Reasonable Rascal
07-21-09, 18:37
INFLUENZA A (H1N1) - WORLDWIDE (81): EPIDEMIC ANALYSIS
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A ProMED-mail post
In this update:
[1] Epidemic pneumonia
[2] Origins
[3] CFR estimations
[4] Tamiflu resistance - Japan
******
[1] Epidemic pneumonia
Date: Tue 29 Jun 2009
Source: The New England Journal of Medicine [edited]
<http://content.nejm.org/cgi/content/full/NEJMoa0904023>
[The following paper appeared in the 29 June issue of the New England
Journal of Medicine. - Mod.CP]
G Chowell, SM Bertozzi, MA Colchero, H Lopez-Gatell, C Alpuche-Aranda, M Hernandez, et al. Severe respiratory disease concurrent with the
circulation of H1N1 influenza. N Engl J Med 2009 (10.1056/NEJMoa0904023)
Abstract
--------
Background: In the spring of 2009, an outbreak of severe pneumonia was reported in conjunction with the concurrent isolation of a novel swine-origin influenza A (H1N1) virus (S-OIV), widely known as swine flu, in Mexico. Influenza A (H1N1) subtype viruses have rarely predominated since the 1957 pandemic. The analysis of epidemic pneumonia in the absence of routine diagnostic tests can provide information about risk factors for severe disease from this virus and prospects for its control.
Methods: From 24 Mar to 29 Apr 2009, a total of 2155 cases of severe
pneumonia, involving 821 hospitalizations and 100 deaths, were reported to
the Mexican Ministry of Health. During this period, of the 8817 nasopharyngeal specimens that were submitted to the National Epidemiological Reference Laboratory, 2582 were positive for S-OIV. We compared the age distribution of patients who were reported to have severe pneumonia with that during recent influenza epidemics to document an age shift in rates of death and illness.
Results: During the study period, 87 per cent of deaths and 71 per cent of cases of severe pneumonia involved patients between the ages of 5 and 59 years, as compared with average rates of 17 per cent and 32 per cent, respectively, in that age group during the referent periods. Features of this epidemic were similar to those of past influenza pandemics in that circulation of the new influenza virus was associated with an off-season wave of disease affecting a younger population.
Conclusions: During the early phase of this influenza pandemic, there was a sudden increase in the rate of severe pneumonia and a shift in the age distribution of patients with such illness, which was reminiscent of past pandemics and suggested relative protection for persons who were exposed to H1N1 strains during childhood before the 1957 pandemic. If resources or vaccine supplies are limited, these findings suggest a rationale for focusing prevention efforts on younger populations.
--
communicated by:
ProMED-mail rapporteur Mary Marshall
[The authors add the following in their Discussion. "Of note, during the study period, there was proportionately lower morbidity among persons who were 60 years of age or older, the age group in which all persons were born before the 1957 pandemic. With an annual influenza incidence of 15 to 20 per cent, most of these persons would have been 1st exposed to influenza A (H1N1) strains, which disappeared from circulation after the 1957 A (H2N2) influenza pandemic. Francis described the concept of "original antigenic sin," in which the immune response is greatest to antigens to which 1st exposure occurred in childhood. According to this concept, persons born before 1957 who were exposed in childhood to influenza A (H1N1) viruses might be better protected against this viral subtype than those who were 1st exposed to other influenza A subtypes, H2N2 and H3N2, at a later date. Age shifts in mortality to younger populations during pandemics have been described from the reemergence of a subtype. Although persons who were born after 1977 may have been 1st exposed to an influenza A (H1N1) subtype virus, such strains rarely predominate. In this data series, persons who were 60 years of age or older were proportionately less likely to have severe pneumonia, a consideration for future strategies for vaccine allocation.
"Our outline of the age-stratification profile of risk provides a possible foundation for control strategies on the basis of the biologic plausibility of partial protection from earlier exposure. Further studies are under way in Mexico to elucidate other potential risk factors for severity of S-OIV infection to guide targeted control efforts." - Mod.CP]
******
[2] Origins
Date: Mon 29 Jun 2009
Source: ScienceDaily, News [edited]
<http://www.sciencedaily.com/releases/2009/06/090629200641.htm>
The current H1N1 swine flu strain has genetic roots in an illness that sickened pigs at the 1918 Cedar Rapids Swine Show in Iowa, report infectious disease experts at the University of Pittsburgh Graduate School of Public Health in the New England Journal of Medicine. Their paper, published online 29 Jun 2009 and slated for the 16 Jul 2009 print issue, describes H1N1's nearly century-long and often convoluted journey, which may include the accidental resurrection of an extinct strain.
