Avian Flu and H1N1 - Reductionism + Speculation = Big Waste

Does modelling help to predict outbreaks? LONDON « Ignorance and blindness » 03.04.2012 WHY SHOULD WE FIGHT THIS?

France based on the fear of H5NI

 Prevision of 700 beds devoted to flu H1N1 for Marseilles (1M inhibition) we needed 20!

 Vaccination using cells (no eggs), double injection, with adjuvant (90 M doses!)

 Proposing of vaccination© byby authority author Vs doctors

 Lower vacination in our hospital personnel ever!

ESCMIDFalse prediction Online => Lecture mismanagement Library IGNORANCE AND BLINDNESS

1- Rationale of modelling when we are ignorant  2- Future outbreaks  Avian flu and H1N1 - Reductionism + speculation = big waste

Bioterrorism and smallpox

3- Is it science or religion© by ?author

ESCMID Online Lecture Library IGNORANCE

Autopsy series of 68 cases dying before and during We ignore the cause of death Measle, flu kills by super the 1918 influenza pandemic peak. Sheng ZM, et al. infection Proc Natl Acad Sci U S A. 2011 Sep 27;108(39):16416- 21.

Microbiota regulates immune defense against  We ignore the role of environment respiratory tract influenza A virus infection. Ichinohe (role of microbiota, temperature, sun, T, et al. Proc Natl Acad Sci USA. 2011 Mar 29;108(13):5354-9 reservoirs) Microbe interactions undermine predictions. Raoult D. Science. 2011 Jan 14;331(6014):144-5 Molecular, epidemiological, and clinical complexities of predicting patterns of infectious diseases. Raoult D. Front Microbiol. 2011;2:25

 We ignore the « learning » capabilities Malaria morbidity and pyrethroid resistance after the - societies introduction of insecticide-treated bednets and artemisinin-based combination therapies: a - individuals longitudinal study.Trape JF, et al. Lancet Infect Dis. - Animals (anopheles gambiae) 2011 Dec;11(12):925-32 - infectious agents

 We ignore the transmission ways © by author

ESCMID Online Lecture Library The 1918 to 1919 “Spanish” influenza pandemic virus killed up to 50 million people. We report here clinical, pathological, bacteriological, and virological findings in 68 fatal American influenza/pneumonia military patients dying between May and October of 1918, a period that includes 4 mo before the 1918 pandemic was recognized, and 2 mo (September–October 1918)  Several variable during which it appeared and peaked. The lung tissues of 37 ∼of these cases were positive for influenza viral antigens or viral RNA, including four from the prepandemic period (May–August). The prepandemic and pandemic peak cases were indistinguishable clinically and pathologically. All 68 cases  Not different had histological evidence of bacterial pneumonia, and 94% showed from the other abundant bacteria on Gram stain. Sequence analysis of the viral hemagglutinin receptor-binding domain performed on RNA from 13 cases influenzas suggested a trend from a more “avian-like” viral receptor specificity with G222 in prepandemic cases to a more “human-like” specificity associated with D222 in pandemic peak cases. Viral antigen distribution in the  Bacterial respiratory tree, however, was not apparently© by different author between prepandemic and pandemic peak cases, or between infections with viruses pneumonias! bearing different receptor-binding polymorphisms. The 1918 pandemic virus was circulating for at least 4 mo in the United States before it was recognized epidemiologically in September 1918. The causes of the unusually high mortality in the 1918 pandemic were not explained by the pathological and virological parameters examined. These findings have important implicationsESCMID for understanding Online the origins Lectureand evolution of Library pandemic influenza viruses.

ESCMID Online Lecture Library AGE-RELATED COMPLICATIONS OF PNEUMONIA AND DEATH, AND CASE FATALITY RATE, 1918–1919 PANDEMIC

100

1 Pneumonia case-fatality Complicated by pneumonia Percentage of cases(Log scale) © by author Total case-fatality 0 0 10 20 30 40 50 60 70 80 Age (years) ESCMID Online Lecture Library Nicholson, Human Influenza, In Nicholson, Webster, Hay, Textbook of Influenza, Blackwell; Oxford 1998:p237 TIMELINE POST-INFECTION OF INFLUENZA DEATHS: 1918 EPIDEMIC

0,1

0,08

0,06

Proportion 0,04

0,02 © by author 0 7 14 21 28 Days since infection ESCMID Online Lecture Library Mills et al. Nature 2004;432:904–6, Supplementary fig 2 1918 PNEUMONIA DEATHS DUE TO BACTERIAL INFECTION – 58 AUTOPSIES REVIEWED IN 2008

A B A: Typical picture of severe, widespread bacterial bronchopneumonia B: Massive infiltration of neutrophils in the airspaces of alveoli associated with bacterial C D bronchopneumonia C: Bronchopneumonia with intra-alveolar edema and © by authorhemorrhage D: Bronchopneumonia with evidence of pulmonary repair ESCMID Online Lecture Library Morens et al. JID 2008;198:962–70 POSITIVE BLOOD CULTURES IN PNEUMONIA CASES DURING 1918 PANDEMIC

It will never be the same!

