Planning for the next influenza H1N1 season: a modelling study

<p>Abstract</p> <p>Background</p> <p>The level of herd immunity before and after the first 2009 pandemic season is not precisely known, and predicting the shape of the next pandemic H1N1 season is a difficult challenge.</p> <p>Methods</p> <p>This was a modelling study based on data on medical visits for influenza-like illness collected by the French General Practitioner Sentinel network, as well as pandemic H1N1 vaccination coverage rates, and an individual-centred model devoted to influenza. We estimated infection attack rates during the first 2009 pandemic H1N1 season in France, and the rates of pre- and post-exposure immunity. We then simulated various scenarios in which a pandemic influenza H1N1 virus would be reintroduced into a population with varying levels of protective cross-immunity, and considered the impact of extending influenza vaccination.</p> <p>Results</p> <p>During the first pandemic season in France, the proportion of infected persons was 18.1% overall, 38.3% among children, 14.8% among younger adults and 1.6% among the elderly. The rates of pre-exposure immunity required to fit data collected during the first pandemic season were 36% in younger adults and 85% in the elderly. We estimated that the rate of post-exposure immunity was 57.3% (95% Confidence Interval (95%CI) 49.6%-65.0%) overall, 44.6% (95%CI 35.5%-53.6%) in children, 53.8% (95%CI 44.5%-63.1%) in younger adults, and 87.4% (95%CI 82.0%-92.8%) in the elderly.</p> <p>The shape of a second season would depend on the degree of persistent protective cross-immunity to descendants of the 2009 H1N1 viruses. A cross-protection rate of 70% would imply that only a small proportion of the population would be affected. With a cross-protection rate of 50%, the second season would have a disease burden similar to the first, while vaccination of 50% of the entire population, in addition to the population vaccinated during the first pandemic season, would halve this burden. With a cross-protection rate of 30%, the second season could be more substantial, and vaccination would not provide a significant benefit.</p> <p>Conclusions</p> <p>These model-based findings should help to prepare for a second pandemic season, and highlight the need for studies of the different components of immune protection.</p

Hypothalamic arcuate nucleus glucokinase regulates insulin secretion and glucose homeostasis

Aims Glucokinase (GK) serves as a glucose sensor in several tissues including glucose‐sensitive neurons of the arcuate nucleus within the hypothalamus. We have previously demonstrated a role for arcuate GK in the regulation of food and glucose intake. However, its role in the regulation of glucose homeostasis is less clear. We therefore sought to investigate the role of arcuate GK in the regulation of glucose homeostasis. Materials and Methods Recombinant adeno‐associated virus expressing either GK or an antisense GK construct was used to alter GK activity specifically in the hypothalamic arcuate nucleus. GK activity in this nucleus was also increased by stereotactic injection of the GK activator, compound A. The effect of altered arcuate nucleus GK activity on glucose homeostasis was subsequently investigated using glucose and insulin tolerance tests. Results Increased GK activity specifically within the arcuate nucleus increased insulin secretion and improved glucose tolerance in rats during oral glucose tolerance tests. Decreased GK activity in this nucleus reduced insulin secretion and increased glucose levels during the same tests. Insulin sensitivity was not affected in either case. The effect of arcuate nucleus glucokinase was maintained in a model of type 2 diabetes. Conclusions These results demonstrate a role for arcuate nucleus GK in systemic glucose homeostasis

Canalization of the evolutionary trajectory of the human influenza virus

Since its emergence in 1968, influenza A (H3N2) has evolved extensively in genotype and antigenic phenotype. Antigenic evolution occurs in the context of a two-dimensional 'antigenic map', while genetic evolution shows a characteristic ladder-like genealogical tree. Here, we use a large-scale individual-based model to show that evolution in a Euclidean antigenic space provides a remarkable correspondence between model behavior and the epidemiological, antigenic, genealogical and geographic patterns observed in influenza virus. We find that evolution away from existing human immunity results in rapid population turnover in the influenza virus and that this population turnover occurs primarily along a single antigenic axis. Thus, selective dynamics induce a canalized evolutionary trajectory, in which the evolutionary fate of the influenza population is surprisingly repeatable and hence, in theory, predictable.Comment: 29 pages, 5 figures, 10 supporting figure