"At the same time the 1918 flu pandemic was rapidly spreading among humans, pigs were hit with a respiratory illness that closely resembled symptoms seen in people," said senior author Donald S Burke, MD, dean, University of Pittsburgh Graduate School of Public Health. "Early experiments confirmed that this 1918 swine virus and a human strain emerged about the same time.
Since then, this ancestor virus has re-assorted genetically with other influenza strains at least 4 times, leading to the emergence of the new 2009 strain, which has retained some similarities to the original virus."
In the paper, Dr Burke and lead author Shanta M Zimmer, MD, assistant professor, University of Pittsburgh School of Medicine, describe the temporary "extinction" of the H1N1 virus from humans in 1957 and its subsequent re-emergence 20 years later. They note a small 230 person outbreak of H1N1 in 1976 among soldiers in Fort Dix, New Jersey that did not extend outside the military base. Then, H1N1 influenza re-emerged in 1977 among people in the former Soviet Union, Hong Kong and north eastern China. Careful study of the genetic origin of the 1977 strain showed that it was not the Fort Dix strain, but, surprisingly, was related closely to a 1950 human strain. Given the genetic similarity of these strains, re-emergence was likely due to an accidental release during laboratory studies of the 1950 strain that had been preserved as a "freezer" virus, they said.
The authors hypothesize that concerns about the Fort Dix outbreak stimulated a flurry of research on H1N1 viruses in 1976, which led to an accidental release and re-emergence of the previously extinct virus a year later. The re-emerged 1977 H1N1 strain has continued to circulate among humans as seasonal flu for the past 32 years.
Although originally traced to Mexico, the exact physical origins of the 2009 H1N1 pandemic virus are unknown. Because the current strain shares
common ancestry with older flu strains, it is possible that portions of the population may have partial immunity to the new pandemic virus.
The authors also go on to explain that the danger posed by a virus isn't based solely on its lethality but also on its transmissibility, which is the ability to jump from animals to humans and to survive by mutating to adapt to its new human host. H1N1 influenza viruses have demonstrated this ability throughout their history.
"Studying the history of emergence and evolution of flu viruses doesn't provide us with a blueprint for the future, but it does reveal general patterns, and this kind of information is critical if we are to be as prepared as possible," said Dr Burke.
--
communicated by:
ProMED-mail rapporteur Susan Baekeland
*****
[3] CFR estimations
Date: Thu 2 Jul 2009
Source: Eurosurveillance, Volume 14, Issue 26, 2009 [edited]
<http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=19255>
The emerging influenza pandemic: estimating the case fatality ratio
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By: N Wilson, M G Baker (Department of Public Health, University of Otago, Wellington, New Zealand)
To determine appropriate influenza pandemic containment and mitigation
measures, health authorities need to know the approximate case fatality
ratio (CFR) for this new infection. We present 4 different methods for very provisionally estimating the plausible range of the CFR for symptomatic infection by this pandemic strain in developed countries. All of the methods produce substantially lower values (range 0.06 percent to 0.0004 percent) than a previously published estimate for Mexico (0.4 percent). As these results have many limitations, improved surveillance and serological surveys are needed in both developed and developing countries to produce more accurate estimates.
Introduction
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The 1st published estimate of the case fatality ratio (CFR) for those infected by the influenza A(H1N1)v pandemic strain was based on data from Mexico [1]. This work estimated the CFR to be 0.4 per cent (range 0.3 per cent to 1.5 per cent) based on confirmed and suspected influenza A(H1N1)v-related deaths reported up to late April 2009. Since that date, the new pandemic strain has spread globally, and new impact data are available, but we were unable to identify new estimates of the CFR in the literature. Yet this figure is critical if health authorities are to produce reasonable estimates of the likely impact of the pandemic in their particular countries. The estimated mortality burden is particularly useful for calibrating appropriate containment and mitigation measures that balance the likely health gains from interventions against their social and economic costs.