ESCMID Online Lecture Library Chien, Klugman, Morens, NEJM, 2009, 361,2582-3 9 Association between use of statins and mortality among patients hospitalized with laboratory- confirmed influenza virus infections: a multistate study. Vandermeer ML, Thomas AR, Kamimoto L, Reingold A, Gershman K, Meek J, Farley MM, Ryan P, Lynfield R, Baumbach J, Schaffner W, Bennett N, Zansky S. J Infect Dis. 2012 Jan;205(1):13-9.

Abstract BACKGROUND: Statins may have anti-inflammatory and immunomodulatory effects that could reduce the risk of mortality from influenza virus infections. METHODS: The Centers for Disease Control and Prevention's Emerging Infections Program conducts active surveillance for persons hospitalized with laboratory-confirmed influenza in 59 counties in 10 states. We analyzed data for hospitalized adults during the 2007-2008 influenza season to evaluate the association between receiving statins and influenza-related death. RESULTS: We identified 3043 patients hospitalized with laboratory-confirmed influenza, of whom 1013 (33.3%) received statins and 151 (5.0%) died within 30 days of their influenza test. Patients who received statins were more likely to be older, male, and white; to suffer from cardiovascular, metabolic, renal, and chronic lung disease; and to have been vaccinated against influenza that season. In a multivariable logistic regression model, administration of© statins by prior author to or during hospitalization was associated with a protective odds of death (adjusted odds ratio, 0.59 [95% confidence interval, .38-.92]) when adjusting for age; race; cardiovascular, lung, and renal disease; influenza vaccination; and antiviral administration. CONCLUSIONS: Statin use mayESCMID be associated with reduced Online mortality Lecturein patients hospitalized Library with influenza . IGNORANCE

Autopsy series of 68 cases dying before and during the 1918 We ignore the cause of death Measle, flu kills by super influenza pandemic peak. Sheng ZM, et al. infection Proc Natl Acad Sci U S A. 2011 Sep 27;108(39):16416-21.

Microbiota regulates immune defense against respiratory  We ignore the role of environment tract influenza A virus infection. Ichinohe T, et al. Proc Natl (role of microbiota, temperature, sun, Acad Sci USA. 2011 Mar 29;108(13):5354-9 Microbe interactions undermine predictions. reservoirs) Raoult D. Science. 2011 Jan 14;331(6014):144-5 Molecular, epidemiological, and clinical complexities of predicting patterns of infectious diseases. Raoult D. Front Microbiol. 2011;2:25

 We ignore the « learning » capabilities Malaria morbidity and pyrethroid resistance after the - societies introduction of insecticide-treated bednets and artemisinin- based combination therapies: a longitudinal study.Trape JF, - individuals et al. Lancet Infect Dis. 2011 Dec;11(12):925-32 - Animals (anopheles gambiae) - infectious agents

 We ignore the transmission ways © by author

ESCMID Online Lecture Library Microbiota regulates immune defense against respiratory tract influenza A virus infection. Ichinohe T, Pang IK, Kumamoto Y, Peaper DR, Ho JH, Murray TS, Iwasaki A. Proc Natl Acad Sci U S A. 2011 Mar 29;108(13):5354-9.

Although commensal bacteria are crucial in maintaining immune homeostasis of the intestine, the role of commensal bacteria in immune responses at other mucosal surfaces remains less clear. Here, we show that commensal microbiota composition critically regulates the generation of virus-specific CD4 and CD8 T cells and antibody responses following respiratory influenza virus infection . By using various antibiotic treatments, we found that neomycin-sensitive bacteria are associated with the induction of productive immune responses in the lung. Local or distal injection of Toll-like receptor (TLR) ligands could rescue the immune impairment in the antibiotic-treated mice. Intact microbiota provided signals leading to the expression of mRNA for pro-IL-1β and pro-IL-18 at steady state. Following influenza virus infection, inflammasome activation led to migration of dendritic cells (DCs) from the lung to the draining lymph node and T-cell priming. Our results reveal the importance of commensal microbiota in regulating immunity in the respiratory mucosa through the proper© activation by authorof inflammasomes .

