pasteur) in November 2003. Patients in SLE2 (46 patients) and RA2 (31 patients) were not vaccinated. Throughout the following year, we studied parameters of disease activity and the occurrence of viral respiratory and bacterial infections in our patients. The vaccine was well tolerated in all cases. Vaccinated patients had significantly fewer occurrences of infections. Every viral and bacterial infection resulted in the worsening of the main disease. We believe that influenza vaccine is indicated for SLE and RA patients in stable condition. However, this decision must be made on a patient-by-patient basis. We plan to continue our study with the goal of formulating a better protocol for the clinical practice.     

Influenza Vaccination and Asthma

Influenza is an important epidemic and pandemic illness associated with serious morbidity and mortality in unprotected communities. Patients at increased risk of infection are those with pre-existing cardiopulmonary disease including asthma. The influenza virus has the ability to produce antigenic changes posing problems for vaccine development. Influenza vaccines have been available for over 50 years. Despite the continuing global threat posed by infection and recommendations in many countries that immunisation should be widely given, uptake rates are variable and often poor. It has been demonstrated that infection with influenza and other respiratory viral pathogens can produce exacerbations of asthma throughout the age groups. Despite this, vaccine uptake rates in asthmatic populations are quite low. Poor uptake rates are attributed to a number of factors and we review the evidence for the widely held view that influenza vaccination produces exacerbations of chronic airflow obstruction including asthma. Observational studies have found conflicting results: some post immunisation changes in bronchial hyperreactivity and increased requirements of bronchodilator therapy have been in some, but not all, studies. Placebo-controlled trials have not demonstrated any clinical deterioration although one study showed a small reduction in peak expiratory flow rate. Intranasal administration of cold-adapted live vaccines and new nucleic acid vaccines are briefly considered. Live adapted vaccines have been shown to be effective in influenza immunoprophylaxis and limited data on their use in patients with asthma suggest that they can be administered safely. In conclusion, based up on current studies and evidence, it seems likely that influenza infection produces morbidity in patients with asthma but that any potential adverse effects of influenza immunisation are outweighed by the benefits in this population. However, placebo-controlled trials are few and only small numbers of asthmatic patients have been investigated.     

Inhibitory effects of silver nanoparticles on H1N1 influenza A virus in vitro

Silver nanoparticles have demonstrated efficient inhibitory activities against human immunodeficiency virus (HIV) and hepatitis B virus (HBV). However, the effects of silver nanoparticles against H1N1 influenza A virus remain unexplored. In this study, the interaction of silver nanoparticles with H1N1 influenza A virus was investigated. Silver nanoparticles with mean particle diameters of 10nm were prepared for the hemagglutination inhibition test, the embryo inoculation assay, and the Mosmann-based 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, where these tests were used to determine the inhibitory activity of silver nanoparticles on H1N1 influenza A virus. MDCK cells were used as the infection model. Electron microscopy analysis and flow cytometry assay were used to determine whether silver nanoparticles could reduce H1N1 influenza A virus-induced apoptosis in MDCK cells. This study demonstrates that silver nanoparticles have anti-H1N1 influenza A virus activities. The inhibitory effects of silver nanoparticles on influenza A virus may be a novel clinical strategy for the prevention of influenza virus infection during the early dissemination stage of the virus.