Risk Factors of Household Transmission of Pandemic (H1N1) 2009 among Patients Treated with Antivirals: A Prospective Study at a Primary Clinic in Japan

Background: Household transmission of influenza can affect the daily lives of patients and their families and be a trigger for community transmission, thus it is necessary to take precautions to prevent household transmission. We aimed to determine the risks of household transmission of pandemic (H1N1) 2009 influenza virus from an index patient who visited a primary clinic and was treated with antiviral drugs. Methods: We followed up all the patients who were diagnosed with influenza A by rapid diagnostic test with a questionnaire or interview from July 2009 to April 2010. Secondary cases were defined as patients visiting the clinic or other clinics and being positive for influenza A by rapid diagnostic test within 7 days of onset of an index patient. Logistic regression analysis was used to explore the association between household transmission and the studied variables. Results: We recruited 591 index patients and 1629 household contacts. The crude secondary attack rate was 7.3 % [95% confidence interval (CI): 6.1–8.7]. Age of index patients (0–6 years old: odds ratio 2.56; 95 % CI: 1.31–4.01; 7–12 years old: 2.44, 1.31–3.72; 30–39 years old 3.88; 2.09–5.21; 40 years old or more 2.76; 1.17–4.53) and number of household members with five or more (3.09, 2.11–4.07), medication started 48 hours from the onset of fever (2.38, 1.17–3.87) were significantly associated with household transmission. Conclusions: Household transmission was associated with index patients aged #12 years old and adults 30 years wit

The analysis of myotonia congenita mutations discloses functional clusters of amino acids within the CBS2 domain and the C-terminal peptide of the ClC-1 channel

Myotonia congenita (MC) is a skeletal-muscle hyperexcitability disorder caused by loss-of-function mutations in the ClC-1 chloride channel. Mutations are scattered over the entire sequence of the channel protein, with more than 30\ua0mutations located in the poorly characterized cytosolic C-terminal domain. In this study, we characterized, through patch clamp, seven ClC-1 mutations identified in patients affected by MC of various severities and located in the C-terminal region. The p.Val829Met, p.Thr832Ile, p.Val851Met, p.Gly859Val, and p.Leu861Pro mutations reside in the CBS2 domain, while p.Pro883Thr and p.Val947Glu are in the C-terminal peptide. We showed that the functional properties of mutant channels correlated with the clinical phenotypes of affected individuals. In addition, we defined clusters of ClC-1 mutations within CBS2 and C-terminal peptide subdomains that share the same functional defect: mutations between 829 and 835 residues and in residue 883 induced an alteration of voltage dependence, mutations between 851 and 859 residues, and in residue 947 induced a reduction of chloride currents, whereas mutations on 861 residue showed no obvious change in ClC-1 function. This study improves our understanding of the mechanisms underlying MC, sheds light on the role of the C-terminal region in ClC-1 function, and provides information to develop new antimyotonic drugs

A 'small-world-like' model for comparing interventions aimed at preventing and controlling influenza pandemics