ESCMID Online Lecture Library Rhinoviruses delayed the circulation of the pandemic influenza A (H1N1) 2009 virus in France. Casalegno JS, Ottmann M, Duchamp MB, Escuret V, Billaud G, Frobert E, Morfin F, Lina B. Clin Microbiol Infect. 2010 Apr;16(4):326-9 In contrast to the experience in other European countries, the onset of the A(H1N1)2009 influenza virus epidemic was unexpectedly slow in France during the first part of autumn 2009. Our objective was to test the hypothesis that intense circulation of rhinoviruses might have reduced the probability of infection by A(H1N1)2009 virus at the beginning of autumn 2009. Systematic analysis for the detection of A(H1N1)2009 (H1N1) and human rhinovirus (HRV) was performed by RT-PCR from week 36 to week 48 on respiratory samples sent to the diagnostic laboratory by the paediatric hospital (n = 2121). Retrospective analysis of the obtained data, using 2 x 2 contingency tables with Fisher's exact test, revealed evidence of an inverse relationship between HRV and H1N1 detection. Between weeks 36 and 48 of 2009, both HRV and H1N1 were detected but in different time frames. HRV dispersed widely during early September, peaking at the end of the month, whereas the H1N1 epidemic began during mid-October and was still active at the end of this survey. During the© co- bycirculation author period of these two respiratory viruses (weeks 43-46), HRV detection appeared to reduce the likelihood of H1N1 detection in the same sample (OR = 0.08-0.24 p <0.0001). These results support the hypothesis that HRV infections can reduce the probability of A(H1N1) infection. This viral interference between respiratory viruses could have affected the spread of the H1N1 virusesESCMID and delayed the Online influenza pandemicLecture at the Library beginning of autumn in France. Science 14 January 2011: Vol. 331 no. 6014 pp. 144-145 DOI: 10.1126/science.331.6014.144-c

LETTERS Microbe Interactions Undermine Predictions The Report by S. Telfer et al. (“Species interactions in a parasite community drive infection risk in a wildlife population,” 8 October 2010, p. 243) demonstrates that the history of infection cannot be summarized by a simplified scenario involving only a host and a microbe. Microorganisms interfere with each other and can modify the transmissibility between humans. For example, in the recent flu pandemics, influenza virus interfered with rhinoviruses, which modified the transmission and hence the epidemic of H1N1 in France (1). Moreover, the severity of the disease is modified by associated bacterial pathogens, as demonstrated in the Spanish flu outbreak, in which bacterial secondary infection played a major role in mortality (2). These poorly© known by andauthor badly controlled elements make prediction models for infectious disease outbreaks ineffective. To base decision- making in public health on such models is dangerous, because of our ignorance in the multiple partners prevailing during an epidemic.

Didier RAOULT.ESCMID Online Lecture Library WE IGNORE THE RESERVOIRS

 Gorilla: HIV, Malaria, many parasites

 Soil: Pneumococcus Burden of emerging anaerobes in the MALDI-TOF and 16S rRNA gene sequencing era. La Scola B, Fournier PE, Raoult D. Anaerobe. 2011 Jun;17(3):106-12.  Pig: Staphylococcus aureus E.coli© by author

 Bats : Flu virus! ESCMID Online Lecture Library IGNORANCE

Microbiota regulates immune defense against respiratory  We ignore the role of environment tract influenza A virus infection. Ichinohe T, et al. Proc Natl Acad Sci USA. 2011 Mar 29;108(13):5354-9 (role of microbiota, temperature, sun, Microbe interactions undermine predictions. reservoirs) Raoult D. Science. 2011 Jan 14;331(6014):144-5 Molecular, epidemiological, and clinical complexities of predicting patterns of infectious diseases. Raoult D. Front Microbiol. 2011;2:25

Malaria morbidity and pyrethroid resistance after the  We ignore the « learning » capabilities introduction of insecticide-treated bednets and artemisinin- based combination therapies: a longitudinal study.Trape JF, et al. Lancet Infect Dis. 2011 Dec;11(12):925-32 - societies - individuals - Animals (anopheles gambiae) - infectious agents

ESCMID Online Lecture Library Malaria morbidity and pyrethroid resistance after the introduction of insecticide-treated bednets and artemisinin-based combination therapies: a longitudinal study. Trape JF, Tall A, Diagne N, Ndiath O, Ly AB, Faye J, Dieye-Ba F, Roucher C, Bouganali C, Badiane A, Sarr FD, Mazenot C, Touré-Baldé A, Raoult D, Druilhe P, Mercereau-Puijalon O, Rogier C, Sokhna C. Lancet Infect Dis. 2011 Dec;11(12):925-32

© by author Biting cycle of malaria vectors before and after the introduction of LLINsCumulated number of bites of Monthly incidence density of Plasmodium falciparum malaria attacks Anopheles gambiae sensu lato and Anopheles funestus per h by total number of bites per night 100. ESCMID Online Lecture Library Mosquitoes eat earlier and became resistant ! IGNORANCE

 We ignore the « learning » capabilities Malaria morbidity and pyrethroid resistance after the - societies introduction of insecticide-treated bednets and artemisinin- based combination therapies: a longitudinal study.Trape JF, - individuals et al. Lancet Infect Dis. 2011 Dec;11(12):925-32 - Animals (anopheles gambiae) - infectious agents

 We ignore the transmission ways © by author

ESCMID Online Lecture Library Effect of handwashing on child health: a randomised controlled trial Luby SP, Agboatwalla M, Feikin DR, Painter J, Billhimer W, Altaf A, Hoekstra RM. Lancet. 2005 Jul 16-22;366(9481):225-33.

