Drug-Resistant Flu Linked With Pneumonia, Norwegian Doctors Say

[HenryN]

Drug-Resistant Flu Linked With Pneumonia, Norwegian Doctors Say


By Jason Gale
Dec. 31 (Bloomberg) -- A drug-resistant influenza strain that has spread globally this year needs further study to gauge its virulence, according to doctors in Norway who found the bug was linked with patients suffering more severe symptoms.
A form of the H1N1 seasonal flu virus that evades Roche Holding AG's Tamiflu appeared more likely to cause pneumonia and sinusitis than the H1N1 strain without the resistance-causing mutation, researchers from the Norwegian Institute of Public Health in Oslo and the U.K.'s Health Protection Agency said.
While ``not a statistically significant finding,'' results of the study, involving fewer than 300 patients, ``warrant further investigation,'' the authors said. The study was released online today ahead of publication in the February edition of Emerging Infectious Diseases by the U.S. Centers for Disease Control and Prevention.
Tamiflu-evading influenza has been reported in 50 countries on six continents since widespread resistance to the bestselling antiviral was first reported to the World Health Organization by Norway in January. Its emergence prompted doctors to consider other medicines, such as GlaxoSmithKline Plc's Relenza, to fight a disease the WHO estimates causes 250,000 to 500,000 deaths annually.
In the U.S., doctors prescribing anti-flu treatments should give their patients Relenza, an orally inhaled medicine, or a combination of Tamiflu and an older drug called rimantadine, the CDC said in a Dec. 19 statement. Basel, Geneva-based Roche had worldwide Tamiflu sales of $1.74 billion in 2007 and $2.1 billion in 2006.
Dominant Strain
Of the 65 H1N1 viruses tested in the U.S. since October, 99 percent were resistant to oseltamivir, and all were susceptible to Relenza, rimantadine and amantadine, a similar drug, the CDC said. H1N1 is the dominant flu strain currently circulating in the U.S. this winter.
Preliminary data indicate that Tamiflu-resistant H1N1 flu viruses don't cause different or more severe symptoms compared with Tamiflu-sensitive H1N1 viruses, the CDC said in its Dec. 19 health advisory. Flu typically causes fever, joint and muscle ache, cough, sore throat and runny nose.
Of patients infected with the mutant strain in the Norwegian study, 9.2 percent had pneumonia and 6.2 percent had sinusitis. That compares with a pneumonia risk of 2.9 percent and sinusitis risk of 3 percent in patients infected with a non- resistant H1N1 strain. Risk ratios weren't statistically significant after adjusting for age, gender, and predisposing disease, according to the study.
Pandemic Plans
The emergence of Tamiflu-resistance has raised concern that the medicine, stockpiled by governments worldwide, might become a less powerful weapon in the fight against the H5N1 avian strain and any global contagion it spawns because of the potential for bird flu and pandemic flu to exchange genes with drug-resistant seasonal flu.
``Resistance in a more virulent influenza virus can have serious public health implications because of fewer therapeutic and prophylactic options, which may result in more persons being affected by influenza and more severe illness and death in those who become infected,'' Siri H. Hauge and colleagues wrote. ``These findings should be taken into consideration when shaping future strategies for treating and preventing seasonal and pandemic influenza.''
The researchers found the resistant strain occurred in the absence of selective pressure caused by widespread Tamiflu usage. The pill is not available in Norway without a prescription and it is rarely prescribed there, they said.
``Our data indicate that the viruses carrying this resistance mutation are fully capable of persistence and spread in the absence of selective pressure,'' the authors wrote.
To contact the reporters on this story: Jason Gale in Singapore at j.gale@bloomberg.net
Last Updated: December 31, 2008 00:57 EST

 

[HenryN]

Re: Drug-Resistant Flu Linked With Pneumonia, Norwegian Doctors Say

DOI: 10.3201/eid1502.081031 ​

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Suggested citation for this article​

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[/FONT][FONT=Times New Roman,Times New Roman]: Hauge SH, Dudman S, Borgen K, Lackenby A, Hungnes O. Oseltamivir-resistant influenza viruses A (H1N1), Norway, 2007?08. Emerg Infect Dis. 2009 Feb; [Epub ahead of print] ​

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Oseltamivir-Resistant Influenza Viruses A (H1N1), Norway, 2007?08​

Siri H. Hauge, Susanne Dudman, Katrine Borgen, Angie Lackenby, and Olav Hungnes​

Author affiliations: Norwegian Institute of Public Health, Oslo, Norway (S.H. Hauge, S. Dudman, K. Borgen, O. Hungnes); and Health Protection Agency, London, UK (A. Lackenby)​

In Norway in January 2008, unprecedented levels of oseltamivir resistance were found in 12/16 influenza viruses A (H1N1) tested. To investigate the epidemiologic and clinical characteristics of these viruses, we used sequence analysis to test all available subtype H1N1 viruses from the 2007?08 season for resistance. Questionnaires from physicians provided information on predisposing diseases, oseltamivir use, symptoms, and complications. Clinical data were obtained for 265 patients. In total, 183 (67.3%) of 272 viruses were oseltamivir resistant. Resistance was not associated with prior use of antiviral drugs. Symptoms and hospitalization rates did not differ for patients infected with a resistant or a susceptible virus. Oseltamivir-resistant influenza viruses A (H1N1) did not show diminished capability to spread in the absence of selective pressure. The ability of these viruses to sustain their fitness and spread among persons should be considered when shaping future strategies for treating and preventing seasonal and pandemic influenza.​

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Seasonal influenza, caused by influenza A subtypes H3N2 and H1N1 and influenza B viruses, occurs as annual epidemics. Although vaccination remains the primary measure for prevention, antiviral drugs are available for prevention and treatment of influenza. The influenza virus neuraminidase inhibitors zanamivir and oseltamivir were introduced into clinical practice in various parts of the world from 1999 through 2002 (​

[/FONT][FONT=Times New Roman,Times New Roman]1[/FONT][FONT=Times New Roman,Times New Roman]). Oseltamivir limits replication of both influenza A and B viruses ([/FONT][FONT=Times New Roman,Times New Roman]1[/FONT][FONT=Times New Roman,Times New Roman]). In most European countries, neuraminidase inhibitors are not widely used to treat seasonal influenza, but they are being stockpiled in many countries as part of their pandemic influenza preparedness. In Norway, oseltamivir is registered for prophylactic and ​

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therapeutic use in persons >1 year of age; however, it is not available without a prescription and it is rarely prescribed (​

[/FONT][FONT=Times New Roman,Times New Roman]2[/FONT][FONT=Times New Roman,Times New Roman]).
Until 2007, resistance against neuraminidase inhibitors was rarely observed ([/FONT][FONT=Times New Roman,Times New Roman]1[/FONT][FONT=Times New Roman,Times New Roman],[/FONT][FONT=Times New Roman,Times New Roman]3[/FONT][FONT=Times New Roman,Times New Roman],[/FONT][FONT=Times New Roman,Times New Roman]4[/FONT][FONT=Times New Roman,Times New Roman]). Nevertheless, to better understand the potential for development of resistance against neuraminidase inhibitors, surveillance of antiviral susceptibility in influenza virus in Europe has been ongoing since 2004 ([/FONT][FONT=Times New Roman,Times New Roman]5[/FONT][FONT=Times New Roman,Times New Roman]). As part of the World Health Organization (WHO) Global Influenza Surveillance Network, the national influenza centers in Europe submit influenza viruses to the WHO Influenza Collaborating Centre in the United Kingdom each influenza season. Within the framework of the European Surveillance Network for Vigilance against Viral Resistance (VIRGIL), these viruses are also tested for drug susceptibility at the Health Protection Agency in London.
In mid-January 2008, antiviral susceptibility testing (enzyme inhibition assays) of the first shipment of influenza viruses from Norway for the 2007?08 season showed an unusually large proportion (5/7) of influenza viruses A (H1N1) with high-level resistance to oseltamivir. In subsequent days, testing of additional viruses from Norway at the Norwegian national influenza center and at the Health Protection Agency confirmed the high proportion of oseltamivir resistance. This unexpected and unprecedented discovery had possible public health implications of international concern. On January 25, 2008, the Norwegian Institute of Public Health notified WHO of these findings under the International Health Regulations ([/FONT][FONT=Times New Roman,Times New Roman]6[/FONT][FONT=Times New Roman,Times New Roman]) and notified the European Commission through the Early Warning and Response System. The Institute also informed hospitals and physicians in Norway about a possible lack of therapeutic effect when treating patients with oseltamivir. By the end of January, oseltamivir-resistant viruses had been reported from several European countries ([/FONT][FONT=Times New Roman,Times New Roman]7[/FONT][FONT=Times New Roman,Times New Roman]).
The oseltamivir-resistance trait is caused by a previously described point mutation in the virus neuraminidase gene (histidine to tyrosine at position 275 of the N1 neuraminidase, commonly referred to as H274Y in N2 numbering), which is known to confer high-level resistance to oseltamivir while retaining susceptibility to zanamivir ([/FONT][FONT=Times New Roman,Times New Roman]8[/FONT][FONT=Times New Roman,Times New Roman]). Influenza viruses A (H1N1) carrying the H274Y mutation have reduced ability to replicate and transmit efficiently when compared with parental, susceptible virus, but the clinical implications of infection with these viruses have been largely unknown ([/FONT][FONT=Times New Roman,Times New Roman]9[/FONT][FONT=Times New Roman,Times New Roman]). Consequently, we undertook studies to determine ​