Methods
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We considered 4 different ways to provide provisional estimates for plausible ranges of CFRs in developed countries for this pandemic.
1. Multiplier method: This method used confirmed deaths and cases reported to the World Health Organization (WHO), but with a range of multipliers for the latter to adjust for under-ascertainment. These multipliers were based on expert judgment that most symptomatic cases of the new pandemic involve relatively mild symptoms and that the great majority of cases were not being identified and reported. For example, spokespeople from the United States (US) Centers for Disease Control and Prevention (CDC) have announced "hundreds of thousands of cases that have occurred in the US" in late May and mid-June 2009 [2,3]. Similarly, one estimate for the United Kingdom was 30 000 cases in the community in May 2009 [4]. Regarding the choice of a multiplier to adjust data on laboratory-confirmed cases of pandemic influenza, we considered the above assessments, which are specific to the current pandemic, to be more informative than past experience with seasonal influenza, which only provides very broad estimates of a potential multiplier. For example, it has been estimated for seasonal influenza in the US that there are 2.3 influenza cases in the community for every outpatient consultation, and 84.1 for every case that is hospitalised (derived from Molinari et al. [5]). But during a pandemic, patients are encouraged to remain at home unless they have "severe illness" or are "at high risk for influenza complications." In addition, laboratory testing capacity can be quickly saturated in a pandemic, and priority is given to those who require hospitalisation or are at high risk for severe disease [6]. These processes will tend to push the ratio of community cases to laboratory-confirmed cases upwards to the multiplier in the range of 10-30 that we judged reasonable for this analysis.
In the calculations, we used WHO data for cumulative cases and deaths as of 26 Jun 2009 [7] for all member countries of the Organisation for Economic Cooperation and Development (OECD), but excluding data from Mexico. The reason for this exclusion was that the epidemic appeared to have started in Mexico, and we were concerned about the quality and sensitivity of numerator data in the early stages of the epidemic there -- that is, when it was not recognised that the new pandemic strain was spreading.
2. Community survey method: This method used an estimate for community
cases from a telephone survey done by the New York City Department of
Health [8]. It reported that 6.9 per cent of New Yorkers had symptoms of influenza-like illness (ILI) between 1 and 20 May 2009. The report on this survey did not publish confidence intervals, so we calculated these to be 5.6 per cent to 8.5 per cent (for the survey of 1005 households). Furthermore, at the time of this survey, only 90 per cent of the influenza samples tested in the city were of the current pandemic strain [9], and so we adjusted the CFR estimate accordingly by this proportion. We conservatively used the cumulative death toll for New York City at 3 weeks after the time period used in this survey (when it was n=12) to allow for a lag in illness progression and then in reporting fatalities to health authorities [10]. We identified that there were no pandemic influenza deaths prior to May 2009 [11], and the New York City population of 8 274 500 used in our calculations was that for 2007 [12].
3. Method extrapolating from seasonal influenza mortality: This method was based on evidence that the elderly population appear to have a relatively low mortality rate compared to other age groups in this pandemic. Data from Canada on hospitalisations and deaths [13] and US data indicate a median age of hospitalisation at 19 years and of death at 37 years [14]. Hence, we assumed that a CFR for seasonal influenza in the age group of under 65 years could provide a crude approximation for the CFR of the new pandemic strain. To obtain this value, we used the full range estimates that could be derived from a detailed US study [15] that used 7 models for determining excess mortality attributable to influenza. [These data are presented as a table in the original text].
4. Method extrapolating from a more "mature" epidemic: This method was
restricted to data from Canada and assumed that the epidemic there was
relatively advanced in that the trend data for cases and hospitalisations were suggestive of a peak in early June 2009 with a subsequent waning of the epidemic in the following 3 weeks [17]. To calculate the CFR, we assumed that the epidemic in Canada was half complete in terms of cumulative deaths (with n=21 deaths confirmed as of 26 Jun 2009 [17]), which is possibly a conservative assumption given the low level of new hospitalisations in late June 2009. We also assumed that the cumulative total of symptomatic cases would ultimately reach between 5 per cent of the total population (which is within the range of seasonal influenza) and around 30 per cent (which is about the value predicted by modelling for a pandemic with an R0 value of 1.5 [18] as estimated for the current pandemic using the Mexican data [1]).