Abstract BACKGROUND: More than 3.5 million children aged less than 5 years die from diarrhoea and acute lower respiratory-tract infection every year. We undertook a randomised controlled trial to assess the effect of handwashing promotion with soap on the incidence of acute respiratory infection, impetigo, and diarrhoea. METHODS: In adjoining squatter settlements in Karachi, Pakistan, we randomly assigned 25 neighbourhoods to handwashing promotion; 11 neighbourhoods (306 households) were randomised as controls. In neighbourhoods with handwashing promotion, 300 households each were assigned to antibacterial soap containing 1.2% triclocarban and to plain soap. Fieldworkers visited households weekly for 1 year to encourage handwashing by residents in soap households and to record symptoms in all households. Primary study outcomes were diarrhoea, impetigo, and acute respiratory-tract infections (ie, the number of new episodes of illness per person-weeks at risk). Pneumonia was defined according to the WHO clinical case definition. Analysis was by intention to treat. FINDINGS: Children younger than 5 years in households that received plain soap and handwashing promotion had a 50% lower incidence of pneumonia than controls (95% CI (-65% to -34%). Also compared with controls, children younger than 15 years in households with plain soap had a 53%© lower by incidence author of diarrhoea (-65% to -41%) and a 34% lower incidence of impetigo (-52% to -16%). Incidence of disease did not differ significantly between households given plain soap compared with those given antibacterial soap. INTERPRETATION: Handwashing with soap prevents the two clinical syndromes that cause the largest number of childhood deaths globally-namely, diarrhoea and acute lower respiratory infections. Handwashing with daily bathing also prevents impetigo. ESCMID Online Lecture Library BLINDNESS The theory of the idols Francis Bacon (1561-1626) For this purpose of obtaining knowledge of and power over nature, Bacon outlined in this work a new system of logic he believed to be superior to the old ways of syllogism, developing his scientific method, consisting of procedures for isolating the formal cause of a phenomenon (heat, for example) through eliminative induction. For him, the philosopher should proceed through inductive reasoning from fact to axiom to physical law. Before beginning this induction, though, the enquirer must free his or her mind from certain false notions or tendencies which distort the truth. These are called "Idols" (idola), and are of four kinds: ."Idols of the Tribe" (idola tribus), which are common to© the byrace; author

We count one ESCMID Online Lecture Library Use of a human influenza challenge model to assess person-to-person transmission: proof-of-concept study Killingley B, Enstone JE, Greatorex J, Gilbert AS, Lambkin-Williams R, Cauchemez S, Katz JM, Booy R, Hayward A, Oxford J, Bridges CB, Ferguson NM, Nguyen Van-Tam JS. J Infect Dis. 2012 Jan;205(1):35-43

Abstract BACKGROUND: Influenza transmission in humans remains poorly understood. In particular, the relative contribution of contact, large droplet, and aerosol transmission is unknown. The aims of this proof-of-concept study were to determine whether an experimentally induced influenza infection is transmissible between humans and whether this would form a viable platform for future studies. METHODS: In a quarantine facility, healthy volunteers ("donors") were inoculated with A/Wisconsin/67/2005 (H3N2) influenza virus via intranasal drops. On study days 2 and 3 "recipient" volunteers were exposed to donors under close living conditions. Volunteers socialized for 30 hours during a 2-day period. Infection was confirmed by ≥1 positive results from polymerase chain reaction, virus culture, or serology. RESULTS: After inoculation, 4 of 9 donors developed symptoms consistent an influenza-like illness (ILI) and 7 of 9 were proven to be influenza-infected. After exposure, 4 of 15 recipients developed symptoms of ILI and 3 of 15 were proven to be infected. Serum collected within 2 days of study initiation indicated that 1 donor and 3 recipients were seropositive at study© initiation by. After author adjustment for preexposure immunity, the overall secondary attack rate was 25% (3 of 12). CONCLUSIONS: Experimental human exposure studies offer an attractive potential method for answering outstanding questions related to influenza transmission and the evaluation of interventions to reduce it. ESCMID Online Lecture Library CONCLUSIONS

Studying influenza transmission is difficult: seasonality, unpredictable attack rates, numbers of participants required, and confounding variables all present considerable obstacles to studying transmission of wild-type infections. Human influenza challenge studies could offer a promising approach to gain insights into both the mechanisms of influenza transmission and its prevention, so long as a reliable model of transmission can be developed. We demonstrate a successful proof of concept for such an approach and propose considerations for optimization of the model. - In fact children are the main vectors - Old people the more sick

ESCMID Online Lecture Library Mortality from pandemic A/H1N1 2009 influenza in England: public health surveillance study. Donaldson LJ, Rutter PD, Ellis BM, Greaves FE, Mytton OT, Pebody RG, Yardley IE. BMJ. 2009 Dec 10;339:b5213 Study question What is the pattern of death attributable to pandemic A/H1N1 2009 influenza in England?