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whether the emergence and spread of the resistant viruses were associated with exposure to oseltamivir, whether resistant viruses would continue to circulate in similar proportions into the epidemic phase of the season, and whether the new resistant viruses differed from their susceptible counterparts in their ability to cause disease. To do so, we tested all influenza viruses A (H1N1) available from the 2007?08 outbreak for oseltamivir susceptibility. We furthermore enhanced surveillance by collecting an extended set of data regarding clinical symptoms, complications, and prior exposure to oseltamivir for all laboratory-verified cases of viruses A (H1N1) virus infection.​

[/FONT][FONT=Arial,Arial]Methods

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The influenza viruses A (H1N1) included in this study were obtained from the sentinel and nonsentinel collaborators as part of routine national virologic influenza surveillance. From all 19 counties, 71 sentinel practices collect samples from patients with influenza-like illness and send them to the national influenza center for diagnostic testing. From all parts of the country, 15 medical microbiology laboratories submit materials containing influenza A or B materials (original specimens, nucleic acid preparations from original specimens, or viral isolates) to the national influenza center for further characterization. Most of these samples originate from primary care clinics; the rest, from hospitals.
Viruses confirmed as influenza A (H1), by either reverse transcription?PCR (RT-PCR) or virus isolation in MDCK cells and subsequent subtyping by immunofluorescence, were included in the study. In-country susceptibility testing was performed by detecting the H274Y mutation by sequence analysis, through either a pyrosequencing assay targeting the single relevant point mutation (​

[/FONT][FONT=Times New Roman,Times New Roman]10[/FONT][FONT=Times New Roman,Times New Roman]) or through full- or partial-length cycle sequencing of the coding region for the viral neuraminidase. These analyses were mostly performed on RNA prepared from the original patient specimen. A large proportion of the isolated viruses were sent to the WHO Collaborative Centre for Influenza Research and Reference in the National Institute of Medical Research, Mill Hill, UK, for further characterization. Within the framework of VIRGIL, these viruses were forwarded to the Health Protection Agency for phenotypic antiviral susceptibility testing and more extensive genotypic analyses. To determine neuraminidase susceptibility, assays to determine the drug concentration that provides 50% inhibition (IC[/FONT][FONT=Times New Roman,Times New Roman]50[/FONT][FONT=Times New Roman,Times New Roman]) were performed by using ​

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the fluorescent substrate methylumbelliferyl N-acetylneuraminic acid based on the method described by Wetherall et al. (​

[/FONT][FONT=Times New Roman,Times New Roman]11[/FONT][FONT=Times New Roman,Times New Roman]) with minor modifications.
Relative quantitative data on virus shedding, i.e., virus RNA content in the patient specimens, were obtained through a real-time RT-PCR targeting a conserved part of the matrix protein (M1) gene of influenza A virus. Two microliters of nucleic acid prepared from specimens (MagNApure LC Total Nucleic Acid Isolation Kit; Roche Diagnostics, Mannheim, Germany) was added to a 23-[/FONT][FONT=Times New Roman,Times New Roman]μ[/FONT][FONT=Times New Roman,Times New Roman]L reaction mixture containing 0.3 [/FONT][FONT=Times New Roman,Times New Roman]μ[/FONT][FONT=Times New Roman,Times New Roman]M forward primer M52c (5[/FONT][FONT=Times New Roman,Times New Roman]′[/FONT][FONT=Times New Roman,Times New Roman]-CTT CTA ACC GAG GTC GAA ACG-3[/FONT][FONT=Times New Roman,Times New Roman]′[/FONT][FONT=Times New Roman,Times New Roman]); 0.3 [/FONT][FONT=Times New Roman,Times New Roman]μ[/FONT][FONT=Times New Roman,Times New Roman]M reverse primer M149r (5[/FONT][FONT=Times New Roman,Times New Roman]′[/FONT][FONT=Times New Roman,Times New Roman]-CTT GTC TTT AGC CAT TCC ATG AG-3[/FONT][FONT=Times New Roman,Times New Roman]′[/FONT][FONT=Times New Roman,Times New Roman]); 0.15 [/FONT][FONT=Times New Roman,Times New Roman]μ[/FONT][FONT=Times New Roman,Times New Roman]M probe M93c (FAM-5[/FONT][FONT=Times New Roman,Times New Roman]′ [/FONT][FONT=Times New Roman,Times New Roman]CCG TCA GGC CCC CTC AAA GCC GA 3[/FONT][FONT=Times New Roman,Times New Roman]′[/FONT][FONT=Times New Roman,Times New Roman]-Black Hole Quencher 1); and 5? QIAGEN OneStep RT-PCR buffer, dNTP mixture, and enzyme mixture according to the manufacturer?s instructions (QIAGEN OneStep RT PCR Kit; QIAGEN, Hilden, Germany). Forward primer and probe sequences were as described by Fouchier et al. ([/FONT][FONT=Times New Roman,Times New Roman]12[/FONT][FONT=Times New Roman,Times New Roman]), and the reverse primer was designed by Tom ?ystein Jonassen (Akershus University Hospital, L?renskog, Norway). Reactions were run in a Corbett Rotorgene RG-3000 or RG-6000 thermocycler (Corbett Research Pty Ltd, Sydney, New South Wales, Australia) with the following cycling conditions: reverse trancription for 30 min at 50?C, then 15 min at 95?C, followed by 50 cycles at 95?C for 10 sec, 54?C for 30 sec, and 72?C for 20 sec. ​

[/FONT][FONT=Arial,Arial]Participants and Study Design

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We included all patients with a diagnosis of influenza virus A (H1N1) infection made by national influenza center during the 2007?08 influenza season. For the 72 patients who received this diagnosis before the end of January 2008, data were collected retrospectively. From February on, data were collected as soon as possible after laboratory confirmation of influenza virus A (H1N1) infection. Structured questionnaires returned from consulting physicians provided auxiliary information about clinical signs and symptoms, complications, predisposing diseases for severe outcome of influenza (diabetes, cardiac disease, lung disease, and immunodeficiency), use of oseltamivir, and influenza vaccination status. If the questionnaire was not returned by mail within 3 weeks, a reminder call was made. When available, relevant clinical information on the original referral sample form was used to supplement the data from the written questionnaire. The consulting physician, usually the primary care physician, was not informed about the result of the susceptibility testing when the information was collected.​

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Information for the first 12 patients infected with a resistant virus was collected from the consulting physicians by telephone.​

[/FONT][FONT=Arial,Arial]Statistical Analysis

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Data from the questionnaires and selected laboratory testing outcomes were merged, checked for quality, and analyzed by using Stata version 9.0 (StataCorp LP, College Station, TX, USA). We used the Fisher exact test to compare the proportions of possible confounders among those infected with a resistant and a susceptible virus. To estimate the association between exposure (resistant virus infection) and outcome (subsequent clinical findings and complications), we calculated crude risk ratios (RRs) and 95% confidence intervals (CIs). We used binomial regression to calculate RRs adjusted for possible confounders. For each variable we used the number of respondents as the denominator, except for predisposing disease, for which missing values were coded as "no."​

[/FONT][FONT=Arial,Arial]Results

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The overall influenza activity in Norway was low in 2007?08 compared with that of previous years. Virologic surveillance showed most influenza virus A and 95% of subtyped viruses to be subtype H1N1 (​

[/FONT][FONT=Times New Roman,Times New Roman]13[/FONT][FONT=Times New Roman,Times New Roman]). From the sentinel practices, the national influenza center received 229 specimens for influenza testing. Of the 108 that were positive for influenza virus, 61 were type A, subtype H1N1, and most of the rest were type B. In total, 297 patients had an influenza virus A (H1N1) infection confirmed by the national influenza center in Norway from week 47 in 2007 until the end of week 20 in 2008. We obtained a resistance profile for 272 of the 297 viruses. We could not determine the resistance profile of the remaining 25 because of low virus content and consequently excluded them from analysis.
A total of 196 viral isolates were available (133 carried the resistance mutation); of these, 113 (79 with the resistant genotype) were reference tested by the VIRGIL laboratory. Phenotypic and genotypic reference analysis results agreed completely with the in-country genotypic testing results; all mutant viruses showed large reductions in susceptibility to oseltamivir when compared with non-H274Y viruses (IC[/FONT][FONT=Times New Roman,Times New Roman]50 [/FONT][FONT=Times New Roman,Times New Roman]260?2,161 nM, mean 673 nM, for the 274Y mutant and 0.4?5.6 nM, mean 2.6 nM, for the nonmutant viruses). No evidence of mixed genotype or phenotype was observed. In phylogenetic analysis of the H1 gene, all viruses tested grouped ​