Results
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The 4 different methods produced a wide range of estimates for the CFR in developed countries, from 0.0004 per cent to 0.06 per cent, a range of 150-fold (table 2). The ranges for each model overlapped with at least one other model. When these CFR estimates were applied to a country with a population of 10 million that ultimately experienced a cumulative incidence of symptomatic infection with the pandemic strain of 30 per cent, the total number of deaths would range from 12 to 1800.
Table: Case fatality ratio for symptomatic infection with influenza A(H1N1)v pandemic strain in developed countries, estimated by 4 different methods [abbreviated]:
Method / Range of CFR (per cent) / Projected number of deaths in developed country of 10 million inhabitants
1 / 0.004 - 0.06 / 120 - 1800
2 / 0.01 - 0.03 / 300 - 900
3 / 0.002 - 0.003 / 60 - 90
4 / 0.0004 - 0.003 / 12 - 90
Discussion
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All these estimated CFRs are substantially lower than the previously
published estimate (0.4 per cent for Mexico). They also differ markedly
from the simplistic estimate that would be derived from using surveillance data available only for confirmed cases reported to WHO (that is, CFR = 0.29 per cent, based on 110 deaths in 38 409 cases for the 29 OECD countries used in this analysis [7]). A low CFR would be consistent with the mild 1st wave seen in previous pandemics which caused widespread infection but low mortality [19]. It could also be related to the relatively young age of the majority of cases and the use of highly effective modern treatment for those who are seriously ill.
Although based on the most current data possible, all the methods used
still have substantial limitations. The multiplier method merely relied on the judgment (from other experts as well as ours) of widespread and relatively mild disease that is not being reported. Nevertheless, the suggestion of widespread community spread in the US is broadly consistent with the community survey in New York City and another community survey in the US with around 6 per cent cumulative incidence of ILI [14].
The New York City survey was limited by asking only about ILI that occurred during a 20 day period in May 2009 and by ignoring illness in April 2009 even though there were hospitalisations in New York City in that month. Therefore, the method using this survey could have overestimated the CFR, although the opposite could have occurred if some of the reported ILI symptoms were due to other respiratory infections and allergic conditions such as hay fever.
The method that extrapolated from seasonal influenza mortality data in
people under 65 years of age was limited in that it effectively considered no aspects of the epidemiology of the new pandemic influenza virus other than the age distribution -- that is, that it seems to affect younger age groups more than older age groups. Yet there is little information comparing the current pandemic strain with seasonal influenza strains in terms of mortality risk in this younger age group. Furthermore, the data from which the estimated range was derived may be outdated in that modern medical care has progressed since the early part of the period used in the particular US study [15] that the estimates were based on.
Although the Canadian epidemic appears to be waning, the method using the crude extrapolation of the course of this epidemic was very simplistic. Indeed, rather than being half complete, this epidemic wave could continue throughout the northern hemisphere summer and beyond.
These methods tended to focus on correcting for under-ascertainment of the denominator, yet there is also a potential bias from underascertainment of the numerator of the CFR. Particularly in the early stages of an epidemic, there will be a lag in reported deaths and other severe outcomes. Sophisticated statistical methods have been proposed for obtaining adjusted CFR estimates using data from the early phase of an epidemic [20], and these result in adjustment for various time lags and an upward shift of the CFR. However, such adjustments would probably have little effect on the estimates presented in this article which are based on data from country epidemics which have progressed well beyond their early stages (for example, the Canadian data). There is also the potential for under-recognition of deaths attributable to influenza in those with serious co-morbidities, but this can only be addressed by careful research studies and post-epidemic modelling to determine total excess deaths. Nevertheless, this bias might be relatively smaller in this pandemic where more deaths involve young people. Also, once the new influenza A(H1N1)v strain was recognised, there is likely to have been increased sensitivity for diagnosing influenza-related deaths (at least in developed countries where hospitalisation is likely to precede influenza-related death).
All of the presented methods have limitations and could be refined using additional data to provide more robust estimates. Ultimately, such estimates require enhanced surveillance, outbreak investigations in a range of settings, and carefully designed population studies, ideally with serological testing [21]. Additionally, the ranges of CFRs for disadvantaged populations in developed countries and for most of the population in developing countries are likely to be much higher than those estimated here, given likely differences in disease transmission, co-morbidity, access to antivirals and standards of medical care.