BACKGROUND: With an influenza pandemic seemingly imminent, we constructed a model simulating the spread of influenza within the community, in order to test the impact of various interventions. METHODS: The model includes an individual level, in which the risk of influenza virus infection and the dynamics of viral shedding are simulated according to age, treatment, and vaccination status; and a community level, in which meetings between individuals are simulated on randomly generated graphs. We used data on real pandemics to calibrate some parameters of the model. The reference scenario assumes no vaccination, no use of antiviral drugs, and no preexisting herd immunity. We explored the impact of interventions such as vaccination, treatment/prophylaxis with neuraminidase inhibitors, quarantine, and closure of schools or workplaces. RESULTS: In the reference scenario, 57% of realizations lead to an explosive outbreak, lasting a mean of 82 days (standard deviation (SD) 12 days) and affecting 46.8% of the population on average. Interventions aimed at reducing the number of meetings, combined with measures reducing individual transmissibility, would be partly effective: coverage of 70% of affected households, with treatment of the index patient, prophylaxis of household contacts, and confinement to home of all household members, would reduce the probability of an outbreak by 52%, and the remaining outbreaks would be limited to 17% of the population (range 0.8%–25%). Reactive vaccination of 70% of the susceptible population would significantly reduce the frequency, size, and mean duration of outbreaks, but the benefit would depend markedly on the interval between identification of the first case and the beginning of mass vaccination. The epidemic would affect 4% of the population if vaccination started immediately, 17% if there was a 14-day delay, and 36% if there was a 28-day delay. Closing schools when the number of infections in the community exceeded 50 would be very effective, limiting the size of outbreaks to 10% of the population (range 0.9%–22%). CONCLUSION: This flexible tool can help to determine the interventions most likely to contain an influenza pandemic. These results support the stockpiling of antiviral drugs and accelerated vaccine development

Differing clinical characteristics between influenza strains among young healthy adults in the tropics

<p>Abstract</p> <p>Background</p> <p>Influenza infections may result in different clinical presentations. This study aims to determine the clinical differences between circulating influenza strains in a young healthy adult population in the tropics.</p> <p>Methods</p> <p>A febrile respiratory illness (FRI) (fever ≥ 37.5°C with cough and/or sore throat) surveillance program was started in 4 large military camps in Singapore on May 2009. Personnel with FRI who visited the camp clinics from 11 May 2009 to 25 June 2010 were recruited. Nasal washes and interviewer-administered questionnaires on demographic information and clinical features were obtained from consenting participants. All personnel who tested positive for influenza were included in the study. Overall symptom load was quantified by counting the symptoms or signs, and differences between strains evaluated using linear models.</p> <p>Results</p> <p>There were 434 (52.9%) pandemic H1N1-2009, 58 (7.1%) seasonal H3N2, 269 (32.8%) influenza B, and 10 (1.2%) seasonal H1N1 cases. Few seasonal influenza A (H1N1) infections were detected and were therefore excluded from analyses, together with undetermined influenza subtypes (44 (1.5%)), or more than 1 co-infecting subtype (6 (0.2%)). Pandemic H1N1-2009 cases had significantly fewer symptoms or signs (mean 7.2, 95%CI 6.9-7.4, difference 1.6, 95%CI 1.2-2.0, <it>p </it>< 0.001) than the other two subtypes (mean 8.7, 95%CI 8.5-9.0). There were no statistical differences between H3N2 and influenza B (<it>p </it>= 0.58). Those with nasal congestion, rash, eye symptoms, injected pharynx or fever were more likely to have H3N2; and those with sore throat, fever, injected pharynx or rhinorrhoea were more likely to have influenza B than H1N1-2009.</p> <p>Conclusions</p> <p>Influenza cases have different clinical presentations in the young adult population. Pandemic H1N1 influenza cases had fewer and milder clinical symptoms than seasonal influenza. As we only included febrile cases and had no information on the proportion of afebrile infections, further research is needed to confirm whether the relatively milder presentation of pandemic versus seasonal influenza infections applies to all infections or only febrile illnesses.</p

Molecular Analysis of Serum and Bronchoalveolar Lavage in a Mouse Model of Influenza Reveals Markers of Disease Severity That Can Be Clinically Useful in Humans