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together in subclade 2B (Figure 1). In the phylogenetic tree, the resistant viruses from Norway all formed a single branch that was distinct, but closely related, to the susceptible viruses from Norway.
Of the 272 influenza viruses A (H1N1), 183 (67.3%) were oseltamivir resistant (Table 1). The proportion of resistant viruses did not differ between samples from sentinel 67.9% (38/56) and nonsentinel 67.1% (145/216) practices and persisted throughout the season (Figure 2). No difference in virus shedding, as quantified by real-time RT-PCR of available patient specimens, was observed between susceptible and resistant viruses (Figure 3). From the original sample form we obtained demographic information for all 272 patients. Returned questionnaires provided information for 265 patients (97.4%), but the response rate on individual questions varied. Of the 272 patients infected with influenza viruses A (H1N1), 132 (48.5%) were male (Table 1), and slightly more than half (50.7%) were 29?64 years of age (median 27 years, range 2 months?71 years); median ages of those infected with a resistant and a susceptible virus were 31 and 21 years, respectively. The highest proportion of resistant virus infection was found for those 25?59 years of age (102/138, 73.9%) and differed significantly from the proportion for only those 5?14 years of age (25/45, 55.6%) (Fisher exact p = 0.03). We obtained influenza viruses A (H1N1) from 18/19 counties (Figure 4).The oseltamivir resistance proportion was >80% in 8 counties in southern Norway, compared with 63.5% in the rest of the country (Fisher exact p = 0.001).
Information about use of antiviral drugs was obtained for 237 patients. No patients had received antiviral treatment in the 14 days before the onset of symptoms, and none had been in close contact with others known to have used antiviral drugs. Oseltamivir was received after sampling by 7 patients, 5 of whom were infected with an oseltamivir-resistant virus. Of 225 patients, 9 had traveled abroad in the week before symptom onset; 4 were infected with a resistant virus. Of all 272 patients, 2 had been vaccinated against influenza and were both infected with a resistant virus.
We received information about predisposing disease for 213 patients. Having a predisposing disease more than doubled the risk for complications (RR 2.5, 95% CI 1.2?5.4) but was not clearly associated with being infected with a resistant virus (RR 1.4, 95% CI 0.6?3.2). Information about clinical symptoms was obtained for 252/272 patients; most frequently​

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reported were fever (229/242) and headache (122/189). Resistant virus infection was not associated with any particular symptom (Table 2). Of 241 patients, 58 (24.1%) had >1 complications recorded, but no difference was observed between those infected with a resistant virus and those infected with a susceptible virus (Table 2). Bronchitis and pneumonia were the most frequent complications, reported for 22 and 17 patients, respectively. The age of the 17 patients who had pneumonia ranged from 8 months to 65 years (mean 29 years): 2 (12.5%) were 0?4 years of age, 5 (31.3%) were 5?14 years of age, 2 (12.5%) were 5?24 years of age, 4 (25.0%) were 5?59 years of age, and 3 (18.8%) were >59 years of age. Of the 17 patients with pneumonia, 15 were infected with a resistant virus. The attack rates of pneumonia and of sinusitis were higher for those infected with a resistant virus than for those infected with a susceptible virus, although the risk ratios were not statistically significant after adjusting for age, gender, and predisposing disease (pneumonia RR 3.2, 95% CI 0.7?13.7; sinusitis RR 1.7, 95% CI 0.4?7.5) (Table 2). Of 264 patients, 45 had been hospitalized, 28 and 17 infected with a resistant and a susceptible virus, respectively. No deaths were reported for patients included in the study.​

[/FONT][FONT=Arial,Arial]Discussion

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During the 2007?08 influenza season in the Northern Hemisphere, widespread circulation of oseltamivir-resistant influenza viruses A (H1N1) was observed. Percentage of resistant viruses circulating in different countries varied markedly; the highest proportion reported worldwide (67%) was in Norway (​

[/FONT][FONT=Times New Roman,Times New Roman]17,18[/FONT][FONT=Times New Roman,Times New Roman]).
Our study did not show any association between oseltamivir use in Norway and emergence of the oseltamivir-resistant influenza viruses A (H1N1). Because only a minority of influenza cases are laboratory confirmed, oseltamivir use in nonsampled persons could have contributed to the development of resistance. However, for this suggestion to be plausible, use of oseltamivir would have to be widespread to exert substantial selective pressure on the viruses. Sales of oseltamivir in Norway have been low: 699 5-day regimens (0.15/1,000 population) were sold in 2004; 66,249 (14.4/1,000 population) in 2005; 33,573 (7.3/1,000 population) in 2006; and 4,686 (1.0/1,000 population) in 2007 ([/FONT][FONT=Times New Roman,Times New Roman]2[/FONT][FONT=Times New Roman,Times New Roman]). In countries where oseltamivir use has been high, e.g., Japan, the proportion of oseltamivir-resistant influenza viruses A (H1N1) reported during the ​

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2007?08 season was low (​

[/FONT][FONT=Times New Roman,Times New Roman]18[/FONT][FONT=Times New Roman,Times New Roman]). Because influenza strains from Norway were genetically similar to resistant viruses that appeared just as early in several other European countries (A. Hay, pers. comm.), we consider it unlikely that the resistant variant originated in Norway. Conceivably, the initial emergence of a resistant virus could be associated with oseltamivir use elsewhere. Our data indicate that the viruses carrying this resistance mutation are fully capable of persistence and spread in the absence of selective pressure.
In Norway, the initially high proportion of resistant influenza viruses A (H1N1) was maintained throughout the entire 2007?08 influenza season; countrywide, 2 of 3 viruses were resistant. The reason for this exceptionally high resistance proportion is unknown. However, it likely reflects the proportion of resistant viruses introduced into Norway in the autumn 2007. Globally, the proportion of resistant influenza viruses A (H1N1) reported is highly variable between the different countries for which data are available ([/FONT][FONT=Times New Roman,Times New Roman]18[/FONT][FONT=Times New Roman,Times New Roman]). This large variation, apparently in the absence of oseltamivir selective pressure, suggests that a high level of randomness determined the frequency of resistance. In temperate countries, the influenza viruses are reintroduced each autumn after the absence of influenza during the summer. If only a limited number of viruses are reintroduced into each country and initiate virus circulation and outbreaks, the result will be considerable random variation in virus variant proportions between the different countries. Consistent with this result, almost all the characterized influenza viruses A (H1N1) in Norway could be assembled into a small number of genetically discernible groups (Figure 1). We propose that such randomness in virus introductions may be sufficient to explain the differences in the proportions of resistant viruses between the countries.
Conceivably, a difference in the antigenic characteristics of the resistant and susceptible viruses could have favored 1 virus over the other in the face of host population immunity. Such differences might contribute to different relative effect of the 2 viruses in different populations (e.g., countries) or subpopulations (e.g., age groups). However, the resistant and susceptible viruses were closely related and were not distinguishable in hemagglutination inhibition tests ([/FONT][FONT=Times New Roman,Times New Roman]19[/FONT][FONT=Times New Roman,Times New Roman]).
Overall, the observed clinical manifestations associated with influenza viruses A (H1N1) in this study were as expected for seasonal influenza. No differences were noted for virus shedding, primary symptoms, or overall complication and hospitalization rates caused by ​

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oseltamivir-resistant and -susceptible viruses. We did find, although not a statistically significant finding, that patients infected with a resistant virus appeared to be more likely than those infected with a susceptible virus to have pneumonia or sinusitis. Patients with more severe illness may be more likely to be sampled; however, the resistance pattern of the virus was not known by the physician at the time of sampling and reporting. We therefore believe that these findings are not influenced by selection bias. Adjusting for possible confounders (age, sex, and predisposing disease) did not change the results. Because of our limited sample size, the precision of our estimates is low, but they do indicate findings that warrant further investigation. Our data will also be analyzed with data from other European countries, and the findings may strengthen the conclusions about the clinical implications of oseltamivir-resistant influenza viruses A (H1N1) .
The future effect of resistant influenza viruses A (H1N1) is unpredictable. In Europe, the H1N1 subtype was predominant during the 2007?08 influenza season and, according to historical patterns, is unlikely to predominate during the 2008?09 influenza season. In the following 2008?09 season in the Northern Hemisphere, influenza viruses A (H1N1) may well predominate in areas where they had not recently been present in large numbers. Early reporting from the Southern Hemisphere 2008 influenza season indicates that detection of influenza virus A (H1N1) is low (​