Conclusion
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We present several methods for provisionally estimating the plausible range for the CFR of the emerging influenza pandemic in developed countries. All methods used have significant limitations, but they collectively suggest that infection with this particular pandemic strain is likely to cause illness with a relatively low CFR compared to an earlier estimate and also to historical standards. A further reason for presenting this range of methods is to encourage data collection that can start to reduce the uncertainty around this important pandemic parameter.
References
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1. Fraser C, Donnelly CA, Cauchemez S, Hanage WP, Van Kerkhove MD,
Hollingsworth TD, et al. Pandemic potential of a strain of influenza A
(H1N1): early findings. Science 2009; 324(5934): 1557-61.
2. CDC. CDC telebriefing on investigation of human cases of novel influenza A (H1N1). 18 June 2009. Atlanta: CDC; 2009. Available from:
<http://www.cdc.gov/media/transcripts/2009/t090618.htm>.
3. CDC. Update on the novel influenza A H1N1 virus and new findings
published today. 22 May 2009. Atlanta: CDC; 2009. Available from:
<http://www.cdc.gov/media/transcripts/2009/t090522.htm>.
4. Lean G. UK swine flu toll is really 30 000, says leading scientist.
London: The Independent; 24 May 2009. Available from:
Link (<http://www.independent.co.uk/life-style/health-and-families/health-news/uk-swine-flu-toll-is-really-30000-says-leading-scientist-1690130.html>.)
5. Molinari NA, Ortega-Sanchez IR, Messonnier ML, Thompson WW, Wortley PM, Weintraub E, et al. The annual impact of seasonal influenza in the US: measuring disease burden and costs. Vaccine 2007; 25(27): 5086-96.
6. CDC. Interim guidance for clinicians on identifying and caring for
patients with swine-origin influenza A (H1N1) virus infection (4 May). Atlanta: CDC; 2009. Available from: <http://www.cdc.gov/h1n1flu/identifyingpatients.htm>.
7 WHO. Influenza A(H1N1) - update 54. 26 June 2009. Geneva: WHO; 2009.
Available from: <http://www.who.int/csr/don/2009_06_26/en/index.html>.
8. New York City Department of Health and Mental Hygiene (NYCDHMH).
Prevalence of flu-like illness in New York City: May 2009. A preliminary report from the Health Department. New York: NYCDHMH; 2009. Available from:
<http://www.nyc.gov/html/doh/downloads/pdf/cd/h1n1_citywide_survey.pdf>.
9. NYCDHMH. Community transmission of H1N1 flu appears to decline in New York City (press release 12 Jun 2009). New York: NYCDHMH; 2009. Available from: <http://www.nyc.gov/html/doh/html/pr2009/pr042-09.shtml>.
10. NYCDHMH. Health Department survey suggests that 7 per cent of New
Yorkers had flu-like illness in May (press release 10 June 2009). New York: NYCDHMH; 2009. Available from:
<http://www.nyc.gov/html/doh/html/pr2009/pr041-09.shtml>.
11. NYCDHMH. Health Department updates flu status (press release, 2 May
2009). New York: NYCDHMH; 2009. Available from:
<http://www.nyc.gov/html/doh/html/pr2009/pr021-09.shtml>.
12. United States Census Bureau. Population finder. Washington DC: US
Census Bureau; 2009. Available from:
<http://factfinder.census.gov/servlet/SAFFPopulation?_submenuId=population_0&_sse=on>.
13. Public Health Agency of Canada. FluWatch: June 14, 2009 to June 20,
2009 (Week 24). Public Health Agency of Canada. Ottawa; 2009. Available
from: <http://www.phac-aspc.gc.ca/fluwatch/08-09/w24_09/index-eng.php>.
14. CDC. CDC telebriefing on investigation of human cases of novel
influenza A (H1N1). 26 June 2009. Atlanta: CDC; 2009. Available from:
<http://www.cdc.gov/media/transcripts/2009/t090626.htm>.
15. Thompson WW, Weintraub E, Dhankhar P, Cheng PY, Brammer L, Meltzer MI, et al. Estimates of US influenza-associated deaths made using four
different methods. