E-Letter responses to:

reports: Christophe Fraser, Christl A. Donnelly, Simon Cauchemez, William P. Hanage, Maria D. Van Kerkhove, T. Déirdre Hollingsworth, Jamie Griffin, Rebecca F. Baggaley, Helen E. Jenkins, Emily J. Lyons, Thibaut Jombart, Wes R. Hinsley, Nicholas C. Grassly, Francois Balloux, Azra C. Ghani, Neil M. Ferguson, Andrew Rambaut, Oliver G. Pybus, Hugo Lopez-Gatell, Celia M. Alpuche-Aranda, Ietza Bojorquez Chapela, Ethel Palacios Zavala, Dulce Ma. Espejo Guevara, Francesco Checchi, Erika Garcia, Stephane Hugonnet, Cathy Roth, and The WHO Rapid Pandemic Assessment Collaboration Pandemic Potential of a Strain of Influenza A (H1N1): Early Findings Science 2009; 324: 1557-1561 [Abstract] [Full text] [PDF]

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Published E-Letter responses:

More Evidence in the Same Direction

Claudio A. Ramirez   (29 July 2009)

Response to Pandemic Influenza Study Findings

Rainer Beier   (29 July 2009)

Uncertainties in Predicting A (H1N1) Pandemic Spread

Julian W. Tang, Division of Microbiology, National University Hospital, Singapore   (25 June 2009)