[/FONT][FONT=Times New Roman,Times New Roman]20[/FONT][FONT=Times New Roman,Times New Roman]). However, in South Africa, oseltamivir resistance has been detected in 100% of influenza viruses A (H1N1) tested ([/FONT][FONT=Times New Roman,Times New Roman]21[/FONT][FONT=Times New Roman,Times New Roman]).
Whether oseltamivir-resistant viruses will persist beyond 2008 depends on several factors. First, their persistence will depend on the prevalence of resistant viruses in the populations that are the source of global influenza spread. Countries in East and Southeast Asia have been proposed as the most likely source for global dissemination of new influenza virus variants ([/FONT][FONT=Times New Roman,Times New Roman]22[/FONT][FONT=Times New Roman,Times New Roman]). The prevalence of resistant influenza viruses A (H1N1) in this region may therefore be more likely to influence future occurrence of these viruses than the prevalence in Europe; resistance monitoring thus needs to be global. Second, changes in recent influenza viruses A (H1N1) may have provided a genetic background that permits H274Y mutants to replicate and transmit. Previous studies have concluded that resistant viruses are less pathogenic and less transmissible than their susceptible counterparts ([/FONT][FONT=Times New Roman,Times New Roman]9,23[/FONT][FONT=Times New Roman,Times New Roman]). In contrast, however, reverse genetics?derived mutants (A/WSN/33 or PR8 backbone) had the same phenotype as wild type viruses in vitro and in vivo ([/FONT][FONT=Times New Roman,Times New Roman]24,25[/FONT][FONT=Times New Roman,Times New Roman]). A recent study on the enzymatic properties of the N1 ​

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neuraminidase of the resistant viruses from the 2007?08 season suggested some genetic background changes that could potentially be involved (​

[/FONT][FONT=Times New Roman,Times New Roman]26[/FONT][FONT=Times New Roman,Times New Roman]).
As long as such a postulated permissive genetic background is common, resistant mutants may arise anew in purely oseltamivir-susceptible influenza virus A (H1N1) populations. Identification of such predisposing genetic traits and monitoring of their occurrence in influenza viruses A (H1N1) and other influenza viruses should continue.
Similar resistance can arise in viruses other than the current human influenza viruses A (H1N1). Resistance in a more virulent influenza virus can have serious public health implications because of fewer therapeutic and prophylactic options, which may result in more persons being affected by influenza and more severe illness and death in those who become infected. Oseltamivir is a prime option for influenza treatment and prophylaxis and forms a substantial part of pandemic preparedness in many countries. The prevalence of oseltamivir-resistant viruses reported in Europe throughout the 2007?08 influenza season clearly shows that this resistant mutation is stable and that these viruses sustain their fitness and ability to spread among persons. These findings should be taken into consideration when shaping future strategies for treating and preventing seasonal and pandemic influenza. ​

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Acknowledgments​

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We thank the clinicians and laboratorians who collected specimens and data. Torstein Aune is gratefully acknowledged for substantial help with data entry and management; Kirsten Konsmo, for performing the reminder calls and producing the map; and Remilyn Ramos-Ocao, Marianne Morken, Anne Marie Lund, Valentina Johansen, and Grethe H. Krogh, for expert technical laboratory assistance. We also thank Maria Zambon, Dipa Lakhman, Kameljit Bedi, and Carol Sadler for performing the extensive antiviral testing that initially uncovered the emergence of the resistant viruses, and Alan J. Hay and others for reference analyses on the viruses from Norway.
Dr Hauge is a medical officer at the department of Infectious Disease Epidemiology at the Norwegian Institute of Public Health, Oslo. She is a fellow in the Norwegian Field Epidemiology Training Programme. Her research interests are influenza and other vaccine-preventable diseases.​

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6. World Health Organization. International Health Regulations (IHR) 2005, 2nd ed [cited 2008 December 8]. Available from http://www.who.int/csr/ihr/IHR_2005_en.pdf
7. Lackenby A, Hungnes O, Dudman SG, Meijer A, Paget WJ, Hay A, et al. Emergence of resistance to oseltamivir among influenza A(H1N1) viruses in Europe. Euro Surveill. 2008;13. pii: 8026.
8. Mishin VP, Hayden FG, Gubareva LV. Susceptibilities of antiviral-resistant influenza viruses to novel neuraminidase inhibitors. Antimicrob Agents Chemother. 2005;49:4515?20. PubMed DOI: 10.1128/AAC.49.11.4515-4520.2005
9. Ives JA, Carr JA, Mendel DB, Tai CY, Lambkin R, Kelly L, et al. The H274Y mutation in the influenza A/H1N1 neuraminidase active site following oseltamivir phosphate treatment leaves virus severely compromised both in vitro and in vivo. Antiviral Res. 2002;55:307?17. PubMed DOI: 10.1016/S0166-3542(02)00053-0
10. Lackenby A, Democratis J, Siqueira M, Zambon M. Rapid quantitation of neuraminidase inhibitor drug resistance in influenza virus quasispecies. Antivir Ther. 2008:809?20. PubMed
11. Wetherall NT, Trivedi T, Zeller J, Hodges-Savola C, McKimm-Breschkin JL, Zambon M, et al. Evaluation of neuraminidase enzyme assays using different substrates to measure susceptibility of influenza virus clinical isolates to neuraminidase inhibitors: report of the neuraminidase inhibitor​

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susceptibility network. J Clin Microbiol. 2003;41:742?50. PubMed DOI: 10.1128/JCM.41.2.742-750.2003
12. Fouchier RA, Bestebroer TM, Herfst S, Van Der Kemp L, Rimmelzwaan GF, Osterhaus AD. Detection of influenza A viruses from different species by PCR amplification of conserved sequences in the matrix gene. J Clin Microbiol. 2000;38:4096?101. PubMed
13. Norwegian Institute of Public Health. The 2007/2008 influenza season in Norway [cited 2008 May 28]. Available from http://www.fhi.no/eway/default.aspx...:0:0&MainLeft_5895=5825:66508::1:5896:3:::0:0
14. Felsenstein J. PHYLIP (phylogeny inference package) version 3.2. Cladistics. 1989;5:164?6.
15. Felsenstein J. PHYLIP (phylogeny inference package) version 3.5c. Seattle: Department of Genetics, University of Washington; 1993.
16. Macken C, Lu H, Goodman J, Boykin L. The value of a database in surveillance and vaccine selection. In: Osterhaus ADME, Cox N, Hampson AW, editors. Options for the control of influenza IV. Amsterdam: Elsevier Science; 2001. p. 103?6.
17. European Centre for Disease Prevention and Control. Antivirals and antiviral resistance influenza [cited 2008 May 28]. Available from http://ecdc.europa.eu/en/Health_topics/influenza/antivirals_table.aspx
18. World Health Organization. Influenza A(H1N1) virus resistance to oseltamivir?last quarter 2007 to 5 May 2008 [cited 2008 May 5]. Available from http://www.who.int/csr/disease/influenza/H1N1ResistanceWeb20080505.pdf
19. World Health Organization. Recommended composition of influenza virus vaccines for use in the 2009 southern hemisphere influenza season [cited 2008 October 5]. Available from http://www.who.int/entity/csr/disease/influenza/200809Recommendation.pdf
20. World Health Organization. Seasonal influenza activity in the world, 2008 [cited 2008 July 24]. Available from http://www.who.int/csr/disease/influenza/update/en/index.html
21. World Health Organization. Influenza A(H1N1) virus resistance to oseltamivir [cited 2008 July 18]. Available from http://www.who.int/csr/disease/influenza/h1n1_table/en/index.html
22. Russell CA, Jones TC, Barr IG, Cox NJ, Garten RJ, Gregory V, et al. The global circulation of seasonal influenza A (H3N2) viruses. Science. 2008;320:340?6. PubMed DOI: 10.1126/science.1154137​

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23. Herlocher ML, Carr J, Ives J, Elias S, Truscon R, Roberts N, et al. Influenza virus carrying an R292K mutation in the neuraminidase gene is not transmitted in ferrets. Antiviral Res. 2002;54:99?111. PubMed DOI: 10.1016/S0166-3542(01)00214-5
24. Abed Y, Baz M, Boivin G. Impact of neuraminidase mutations conferring influenza resistance to neuraminidase inhibitors in the N1 and N2 genetic backgrounds. Antivir Ther. 2006;11:971?6. PubMed
25. Yen HL, Ilyushina NA, Salomon R, Hoffmann E, Webster RG, Govorkova EA. Neuraminidase inhibitor-resistant recombinant A/Vietnam/1203/04 (H5N1) influenza viruses retain their replication efficiency and pathogenicity in vitro and in vivo. J Virol. 2007;81:12418?26. PubMed DOI: 10.1128/JVI.01067-07
26. Rameix-Welti MA, Enouf V, Cuvelier F, Jeannin P, van der Werf S. Enzymatic properties of the neuraminidase of seasonal H1N1 influenza viruses provide insights for the emergence of natural resistance to oseltamivir. PLoS Pathog. 2008;4:e1000103. PubMed DOI: 10.1371/journal.ppat.1000103​