Summary answer The lowest case fatality rates are in children, while older people, who are much less susceptible, are more likely to die when affected. Two thirds of deaths have occurred in people with recognised risk factors. The overall case fatality rate so far is 26 per 100 000 (range 11-66/100 000) = 0,026%

What is known and what this paper adds Early reports of case fatality rates for the present pandemic have been in the range 0.1-0.9%. These have tended to use laboratory confirmed cases as the denominator, which probably grossly underestimates the true incidence. Our estimated case fatality rate uses an estimate of symptomatic cases in the community by age as the denominator.

ESCMID Online Lecture Library The Japanese experience with vaccinating schoolchildren against influenza Reichert TA, Sugaya N, Fedson DS, Glezen WP, Simonsen L, Tashiro M. N Engl J Med. 2001 Mar 22;344(12):889-96

Conclusions

The effect of influenza on mortality is much greater in Japan than in the United States and can be measured about equally well in terms of deaths from all causes and deaths attributed to pneumonia or influenza. Vaccinating schoolchildren against influenza provides protection and reduces mortality from influenza among older persons. © by author

ESCMID Online Lecture Library Origin and primary dispersal of the Mycobacterium tuberculosis Beijing genotype: clues from human phylogeography. Mokrousov I, Ly HM, Otten T, Lan NN, Vyshnevskyi B, Hoffner S, Narvskaya O. Genome Res. 2005 Oct;15(10):1357-64.

We suggest that the evolution of the population structure of microbial pathogens is influenced by that of modern humans. Consequently, the timing of hallmark changes in bacterial genomes within the last 100,000 yr may be attempted by comparison with relevant human migrations. Here, we used a lineage within Mycobacterium tuberculosis, a Beijing genotype, as a model and compared its phylogeography with human demography and Y chromosome-based phylogeography. We hypothesize that two key events shaped the early history of the Beijing genotype: (1) its Upper Palaeolithic origin in the Homo sapiens sapiens K-M9 cluster in Central Asia, and (2) primary Neolithic dispersal of the secondary Beijing NTF::IS6110 lineage by Proto- Sino-Tibetan farmers within east Asia (human O-M214/M122 haplogroup). The independent introductions of the Beijing strains from east Asia to northern Eurasia and South Africa were likely historically© by authorrecent, whereas their differential dissemination within these areas has been influenced by demographic and climatic factors.

One cloneESCMID is pandemic Online Lecture other are Library endemics BLINDNESS The theory of the idols Francis Bacon (1561-1626) For this purpose of obtaining knowledge of and power over nature, Bacon outlined in this work a new system of logic he believed to be superior to the old ways of syllogism, developing his scientific method, consisting of procedures for isolating the formal cause of a phenomenon (heat, for example) through eliminative induction. For him, the philosopher should proceed through inductive reasoning from fact to axiom to physical law. Before beginning this induction, though, the enquirer must free his or her mind from certain false notions or tendencies which distort the truth. These are called "Idols" (idola), and are of four kinds: ."Idols of the Tribe" (idola tribus), which are common to the© race by; author ."Idols of the Den" (idola specus), which are peculiar to the individual; ESCMID Online Lecture Library PCV9 PREVENTS HOSPITALIZATION FOR PNEUMONIA IN PATIENTS WITH SEASONAL INFLUENZA

Virus PCV9 Controls Vaccine P vaccinees efficacy (95% CI) Influenza 31 56 45 0.01 (14 to 64)

VT pneumococcal bacteremia 0 vs 1

ESCMIDMadhi, Online Klugman Lecture et al. Nature MedicineLibrary 2004;10:811 –13 BLIND TO OTHER FIELDS