Background: Management of influenza, a major contributor to the worldwide disease burden, is complicated by lack of reliable methods for early identification of susceptible individuals. Identification of molecular markers that can augment existing diagnostic tools for prediction of severity can be expected to greatly improve disease management capabilities. Methodology/Principal Findings: We have analyzed cytokines, proteome flux and protein adducts in bronchoalveolar lavage (BAL) and sera from mice infected with influenza A virus (PR8 strain) using a previously established non-lethal model of influenza infection. Through detailed cytokine and protein adduct measurements of murine BAL, we first established the temporal profile of innate and adaptive responses as well as macrophage and neutrophil activities in response to influenza infection. A similar analysis was also performed with sera from a longitudinal cohort of influenza patients. We then used an iTRAQ-based, comparative serum proteome analysis to catalog the proteome flux in the murine BAL during the stages correlating with “peak viremia,” “inflammatory damage,” as well as the “recovery phase.” In addition to activation of acute phase responses, a distinct class of lung proteins including surfactant proteins was found to be depleted from the BAL coincident with their “appearance” in the serum, presumably due to leakage of the protein following loss of the integrity of the lung/epithelial barrier. Serum levels of at least two of these proteins were elevated in influenza patients during the febrile phase of infection compared to healthy controls or to the same patients at convalescence. Conclusions/Significance: The findings from this study provide a molecular description of disease progression in a mouse model of influenza and demonstrate its potential for translation into a novel class of markers for measurement of acute lung injury and improved case management.Singapore. National Research FoundationSingapore-MIT Alliance for Research and Technology (ID-IRG research program

Thermal Image Scanning for Influenza Border Screening: Results of an Airport Screening Study

Background: Infrared thermal image scanners (ITIS) appear an attractive option for the mass screening of travellers for influenza, but there are no published data on their performance in airports. Methods: ITIS was used to measure cutaneous temperature in 1275 airline travellers who had agreed to tympanic temperature measurement and respiratory sampling. The prediction by ITIS of tympanic temperature (37.8uC and 37.5uC) and of influenza infection was assessed using Receiver Operating Characteristic (ROC) curves and estimated sensitivity, specificity and positive predictive value (PPV). Findings: Using front of face ITIS for prediction of tympanic temperature $37.8uC, the area under the ROC curve was 0.86 (95$37.8uC at screening (95%CI 0 % to 12%); three had no influenza symptoms. Conclusion: ITIS performed moderately well in detecting fever but in this study, during a seasonal epidemic of predominantly influenza type B, the proportion of influenza-infected travellers who were febrile was low and ITIS were no

Pharmacokinetic/pharmacodynamic analysis of adjuvant pegylated interferon α-2b in patients with resected high-risk melanoma

PurposeHigh-dose pegylated interferon α-2b (peginterferon α-2b) significantly decreased disease recurrence in patients with resected stage III melanoma in a clinical study. We investigated the pharmacokinetics (PK) and safety of high-dose peginterferon α-2b in patients with high-risk melanoma.MethodsFor PK analysis, 32 patients received peginterferon α-2b 6 μg/(kg week) subcutaneously for 8 weeks (induction) then 3 μg/(kg week) for 4 weeks (maintenance). PK profiles were determined at weeks 1, 8, and 12. Exposure-response relationships between peginterferon α-2b and absolute neutrophil count (ANC) and alanine aminotransferase (ALT) level were also studied.ResultsPeginterferon α-2b was well-absorbed following SC administration, with a median T (max) of 24 h. Mean half-life estimates ranged from 43 to 51 h. The accumulation factor was 1.69 after induction therapy. PK parameters showed moderate interpatient variability. PK profiles were described by a one-compartmental model with first-order absorption and first-order elimination. Toxicity was profiled and was acceptable; observed side effects were similar to those previously described. Dose reduction produced proportional decreases in exposure and predictable effects on ANC in an Imax model; however, a PK/pharmacodynamic (PK/PD) relationship between peginterferon α-2b and ALT could not be established with high precision.ConclusionsPeginterferon α-2b was well-absorbed and sustained exposure to peginterferon α-2b was achieved with the doses tested. These data confirm and extend previous PK observations of peginterferon α-2b in melanoma and solid tumors. Our PK/PD model of exposure and ANC effect provides useful information for prediction of peginterferon α-2b-related hematologic toxicity