</DIR></DIR>[/FONT]<TABLE borderColor=#000000 cellSpacing=0 cellPadding=7 width=718 border=1><TBODY><TR><TD vAlign=top colSpan=4 height=7>

Address for correspondence: Olav Hungnes, Norwegian Institute of Public Health, Department of Virology, PO Box 4404, Nydalen Oslo N-0403, Norway; email: olav.hungnes@fhi.no ​

Table 1. Proportion of oseltamivir-resistant and oseltamivir-susceptible influenza viruses A (H1N1), 2007?08 influenza season, Norway​

</TD></TR><TR><TD vAlign=top width="34%" height=7>

Sample source​

​

</TD><TD vAlign=top width="22%" height=7>

Total no. samples​

​

</TD><TD vAlign=top width="22%" height=7>

Resistant samples, %​

​

</TD><TD vAlign=top width="22%" height=7>

Susceptible samples, %​

​

</TD></TR><TR><TD vAlign=top width="34%" height=7>

All​

​

</TD><TD vAlign=top width="22%" height=7>

272​

​

</TD><TD vAlign=top width="22%" height=7>

183 (67.3)​

​

</TD><TD vAlign=top width="22%" height=7>

89 (32.7)​

​

</TD></TR><TR><TD vAlign=top colSpan=4 height=7>

Type of practice​

​

</TD></TR><TR><TD vAlign=top width="34%" height=7>

Sentinel​

​

</TD><TD vAlign=top width="22%" height=7>

56​

​

</TD><TD vAlign=top width="22%" height=7>

38 (67.8)​

​

</TD><TD vAlign=top width="22%" height=7>

18 (32.1)​

​

</TD></TR><TR><TD vAlign=top width="34%" height=7>

Nonsentinel​

​

</TD><TD vAlign=top width="22%" height=7>

216​

​

</TD><TD vAlign=top width="22%" height=7>

145 (67.1)​

​

</TD><TD vAlign=top width="22%" height=7>

71 (32.9)​

​

</TD></TR><TR><TD vAlign=top colSpan=4 height=7>

Patient gender​

​

</TD></TR><TR><TD vAlign=top width="34%" height=7>

Male​

​

</TD><TD vAlign=top width="22%" height=7>

132​

​

</TD><TD vAlign=top width="22%" height=7>

85 (64.4)​

​

</TD><TD vAlign=top width="22%" height=7>

47 (35.6)​

​

</TD></TR><TR><TD vAlign=top width="34%" height=7>

Female​

​

</TD><TD vAlign=top width="22%" height=7>

140​

​

</TD><TD vAlign=top width="22%" height=7>

98 (70.0)​

​

</TD><TD vAlign=top width="22%" height=7>

42 (30.0)​

​

</TD></TR><TR><TD vAlign=top colSpan=4 height=7>

Patient age group, y​

​

</TD></TR><TR><TD vAlign=top width="34%" height=7>

0?4​

​

</TD><TD vAlign=top width="22%" height=7>

45​

​

</TD><TD vAlign=top width="22%" height=7>

27 (60.0)​

​

</TD><TD vAlign=top width="22%" height=7>

18 (40.0)​

​

</TD></TR><TR><TD vAlign=top width="34%" height=7>

5?14​

​

</TD><TD vAlign=top width="22%" height=7>

45​

​

</TD><TD vAlign=top width="22%" height=7>

25 (55.6)​

​

</TD><TD vAlign=top width="22%" height=7>

20 (44.4)​

​

</TD></TR><TR><TD vAlign=top width="34%" height=7>

15?24​

​

</TD><TD vAlign=top width="22%" height=7>

31​

​

</TD><TD vAlign=top width="22%" height=7>

20 (64.5)​

​

</TD><TD vAlign=top width="22%" height=7>

11 (35.5)​

​

</TD></TR><TR><TD vAlign=top width="34%" height=7>

25?59​

​

</TD><TD vAlign=top width="22%" height=7>

138​

​

</TD><TD vAlign=top width="22%" height=7>

102 (73.9)​

​

</TD><TD vAlign=top width="22%" height=7>

36 (26.1)​

​

</TD></TR><TR><TD vAlign=top width="34%" height=7>

60?99​

​

</TD><TD vAlign=top width="22%" height=7>

13​

​

</TD><TD vAlign=top width="22%" height=7>

9 (69.2)​

​

</TD><TD vAlign=top width="22%" height=7>

4 (30.8)​

​

</TD></TR><TR><TD vAlign=top colSpan=4 height=7>

Patient with predisposing disease​

​

</TD></TR><TR><TD vAlign=top width="34%" height=7>

Diabetes​

​

</TD><TD vAlign=top width="22%" height=7>

10​

​

</TD><TD vAlign=top width="22%" height=7>

9 (90.0)​

​

</TD><TD vAlign=top width="22%" height=7>

1 (10.0)​

​

</TD></TR><TR><TD vAlign=top width="34%" height=7>

Lung disease​

​

</TD><TD vAlign=top width="22%" height=7>

11​

​

</TD><TD vAlign=top width="22%" height=7>

8 (72.7)​

​

</TD><TD vAlign=top width="22%" height=7>

3 (27.3)​

​

</TD></TR><TR><TD vAlign=top width="34%" height=7>

Cardiac disease​

​

</TD><TD vAlign=top width="22%" height=7>

5​

​

</TD><TD vAlign=top width="22%" height=7>

2 (40.0)​

​

</TD><TD vAlign=top width="22%" height=7>

3 (60.0)​

​

</TD></TR><TR><TD vAlign=top width="34%" height=7>

Immunodeficiency​

​

</TD><TD vAlign=top width="22%" height=7>

5​

​

</TD><TD vAlign=top width="22%" height=7>

3 (60.0)​

​

</TD><TD vAlign=top width="22%" height=7>

2 (40.0)​

​

</TD></TR><TR><TD vAlign=top width="34%" height=7>

Any​

​

</TD><TD vAlign=top width="22%" height=7>

27​

​

</TD><TD vAlign=top width="22%" height=7>

20 (74.1)​

​

</TD><TD vAlign=top width="22%" height=7>

7 (25.9)​

​

</TD></TR></TBODY></TABLE>

http://cdc.gov/eid/content/15/2/pdfs/08-1031.pdf

 

[tropical]

Re: Drug-Resistant Flu Linked With Pneumonia, Norwegian Doctors Say

Thanks on the article Dr. Niman.
#2:
"Of the 17 patients with pneumonia, 15 were infected with a resistant virus. The attack rates of pneumonia and of sinusitis were higher for those infected with a resistant virus ..."
#1:
"The researchers found the resistant strain occurred in the absence of selective pressure caused by widespread Tamiflu usage."
"``Our data indicate that the viruses carrying this resistance mutation are fully capable of persistence and spread in the absence of selective pressure,'' the authors wrote."


From bad to worst.

Coincidences were possible indeed.
Still it is suspect such natural change in resistance just for the almost only "eff." flu antiviral without its previous usage.
I know, it was used for blanketing, than cross ..., but the whole thing seems a little bit strange.

 

[HenryN]

Re: Drug-Resistant Flu Linked With Pneumonia, Norwegian Doctors Say

Thanks on the article Dr. Niman.
#2:
"Of the 17 patients with pneumonia, 15 were infected with a resistant virus. The attack rates of pneumonia and of sinusitis were higher for those infected with a resistant virus ..."
#1:
"The researchers found the resistant strain occurred in the absence of selective pressure caused by widespread Tamiflu usage."
"``Our data indicate that the viruses carrying this resistance mutation are fully capable of persistence and spread in the absence of selective pressure,'' the authors wrote."


From bad to worst.

Coincidences were possible indeed.
Still it is suspect such natural change in resistance just for the almost only "eff." flu antiviral without its previous usage.
I know, it was used for blanketing, than cross ..., but the whole thing seems a little bit strange.

No, not worst. The Norwegian isolates had not yet acquired HA A193T. The South African and US isolates have.

A193T leads to worlwide dominance. It is in clade IIB with H274Y in patients not taking Tamiflu, in clade IIC with M2 S31N in patients not taking adamantadines, and S193F is in H3N2 with S31N in patients not take adamantadines.

They are all hitch hikers on the 193 worldwide tour driven by recombination.