ESCMID Online Lecture Library Klugman and Madhi, Science, 2007, 316, 49 – 50. Likely correlation between sources of information and acceptability of A/H1N1 swine-origin influenza virus vaccine in Marseille, France. Nougairède A, Lagier JC, Ninove L, Sartor C, Badiaga S, Botelho E, Brouqui P, Zandotti C, De Lamballerie X, La Scola B, Drancourt M, Gould EA, Charrel RN, Raoult D. PLoS One. 2010 Jun 25;5(6):e11292. BACKGROUND: In UK they practice Flu feast! In France, there was a reluctance to accept vaccination against the A/H1N1 pandemic influenza virus despite government recommendation and investment in the vaccine programme. METHODS AND FINDINGS: We examined the willingness of different populations to accept A/H1N1 vaccination (i) in a French hospital among 3315 employees immunized either by in-house medical personnel or mobile teams of MDs and (ii) in a shelter housing 250 homeless persons. Google was used to assess the volume of enquiries concerning incidence of influenza. We analyzed the information on vaccination provided by Google, the website of the major French newspapers, and PubMed. Two trust Surveys were used to assess public opinion on the trustworthiness of people in different professions. Paramedics were significantly more reluctant to accept immunisation than qualified medical staff. Acceptance was significantly increased when recommended directly by MDs. Anecdotal cases of directly observed severe infections were followed by enhanced acceptance of paramedical staff. Scientific literature was significantly more in favour of vaccination than Google and French newspaper websites. In the case of the newspaper websites, information correlated with their recognised political reputations, although they would presumably claim independence from political bias. The Trust Surveys showed that politicians were highly dis-trusted in contrast with doctors and pharmacists who were considered much more trustworthy. © by author CONCLUSIONS: The low uptake of the vaccine could reflect failure to convey high quality medical information and advice relating to the benefits of being vaccinated. We believe that the media and internet contributed to this problem by raising concerns within the general population and that failure to involve GPs in the control programme may have been a mistake. GPs are highly regarded by the public and can provide face-to-face professional advice and information. The top-down strategy of vaccine programme management and information delivered by the Ministry of HealthESCMID could have aggravated Online the problem, Lecturebecause the general Librarypopulation does not always trust politicians. BLINDNESS The theory of the idols Francis Bacon (1561-1626) For this purpose of obtaining knowledge of and power over nature, Bacon outlined in this work a new system of logic he believed to be superior to the old ways of syllogism, developing his scientific method, consisting of procedures for isolating the formal cause of a phenomenon (heat, for example) through eliminative induction. For him, the philosopher should proceed through inductive reasoning from fact to axiom to physical law. Before beginning this induction, though, the enquirer must free his or her mind from certain false notions or tendencies which distort the truth. These are called "Idols" (idola), and are of four kinds: ."Idols of the Tribe" (idola tribus), which are common to the© race by; author ."Idols of the Den" (idola specus), which are peculiar to the individual; ."Idols of the Marketplace" (idola fori), coming from ESCMID Onlinethe misuse Lecture of language; and Library (Flu) FLU FROM INFLUENZA DI FREDO

ESCMID Online Lecture Library We do not test in winter! The incidence (per 100 000 persons) of ILI from 1996 to 2011 in the region of PACA, France and the average temperature (represented by 7 classes) recorded on Marseille. Data from the French sentinel network and from the web source, free available as http://www.wunderground.com/.

In 2009-ESCMID2010 cases Online do not Lecturefollow cold! Library WeeklyInfluenza Activityin A. Diallo,A. Niang,C. Sokhna,M. M ESCMID Online Lecture Library

Jan 2010 Wenot test did hotcountries!in What causes seasonality?? Why Vaccinations December 2011 one predominate? one © by author

- A. Widdowson, J.C. Widdowson, A. Victor,data. unpublished

Niakhar

Jan 2011 , Senegal, July 2009 to

BLINDNESS The theory of the idols Francis Bacon (1561-1626) For this purpose of obtaining knowledge of and power over nature, Bacon outlined in this work a new system of logic he believed to be superior to the old ways of syllogism, developing his scientific method, consisting of procedures for isolating the formal cause of a phenomenon (heat, for example) through eliminative induction. For him, the philosopher should proceed through inductive reasoning from fact to axiom to physical law. Before beginning this induction, though, the enquirer must free his or her mind from certain false notions or tendencies which distort the truth. These are called "Idols" (idola), and are of four kinds: ."Idols of the Tribe" (idola tribus), which are common to the© race by; author ."Idols of the Den" (idola specus), which are peculiar to the individual; ."Idols of the Marketplace" (idola fori), coming from the misuse of language; and (Flu) ESCMID Online."Idols ofLecture the Theater" Library(idola theatri), which result from an abuse of authority!

ESCMID Online Lecture Library The ferret: an animal model to study influenza virus Maher JA, DeStefano J. Lab Anim (NY). 2004 Oct;33(9):50-3.

Abstract There has been much critical influenza research conducted in a little-known laboratory animal--the ferret. The authors review some of these findings, discuss the reasons the ferret often becomes a model for influenza infection, and compare the ferret with other animal models.

Journal influence, modelisation and reductionism © by author Mechanistic science rather than observation!

ESCMID OnlineRole of sponsor? Lecture Library Benefit of experts: Massive conflit of interest IGNORANCE AND BLINDNESS 1- Rationale of modelling when we are ignorant

2- Future outbreaks

 Avian flu and H1N1  - Reductionism + speculation = big waste

Bioterrorism and smallpox

ESCMID Online Lecture Library PUBLIC HEALTH. PUBLIC HEALTH RISK FROM THE AVIAN H5N1 INFLUENZA EPIDEMIC Ferguson NM, Fraser C, Donnelly CA, Ghani AC, Anderson RM. Science. 2004 May 14;304(5673):968-9.