More Evidence in the Same Direction 29 July 2009
Claudio A. Ramirez, Dean, School of the Health Sciences Universidad Rafael Landívar, Guatemala Respond to this E-Letter: Re: More Evidence in the Same Direction	There is another important reason to believe that the number of influenza cases declared in Mexico must be much larger than reported by Mexican health officials: case definitions ("Pandemic potential of a strain of influenza A (H1N1): Early findings," C. Fraser et al., Reports, 19 June 2009, p. 1557; published online 14 May 2009). Mexico's definition for this outbreak included not only "influenza symptoms" but also "respiratory difficulty" (1), whereas everybody else has used only "influenza symptoms" plus confirmation of the strain's type. If the reported need of hospitalization in the U.S. (9%) is a guide of the frequency of respiratory difficulty (2), it follows that Mexico's real caseload should be about 11 times their reported number of cases—2446 as of 14 May, or 26906—very similar to the figure arrived at in the Report by a very different line of reasoning. Claudio A. Ramírez Dean, School of the Health Sciences, Universidad Rafael Landívar, Guatemala. References 1. Department of Epidemiology, Secretary of Health, Mexico, "lineamiento_VE_Porcina_28_abril_09 Dep Epidemiol Mexico"; www.cenavece.salud.gob.mx/indre/, accessed 29 April 2009. 2. Novel Swine-Origin Influenza A (H1N1) Virus Investigation Team, N. Engl. J. Med. 10.1056/NEJMoa0903810 (2009).
Response to Pandemic Influenza Study Findings 29 July 2009
Rainer Beier Federal Institute for Drugs and Medical Devices (BfArM), D 53175 Bonn, Germany Respond to this E-Letter: Re: Response to Pandemic Influenza Study Findings	It is quite right to suggest that a significant correlation exists between airline travelers from Mexico and the detected confirmed cases of influenza A (H1N1) worldwide ("Pandemic potential of a strain of Influenza A (H1N1): early findings," C. Fraser et al., Reports, 19 June 2009, published online 14 May 2009). When we compare the ratio of deaths per cases in Mexico on the days of 5 May 2009 and 25 May 2009 we observe a significantly lower rate on the later date. Using the data of the World Health Organization [80/4174 (1.92%) now vs. 25/590 (4.24%)] we obtain the following results for the risk difference (RD): (–0.023; 95% Confidence Interval: –0.040 to –0.006) with P = 0.007. It seems that there will be more infections in Mexico but the danger of death for infected persons will decrease, considering these two rates. This has to be considered for the next pandemic. However, this may not lead to easy handling of the deaths in Mexico in the future. This is only a consideration for this time point at the end of May. Beier Rainer Division of Pharmacovigilance, Federal Institute for Drugs and Medical Devices (BfArM), Kurt Georg Kiesinger Allee 3, D 53175 Bonn, Germany.
Uncertainties in Predicting A (H1N1) Pandemic Spread 25 June 2009
Julian W. Tang, Clinical Virologist , Division of Microbiology, National University Hospital, Singapore Respond to this E-Letter: Re: Uncertainties in Predicting A (H1N1) Pandemic Spread	The Report by C. Fraser et al. describes the early stages of the recent H1N1 (2009) influenza epidemic emerging from Mexico ("Pandemic potential of a strain of influenza A (H1N1)," 19 June, p. 1557; published online 14 May 2009). It uses mathematical and phylogenetic modeling techniques to derive various epidemiological parameters to describe the early stages of the outbreak of this novel virus. Given the uncertain nature of many of the clinical and epidemiological factors associated with this new virus, the authors have summarized this early situation very well. However, comparisons with the previous pandemics are probably not very accurate for several reasons. For the 1918 pandemic, many of the cases could not have been laboratory-confirmed as caused by influenza virus, because the virus itself was not discovered until 1933 (1). Models attempting to derive an R0 value for this pandemic have used so-called "excess mortality" to estimate deaths due to the 1918 Spanish influenza A (H1N1) virus. Yet this depends heavily on details from death certificates that may have used the term “pneumonia,” which has many bacterial and non-influenza virus causes. The 1957 Asian A (H2N2) and the 1968 Hong Kong A (H3N2) viruses were confirmable by laboratory testing, but this was not possible for all these cases, so again the actual death toll due specifically to these pandemic viruses will be uncertain. Another confounding factor for the specific cause of death in these pandemics is the probable high death rate due to secondary bacterial infections (2–4). This raises the question of how an influenza death is defined and recorded—is it considered a direct or indirect cause? Also, unlike these previous influenza pandemics, the current H1N1 (2009) pandemic influenza strain is co-circulating with a very similar seasonal A (H1N1) influenza virus, which may offer some cross-immunity via its more conserved internal proteins (e.g., the matrix and nucleoprotein) in individuals who have been recently infected naturally with this seasonal A (H1N1) virus. Targeting these internal proteins has been the approach used in developing a universal influenza vaccine for some years now (5–7). If there is any significant cross-immunity conferred by antibodies raised to these internal viral proteins, this may mitigate the future scale of any pandemic with this virus. So, the eventual spread of this novel influenza A (H1N1) virus may not be as widespread as Fraser et al. suggest. However, this cross-immunity does not apply to individuals vaccinated with the seasonal influenza vaccine because the vaccination only contains the outer-envelope HA protein, which has already been shown to offer no cross-immunity to this novel H1N1 (2009) virus (8). Julian W. Tang Division of Microbiology, National University Hospital, Singapore. References 1. W. Smith, C. H. Andrewes, P. P. Laidlaw, Lancet 222, 66 (1933). 2. V. T. Peltola, K. G. Murti, J. A. McCullers, J. Infect. Dis. 192, 249 (2005). 3. D. M. Morens, J. K. Taubenberger, A. S. Fauci, J. Infect. Dis. 198, 962 (2008). 4. J. F. Brundage, G. D. Shanks, Emerg. Infect. Dis 14, 1193 (2008). 5. S. Neirynck et al., Nat. Med. 10, 1157 (1999). 6. W. Fiers, M. De Filette, A. Birkett, S. Neirynck, W. Min Jou, Virus Res. 103, 173 (2004). 7. S. M. Tompkins et al., Emerg. Infect. Dis. 13, 426 (2007). 8. WHO, Vaccines for the new influenza A (H1N1); www.who.int/csr/disease/swineflu/frequently_asked_questions/vaccine_preparedness/en/index.html (2 May 2009, accessed 13 May 2009).