 

[HenryN]

Re: Drug-Resistant Flu Linked With Pneumonia, Norwegian Doctors Say

Earlier comments on Norway sequences

http://www.recombinomics.com/News/12240803/H274Y_Norway_A193T.html

 

[tropical]

Re: Drug-Resistant Flu Linked With Pneumonia, Norwegian Doctors Say

#4:
"No, not worst. ...had not yet acquired HA A193T ..."


I'm not in doubt it would be only a matter of time to see the above also ...

In a hope of at least no worst news, Happy New 2009 and after, to all of you.

 

[gsgs]

Re: Drug-Resistant Flu Linked With Pneumonia, Norwegian Doctors Say

AFAIR they said earlier this year, that the Tamiflu-resistance is _not_
linked to greater virulence.

 

[HenryN]

Re: Drug-Resistant Flu Linked With Pneumonia, Norwegian Doctors Say

AFAIR they said earlier this year, that the Tamiflu-resistance is _not_
linked to greater virulence.

There are MULTIPLE sub-clades that are clade IIB and have H274Y. This paper looked at the Norwegian isolates (which do NOT have A193T) that TREND toward pneumonia.

There are also multiple "they"s.

Phylogenetic analysis goes a long way toward breaking the emergence down into component parts.

 

[HenryN]

Re: Drug-Resistant Flu Linked With Pneumonia, Norwegian Doctors Say

Superflu strikes in the Midlands
Jan 3 2009 By Adam Aspinall

SEVEN Midlanders have been struck by a potentially lethal strain of superflu which is resistant to drugs over the last six months.
The Health Protection Agency said the patients survived the H1N1 virus which cannot be treated with the Tamiflu ? the usual drug prescribed to treat the illness. Tamiflu has been stockpiled by the British Government as the first line of defence against a feared global flu outbreak.
The resistant strain is a form of the H1N1 flu virus and was identified in more than 20 European countries in the last flu season.
It is similar to the Spanish Flu, or La Pesadilla, that killed some 50 million to 100 million people worldwide between 1918 and 1919.
That pandemic was an unusually severe and deadly strain of avian influenza, a viral infectious disease that is thought to have been one of the most deadly pandemics in human history.
It was caused by the H1N1 type of influenza virus, which is similar to bird flu of today, mainly H5N1 and H5N2.
But it has been reported European Scientists have found that the H1N1 strain is three times more likely to cause pneumonia in patients than the normal strain, making it more deadly.
A recent study by researchers from the Norwegian Institute of Public Health and the HPA, found H1N1 not only heightened the possibility of pneumonia, but that twice as many flu patients with the drug-resistant strain developed inflamed sinuses.
?Resistance in a more virulent influenza virus can have serious public health implications,? Siri Hauge, who led the study, said.
Fewer treatment options and a more severe form of the virus can result in ?more severe illness and death in those who become infected?, she warned.
?These findings should be taken into consideration when shaping future strategies for treating and preventing seasonal and pandemic influenza.??
Flu kills thousands of people in Britain every year, particularly the elderly who struggle to fight off secondary infections like pneumonia.
Most flu cases in Britain, around 90 per cent, are caused by the H3 strain of the virus. Last night the Health Protection Agency said symptoms caused by the resistant virus were no more severe than those of normal influenza, but there were fewer treatment options. They say it is essential for those who are vulnerable to receive a jab from their GP.
This includes over-65s and people with chronic conditions such as asthma and diabetes.
A spokesman for the HPA said: ?We are seeing very, very small numbers of cases of this [drug-resistant H1N1] strain of flu.
?There have been seven cases diagnosed in the central region over the last flu season.
?We are also monitoring cases and from our surveillance have no evidence at the moment that it is any more virulent than was previously thought.?

http://www.sundaymercury.net/news/m...erflu-strikes-in-the-midlands-66331-22599394/

 

[JJackson]

Re: Drug-Resistant Flu Linked With Pneumonia, Norwegian Doctors Say

<o:smarttagtype namespaceuri="urn:schemas-microsoft-comffice:smarttags" name="country-region"></o:smarttagtype><o:smarttagtype namespaceuri="urn:schemas-microsoft-comffice:smarttags" name="place"></o:smarttagtype><o:smarttagtype namespaceuri="urn:schemas-microsoft-comffice:smarttags" name="stockticker"></o:smarttagtype><!--[if gte mso 9]><xml> <o:OfficeDocumentSettings> <o:RelyOnVML/> <o:AllowPNG/> </o:OfficeDocumentSettings> </xml><![endif]--><!--[if gte mso 9]><xml> <w:WordDocument> <w:View>Normal</w:View> <w:Zoom>0</w:Zoom> <w:Compatibility> <w:BreakWrappedTables/> <w:SnapToGridInCell/> <w:WrapTextWithPunct/> <w:UseAsianBreakRules/> </w:Compatibility> </w:WordDocument> </xml><![endif]--><!--[if !mso]><object classid="clsid:38481807-CA0E-42D2-BF39-B33AF135CC4D" id=ieooui></object> <style> st1\:*{behavior:url(#ieooui) } </style> <![endif]--><!--[if gte mso 10]> <style> /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-parent:""; mso-padding-alt:0cm 5.4pt 0cm 5.4pt; mso-para-margin:0cm; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:10.0pt; font-family:"Times New Roman";} </style> <![endif]--> Jason Gale’s article in post #1 is clear and accurate but I wish I could say the same for Adam Aspinall’s in post #9.
<o> </o>
I am sorry to pick on Adam’s article as it not the worst I have seen but includes many of the flaws in <st1:stockticker>MSM</st1:stockticker> coverage which we all need to be aware of, both as writers on the subject and readers. In Adam’s defence he is trying to bring the issue to his reading public and is writing for a small regional paper, I have never heard of, so probably has nothing like the time to research his subject that Jason, working for Bloomberg and based in Indonesia, has.
<o> </o>
Firstly the title and opening sentence commits the usual journalistic crime of using a sensationalist headline as a hook which cannot be justified by the body text in this case ‘Superflu’.

SEVEN Midlanders have been struck by a potentially lethal strain of superflu which is resistant to drugs over the last six months.<o></o>
The Health Protection Agency said the patients survived the H1N1 virus which cannot be treated with the Tamiflu – the usual drug prescribed to treat the illness. Tamiflu has been stockpiled by the British Government as the first line of defence against a feared global flu outbreak.

It is not resistant to ‘drugs’ but one drug, Tamiflu, redeemed in the second paragraph which, however, then states the patients ‘survived’ implying they were lucky to do so from this strain which is unjustified. The ‘seven’ patients is also misleading as the vast majority of patients are not tested or treated with anything; a small number of patients are sampled to build up a picture of the dominant circulating strain. <o></o>
For decades there have been two circulating seasonal flu serotypes, H1N1 and H3N2, each of which comes in various strains which vary in virulence. The dominant strain in the <st1:country-region><st1lace>UK</st1lace></st1:country-region> this season is H3N2 (not the H1N1 in this article). The Daily Telegraph (which is a major national <st1:country-region><st1lace>UK</st1lace></st1:country-region> daily and should have known better) called this (H3N2) ‘Killer Flu’, so it appears we are all lucky to be alive. The reality is neither flu is much worse than average.
The following paragraph states that the same flu was found in 20 EU states last year and yet strangely I do not recall a horrific death toll.

It is similar to the Spanish Flu, or La Pesadilla, that killed some 50 million to 100 million people worldwide between 1918 and 1919.<o></o>
That pandemic was an unusually severe and deadly strain of avian influenza, a viral infectious disease that is thought to have been one of the most deadly pandemics in human history.<o></o>
It was caused by the H1N1 type of influenza virus, which is similar to bird flu of today, mainly H5N1 and H5N2.

<o></o>
This section is more worrying as it will confuse the average reader who has does not understand the difference between seasonal H1N1 (including ‘Superflu’ which is only a big danger to the very young, old and already ill), Pandemic H1N1(1918) (which killed ~50 million) and AI H5N1 (which is killing most people who catch it but, mercifully, is not easy to catch – yet). How is it similar to Spanish flu? Certainly not clinically or in any other meaningful way, they are both types of flu but in all other respects ‘It is similar to catching a cold’ would be much more accurate. The last paragraph is awful. I have no idea how H5N2 got in on the act and again ‘similar’ is used but I have no idea what facets are meant to be similar. <st1:stockticker>CFR</st1:stockticker> - as a proxy for -Virulence? AI H5N1 is an order of magnitude worse than H1N1(1918) which was an order of magnitude worse than H1N1(2008).


Jason was careful to state that the authors of the Norwegian research pointed out the small sample size meant the findings were not statistically significant but warranted further research while Adam just picked the juiciest stats without caveat.