H5N1

ESCMID Online Lecture Library Pathogenesis of avian influenza A (H5N1) viruses in ferrets Zitzow LA, Rowe T, Morken T, Shieh WJ, Zaki S, Katz JM. J Virol. 2002 May;76(9):4420-9. Abstract Highly pathogenic avian influenza A H5N1 viruses caused outbreaks of disease in domestic poultry and humans in Hong Kong in 1997. Direct transmission of the H5N1 viruses from birds to humans resulted in 18 documented cases of respiratory illness, including six deaths. Here we evaluated two of the avian H5N1 viruses isolated from humans for their ability to replicate and cause disease in outbred ferrets. A/Hong Kong/483/97 virus was isolated from a fatal case and was highly pathogenic in the BALB/c mouse model, whereas A/Hong Kong/486/97 virus was isolated from a case with mild illness and exhibited a low-pathogenicity phenotype in 7 mice. Ferrets infected intranasally with 10 50% egg infectious doses (EID 50) of either H5N1 virus exhibited severe lethargy, fever, weight loss, transient lymphopenia, and replication in the upper and lower respiratory tract, as well as multiple systemic organs, including the brain. Gastrointestinal symptoms were seen in some animals. In contrast, weight loss and severe lethargy were not noted in 7 ferrets infected with 10 EID 50 of two© recent by authorhuman H3N2 viruses, although these viruses were also isolated from the brains, but not other extrapulmonary organs, of infected animals. The results demonstrate that both H5N1 viruses were highly virulent in the outbred ferret model, unlike the differential pathogenicity documented in inbred BALB/c mice. We propose the ferret as an alternative model system for the study of theseESCMID highly pathogenic Online avian viruses. Lecture Library Identification of H5N1-specific T-cell responses in a high-risk cohort in vietnam indicates the existence of potential asymptomatic infections. Powell TJ, Fox A, Peng Y, Quynh Mai le T, Lien VT, Hang NL, Wang L, Lee LY, Simmons CP, McMichael AJ, Farrar JJ, Askonas BA, Duong TN, Thai PQ, Thu Yen NT, Rowland-Jones SL, Hien NT, Horby P, Dong T. J Infect Dis. 2012 Jan;205(1):20-7.

Evidence for subclinical avian influenza virus infections among rural Thai villagers Khuntirat BP, Yoon IK, Blair PJ, Krueger WS, Chittaganpitch M, Putnam SD, Supawat K, Gibbons RV, Pattamadilok S, Sawanpanyalert P, Heil GL, Friary JA, Capuano AW, Gray GC. Clin Infect Dis. 2011 Oct;53(8):e107-16.

In fact for H5N1 as commonly the deadly cases are diagnosed first! Later mild and asymptomatic cases are evidenced. Currently it is not clear ©that by H5N1 author in humans is more severe, as we have no field series. It is still a zoonotic disease (not inter human) ! ESCMID Online Lecture Library Pathogenesis and transmission of swine-origin 2009 A(H1N1) influenza virus in ferrets Munster VJ, de Wit E, van den Brand JM, Herfst S, Schrauwen EJ, Bestebroer TM, van de Vijver D, Boucher CA, Koopmans M, Rimmelzwaan GF, Kuiken T, Osterhaus AD, Fouchier RA. Science. 2009 Jul 24;325(5939):481-3.

H1N1

Abstract The swine-origin A(H1N1) influenza virus that has emerged in humans in early 2009 has raised concerns about pandemic developments. In a ferret pathogenesis and transmission model, the 2009 A(H1N1) influenza virus was found to be more pathogenic than a seasonal A(H1N1) virus, with more extensive virus replication occurring in the respiratory tract. Replication of seasonal A(H1N1) virus was confined to the nasal cavity of ferrets, but the 2009 A(H1N1) influenza virus also replicated in the trachea, bronchi, and bronchioles. Virus shedding was more abundant from the upper respiratory tract for 2009 A(H1N1) influenza virus as compared with seasonal virus, and ©transmission by author via aerosol or respiratory droplets was equally efficient. These data suggest that the 2009 A(H1N1) influenza virus has the ability to persist in the human population, potentially with more severe clinical consequences. ESCMID Online Lecture Library Avian influenza. The limits of avian flu studies in ferrets Cohen J. Science. 2012 Feb 3;335(6068):512-3.

ESCMID Online Lecture Library IGNORANCE AND BLINDNESS

1- Rationale of modelling when we are ignorant

2- Future outbreaks  Avian flu and H1N1 - Reductionism + speculation = big waste

ESCMID Online Lecture Library Anthrax investigation. Army missed warning signs about alleged anthrax mailer. Bhattacharjee Y. Science. 2011 Apr 1;332(6025):27.

© by author Troubled. Ivins juggled at parties and The only recorded use of microbe as volunteered for the Red Cross but weapons since 45 years 64 is from the was also plagued by strange Russian army Ekaterinbourg 1979 and obsessions and criminal thoughts, American army (Ivins) 2001! saysESCMID a new report. Online Lecture Library Operation Dark Winter From Wikipedia, the free encyclopedia Predicting smallpox