But it has been reported European Scientists have found that the H1N1 strain is three times more likely to cause pneumonia in patients than the normal strain, making it more deadly.<o></o>
A recent study by researchers from the Norwegian Institute of Public Health and the HPA, found H1N1 not only heightened the possibility of pneumonia, but that twice as many flu patients with the drug-resistant strain developed inflamed sinuses.

<o> next
</o>

“Resistance in a more virulent influenza virus can have serious public health implications,” Siri Hauge, who led the study, said.
Fewer treatment options and a more severe form of the virus can result in “more severe illness and death in those who become infected”, she warned.
“These findings should be taken into consideration when shaping future strategies for treating and preventing seasonal and pandemic influenza.’’

This section is fine, taken stand alone, but having mislead us about the virulence of H1N1(2008) ‘Superflu’ the quote “more severe illness and death in those who become infected” now seem to be about Adam’s ‘Superflu’ when I suspect Siri Hauge was referring to the problems of a Tamiflu resistant pandemic strain. This is a recurring problem where quotes in response to one question are inserted near text relating to something different.

Most flu cases in <st1:country-region><st1lace>Britain</st1lace></st1:country-region>, around 90 per cent, are caused by the H3 strain of the virus.

I think this is correct for this season but in some years it H1 is dominant (minor quibble).

Last night the Health Protection Agency said symptoms caused by the resistant virus were no more severe than those of normal influenza, but there were fewer treatment options. They say it is essential for those who are vulnerable to receive a jab from their GP. This includes over-65s and people with chronic conditions such as asthma and diabetes.

Again, we have jumped from a line on H3N2 back to a quote about H1N1, while this may not have caught out your average FluTrackers reader I suspect most of this article's target audience would be thoroughly confused by now. The quote itself is, in fact, contradicting the premise of the article. The HPA are saying that they have been unable to find a difference in severity between the Tamiflu resistant version of H1N1 (AKA ‘Superflu’) and previous H1N1s however, in light of the fact that if you do get it and suffer complications, Tamiflu is not going to be available as a treatment option they are pushing the flu shots.

A spokesman for the HPA said: “We are seeing very, very small numbers of cases of this [drug-resistant H1N1] strain of flu.
“There have been seven cases diagnosed in the central region over the last flu season.
“We are also monitoring cases and from our surveillance have no evidence at the moment that it is any more virulent than was previously thought.”

The very small numbers is not surprising because the circulating flu is H3N2 and the Tamiflu resistance is in H1N1 but that does not mean that Tamiflu resistance makes up a small proportion of the H1N1 samples that are found.


Adam if you do ever read this please do not take it too personally it is genuinely meant as constructive criticism and as a warning to readers that assignment editors are going to give non specialists journalists things to write about when they have no background in the subject. As readers we should always bear that in mind. <o></o>

 

[HenryN]

Re: Drug-Resistant Flu Linked With Pneumonia, Norwegian Doctors Say

<TABLE cellSpacing=0 cellPadding=0 width="100%" border=0><TBODY><TR><TD vAlign=top>PRESS RELEASE: GSK Ready to Supply RELENZA(R) to Meet New CDC Interim Recommendations this Flu Season

</TD></TR><TR><TD height=5></TD></TR><TR><TD class=TexteGrisGras>Friday December 19th, 2008 / 21h06</TD></TR></TBODY></TABLE><TABLE cellSpacing=0 cellPadding=0 width="100%" border=0><TBODY><TR><TD height=10></TD></TR><TR><TD background=../../Images/imagesSite/Separateur_PointilleGrisH.gif height=1>

</TD></TR><TR><TD height=15></TD></TR></TBODY></TABLE><TABLE cellSpacing=0 cellPadding=0 width="100%" border=0><TBODY><TR><TD class=TexteGris vAlign=top colSpan=2>GSK Ready to Supply RELENZA(R) to Meet New CDC Interim Recommendations this Flu Season
RESEARCH TRIANGLE PARK, N.C., Dec. 19 /PRNewswire/ -- GlaxoSmithKline (GSK) is prepared to respond to public health needs for RELENZA(R) (zanamivir) Inhalation Powder this flu season following a Health Alert Advisory issued by the Centers for Disease Control and Prevention (CDC). RELENZA is a preferred medication in the CDC-issued interim recommendations for all circulating subtypes of influenza virus.
This interim guidance is based on early and limited data from the current influenza season that has detected a significant increase in the proportion of influenza A (H1N1) viruses that are resistant to Tamiflu(R) (oseltamivir). It is not possible to predict how common the influenza A (H1N1) viruses will be during the remainder of the 2008-2009 flu season. All tested influenza virus subtypes have shown no resistance to RELENZA. Clinical significance cannot be inferred from this surveillance data.
GSK has sufficient supply available of RELENZA to meet 2008-2009 influenza season needs. Pharmacies can obtain RELENZA from their wholesalers.
Antiviral resistance is a potentially significant issue when considering widespread use during the peak months of influenza season. GSK is committed to making RELENZA available. However, this emergence also underscores the importance of receiving an annual influenza vaccination, as recommended by the CDC's Advisory Committee on Immunization Practices.
CDC's interim recommendations on the use of influenza antiviral medications in the United States for the 2008-2009 flu season was issued in a Health Alert Advisory on December 19th, 2008. Revised guidance is available at www.cdc.gov/flu.
About RELENZA
RELENZA is a medicine for the treatment of influenza and for reducing the chance of getting the flu in community and household settings. It belongs to a group of medicines called neuraminidase inhibitors. These medications attack the influenza virus and prevent it from spreading inside your body. RELENZA treats the cause of influenza at its source, rather than simply masking the symptoms. RELENZA is delivered via inhalation using a diskhaler. Step-by-step instructions for proper use of the diskhaler are available at www.RELENZA.com, including a short instruction video.
Important Safety Information
RELENZA is not recommended for treatment or prophylaxis of influenza in individuals with underlying airways disease (such as asthma or chronic obstructive pulmonary disease).
Serious cases of bronchospasm, including fatalities, have been reported during treatment with RELENZA in patients with and without underlying airways disease. Many of these cases were reported during postmarketing and causality was difficult to assess.
If use of RELENZA is considered for a patient with underlying airways disease, the potential risks and benefits should be carefully weighed. Use in these patients should be done only under conditions of careful monitoring or respiratory function, close observation, and appropriate supportive care including availability of fast-acting bronchodilators.
Discontinue RELENZA and initiate appropriate treatment if an allergic reaction occurs or is suspected.
Patients with influenza, particularly pediatric patients, may be at an increased risk of seizures, confusion, or abnormal behavior early in their illness. Monitor for signs of abnormal behavior.
Safety and efficacy have not been demonstrated in patients with high-risk underlying medical conditions.
RELENZA has not been proven effective for prophylaxis of influenza in the nursing home setting.
RELENZA is not a substitute for early influenza vaccination on an annual basis as recommended by the Centers for Disease Control's Immunization Practices Advisory Committee.
Influenza viruses change over time. Emergence of resistance mutations could decrease drug effectiveness. Other factors (for example, changes in viral virulence) might also diminish clinical benefit of antiviral drugs. Prescribers should consider available information on influenza drug susceptibility patterns and treatment effects when deciding whether to use RELENZA.
GlaxoSmithKline: A Leader in Flu
GlaxoSmithKline has an active research and development program targeted at both seasonal and pandemic flu and has recently invested more than $2 billion to expand capacity for manufacturing its flu vaccines FLUARIX(R) [Influenza Virus Vaccine] and FLULAVAL(TM) [Influenza Virus Vaccine] and its antiviral flu medication RELENZA. GlaxoSmithKline -- one of the world's leading research-based pharmaceutical and healthcare companies -- is committed to improving the quality of human life by enabling people to do more, feel better and live longer. For company information, visit GlaxoSmithKline at www.gsk.com.
*Tamiflu is a registered trademark of Roche Laboratories
Enquiries:
Media enquiries: Jeff McLaughlin (215) 751 7709 Mary Ann Rhyne (919) 483 2839 Sarah Alspach (215) 751 7709 US Analyst/ Investor enquiries: Tom Curry (215) 751 5419 Jen Hill (215) 751 7002 Cautionary statement regarding forward-looking statements
Under the safe harbor provisions of the U.S. Private Securities Litigation Reform Act of 1995, GSK cautions investors that any forward-looking statements or projections made by GSK, including those made in this announcement, are subject to risks and uncertainties that may cause actual results to differ materially from those projected. Factors that may affect GSK' s operations are described under 'Risk Factors' in the 'Business Review' in the company' s Annual Report on Form 20-F for 2007.
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SOURCE GlaxoSmithKline
/CONTACT: Media enquiries, Jeff McLaughlin, +1-215-751-7709, or Mary Ann Rhyne, +1-919-483-2839, or Sarah Alspach, +1-215-751-7709, or US Analyst/Investor enquiries, Tom Curry, +1-215-751-5419, or Jen Hill, +1-215-751-7002, all for GlaxoSmithKline
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</TD></TR><TR><TD colSpan=2 height=10></TD></TR><TR><TD class=TexteGrisPetit>Friday December 19th, 2008 / 21h06</TD><TD class=TexteGrisPetit align=right>Source : Dowjones Business News</TD></TR><TR><TD colSpan=2 height=5></TD></TR></TBODY></TABLE><TABLE cellSpacing=0 cellPadding=0 width="100%" border=0><TBODY><TR><TD height=10>http://www.easybourse.com/bourse-ac...94?PHPSESSID=12e3f05f78debb43a0b8106fe22a91f2</TD></TR><TR><TD background=../../Images/imagesSite/Separateur_PointilleGrisH.gif height=1>