Operation Dark Winter was the code name for a senior-level bio-terrorist attack simulation conducted from June 22–23, 2001.[1][2][3] It was designed to carry out a mock version of a covert and widespread smallpox attack on the United States. Tara O'Toole and Thomas Inglesby of the Johns Hopkins Center for Civilian Biodefense Strategies (CCBS) / Center for Strategic and International Studies (CSIS), and Randy Larsen and Mark DeMier of Analytic Services were the principal designers, authors, and controllers of the Dark Winter project. Dark Winter was focused on evaluating the inadequacies of a national emergency response during the use of a biological weapon against the American populace. The exercise was solely intended to establish preventive measures and response strategies by increasing governmental and public awareness on the magnitude and potential of such a threat posed by biological weapons. Dark Winter's simulated scenario involved a localized smallpox attack on Oklahoma City. The simulation was then designed to spiral out of control. This would create a contingency in which the National Security Council struggles to determine both the origin of the attack as well as deal with containing the spreading virus. By not being able to keep pace with the disease's rate of spread, a new catastrophic contingency emerges in which massive civilian casualties would overwhelm America's emergency response capabilities. The disastrous contingencies that© would by result author in the massive loss of civilian life were used to exploit the weaknesses of the U.S. health care infrastructure and its inability to handle such a threat. The contingencies were also meant to address the widespread panic that would emerge and of which would result in mass social breakdown and mob violence. Exploits would also include the many difficulties that the media would face when providing American citizens with the necessary information regardingESCMID safety procedures Online. Lecture Library Taking stock of the biodefense boom Kaiser J. Science. 2011 Sep 2;333(6047):1214-5.

That isESCMID a conflict of Online interest expertsLecture benefit Library of fundings! H5N1 IN FERRETS THE DANGER IS SMALLPOX!

1- Rationale of modelling when we are ignorant

2- Future outbreaks  Avian flu and H1N1 - Reductionism + speculation = big waste

Bioterrorism and smallpox

 3- Is it science or religion© by ?author ESCMID Online Lecture Library Religion is:  Authoritarian - based on fiat  Based on faith or belief not observation or reason.  Does not permit counter-theories  Unchangeable - cast in words of stone  When confronted with counter evidence the religionist does not give up his or her theory.  A closed shop - if you aren't a card carrying member, you aren't welcome!  Intolerant of disbelievers.  Language specific of the priest! © by author In history, and today we hear of people who are persecuted because they believe in another religion, or because they are heretics. Religion is sometimes tolerant of other religions, but never of heretics. Science can be compared and contrasted with Natural Science, and PsychologyESCMID can be compared Online and contrasted Lecture with Applied Library Psychology . SPECIFIC LANGUAGE AND REVIEWERS FROM THE CLUB J. Math. Biol. (2012) 64:403–422 Mathematical Biology DOI 10.1007/s00285-011-0417-5 The model of Kermack and McKendrick for the plague epidemic in Bombay and the type reproduction number with seasonality Nicolas Bacaër

Abstract: The figure showing how the model of Kermack and McKendrick fits the data from the 1906 plague epidemic in Bombay is themost reproduced figure in books discussing mathematical epidemiology. In this paper we show that the assumption of constant parameters in the model leads to quite unrealistic numerical values for these parameters. Moreover the reports published at the time show that plague epidemics in Bombay occurred in fact with a remarkable seasonal pattern every year since 1897 and at least until 1911. So the 1906 epidemic is clearly not a good example of epidemic stopping because the number of susceptible humans has decreased under a threshold, as suggested by Kermack and McKendrick, but an example of epidemic driven by seasonality. We present a seasonal model for the plague in Bombay and compute the type reproduction numbers associated with rats and fleas, thereby extending to periodic models the notion introduced by Roberts and Heesterbeek. © by author

ESCMID Online Lecture Library Thus the problem which I tried to solve by proposing the criterion of falsifiability was neither a problem of meaningfulness or significance, nor a problem of truth or acceptability. It was the problem of drawing a line (as well as this can be done) between the statements, or systems of statements, of the empirical sciences, and all other statements — whether they are of a religious or of a metaphysical character, or simply pseudo- scientific. Years later — it must have been in 1928 or 1929 — I called this first problem of mine the “problem of demarcation.” The criterion of falsifiability is a solution to this problem of demarcation, for it says that statements or systems of statements, in order to be ranked as scientific, must be capable of conflicting with possible, or conceivable,© observations. by author

The problem of modelling future outbreak is that it is not falsifiableESCMID but false! Online Lecture Library Astrology and astronomy From Wikipedia, the free encyclopedia

Astrology and astronomy were archaically one and the same discipline (Latin: astrologia), and were only gradually recognized as separate in Western 17th century philosophy (the "Age of Reason"). Since the 18th century they have come to be regarded as completely separate disciplines. Astronomy, the study of objects and phenomena originating beyond the Earth's atmosphere, is a science and is a widely-studied academic discipline. Astrology, which uses the apparent positions of celestial objects as the basis for psychology, prediction of future events, and© by other author esoteric knowledge, is not a science and is typically defined as a form of divination.

ESCMID Online Lecture Library FINALLY DISASTERS PREDICTED FOR

 Bovine spongiform encephalopathy  Bioterrorism (USA army mishandling, fear smallpox)  Avian flu (zoonotic)

 H1N1

History repeats itself the first time as a tragedy « Spanish » (in fact american flu!) second as a

K.MARX ESCMID Online Lecture Library