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[HenryN]

Re: Drug-Resistant Flu Linked With Pneumonia, Norwegian Doctors Say

<?xml:namespace prefix = o /><o:smarttagtype name="country-region" namespaceuri="urn:schemas-microsoft-comffice:smarttags"></o:smarttagtype><o:smarttagtype name="place" namespaceuri="urn:schemas-microsoft-comffice:smarttags"></o:smarttagtype><o:smarttagtype name="stockticker" namespaceuri="urn:schemas-microsoft-comffice:smarttags"></o:smarttagtype><OBJECT id=ieooui classid=clsid:38481807-CA0E-42D2-BF39-B33AF135CC4D></OBJECT><STYLE> st1\:*{behavior:url(#ieooui) } </STYLE>Jason Gale’s article in post #1 is clear and accurate but I wish I could say the same for Adam Aspinall’s in post #9.
<o></o>
I am sorry to pick on Adam’s article as it not the worst I have seen but includes many of the flaws in <?xml:namespace prefix = st1 /><st1:stockticker>MSM</st1:stockticker> coverage which we all need to be aware of, both as writers on the subject and readers. In Adam’s defence he is trying to bring the issue to his reading public and is writing for a small regional paper, I have never heard of, so probably has nothing like the time to research his subject that Jason, working for Bloomberg and based in Indonesia, has.
<o></o>
Firstly the title and opening sentence commits the usual journalistic crime of using a sensationalist headline as a hook which cannot be justified by the body text in this case ‘Superflu’.
It is not resistant to ‘drugs’ but one drug, Tamiflu, redeemed in the second paragraph which, however, then states the patients ‘survived’ implying they were lucky to do so from this strain which is unjustified. The ‘seven’ patients is also misleading as the vast majority of patients are not tested or treated with anything; a small number of patients are sampled to build up a picture of the dominant circulating strain. <o></o>
For decades there have been two circulating seasonal flu serotypes, H1N1 and H3N2, each of which comes in various strains which vary in virulence. The dominant strain in the <st1:country-region><st1lace>UK</st1lace></st1:country-region> this season is H3N2 (not the H1N1 in this article). The Daily Telegraph (which is a major national <st1:country-region><st1lace>UK</st1lace></st1:country-region> daily and should have known better) called this ‘Killer Flu’, so it appears we are all lucky to be alive. The reality is neither flu is much worse than average.
The following paragraph states that the same flu was found in 20 EU states last year and yet strangely I do not recall a horrific death toll.
<o></o>
This section is more worrying as it will confuse the average reader who has does not understand the difference between seasonal H1N1 (including ‘Superflu’ which is only a big danger to the very young, old and already ill), Pandemic H1N1(1918) (which killed ~50 million) and AI H5N1 (which is killing most people who catch it but, mercifully, is not easy to catch – yet). How is it similar to Spanish flu? Certainly not clinically or in any other meaningful way, they are both types of flu but in all other respects ‘It is similar to catching a cold’ would be much more accurate. The last paragraph is awful. I have no idea how H5N2 got in on the act and again ‘similar’ is used but I have no idea what facets are meant to be similar. <st1:stockticker>CFR</st1:stockticker> - as a proxy for -Virulence? AI H5N1 is an order of magnitude worse than H1N1(1918) which was an order of magnitude worse than H1N1(2008).


Jason was careful to state that the authors of the Norwegian research pointed out the small sample size meant the findings were not statistically significant but warranted further research while Adam just picked the juiciest stats without caveat.
<o>next
</o>
This section is fine, taken stand alone, but having mislead us about the virulence of H1N1(2008) ‘Superflu’ the quote “more severe illness and death in those who become infected” now seem to be about Adam’s ‘Superflu’ when I suspect Siri Hauge was referring to the problems of a Tamiflu resistant pandemic strain. This is a recurring problem where quotes in response to one question are inserted near text relating to something different.
I think this is correct for this season but in some years it H1 is dominant (minor quibble).
Again, we have jumped from a line on H3N2 back to a quote about H1N1, while this may not have caught out your average FluTrackers reader I suspect most of this article's target audience would be thoroughly confused by now. The quote itself is, in fact, contradicting the premise of the article. The HPA are saying that they have been unable to find a difference in severity between the Tamiflu resistant version of H1N1 (AKA ‘Superflu’) and previous H1N1s however, in light of the fact that if you do get it and suffer complications, Tamiflu is not going to be available as a treatment option they are pushing the flu shots.

The very small numbers is not surprising because the circulating flu is H3N2 and the Tamiflu resistance is in H1N1 but that does not mean that Tamiflu resistance makes up a small proportion of the H1N1 samples that are found.


Adam if you do ever read this please do not take it too personally it is genuinely meant as constructive criticism and as a warning to readers that assignment editors are going to give non specialists journalists things to write about when they have no background in the subject. As readers we should always bear that in mind. <o></o>

Actually, there is more to the H274Y story than can be realistically be covered in an MSM article. The EID story looked at H274Y in Norway and saw a trend toward increased pneumonia, but the sample size was small, and when adjusted for age and underlying conditions was not statistically significant. However, this happenes when the sample size is small, and is subdivided. Since there were more pneumonia cases, the H274Y may simply lead to more infections in older people and/or those with underlying conditions, so this sub-group may be more suscepatble to H1N1 with H274Y (and significance requires a larger sample size since 2/3 of H1N1 had H274Y).

However, this is a new season and H1N1 evolves. Last season H274Y was in about 10% of H1N1 in England and the US. This season it is close to 100%, but in the UK 90% of influenza A is H3N2, while in the US 90% of influenza A is H1N1.

Thus, the H1N1 in Europe is not competing well with H3N2, while in the US it is. The comments from the UK this season is a bit premature, because the number of H1N1 cases is small. It is higher in the US, but is still early and most of the H1N1 analysized in the US is from Hawaii and Texas, so the numbers outside of those two states is relatively small.

However, there hasn't been much comment on severity of disease in those two states, although the first two states to reach "local" levels were Hawaii and Texas, so the H1N1 spreads easily in those two states.

Moreover, the H1N1 in Norway did not have A193T last season

http://www.recombinomics.com/News/12240803/H274Y_Norway_A193T.html

 

[HenryN]

Re: Drug-Resistant Flu Linked With Pneumonia, Norwegian Doctors Say

Actually, there is more to the H274Y story than can be realistically be covered in an MSM article. The EID story looked at H274Y in Norway and saw a trend toward increased pneumonia, but the sample size was small, and when adjusted for age and underlying conditions was not statistically significant. However, this happenes when the sample size is small, and is subdivided. Since there were more pneumonia cases, the H274Y may simply lead to more infections in older people and/or those with underlying conditions, so this sub-group may be more suscepatble to H1N1 with H274Y (and significance requires a larger sample size since 2/3 of H1N1 had H274Y).

However, this is a new season and H1N1 evolves. Last season H274Y was in about 10% of H1N1 in England and the US. This season it is close to 100%, but in the UK 90% of influenza A is H3N2, while in the US 90% of influenza A is H1N1.

Thus, the H1N1 in Europe is not competing well with H3N2, while in the US it is. The comments from the UK this season is a bit premature, because the number of H1N1 cases is small. It is higher in the US, but is still early and most of the H1N1 analysized in the US is from Hawaii and Texas, so the numbers outside of those two states is relatively small.

However, there hasn't been much comment on severity of disease in those two states, although the first two states to reach "local" levels were Hawaii and Texas, so the H1N1 spreads easily in those two states.

Moreover, the H1N1 in Norway did not have A193T last season

http://www.recombinomics.com/News/12240803/H274Y_Norway_A193T.html

In addition, H1N1 with H274Y can kill young people under certain circumstances

http://www.flutrackers.com/forum/showthread.php?t=69196

 

[tropical]

Re: Drug-Resistant Flu Linked With Pneumonia, Norwegian Doctors Say

#11:
"Important Safety Information
RELENZA is not recommended for treatment or prophylaxis of influenza in individuals with underlying airways disease (such as asthma or chronic obstructive pulmonary disease). ..."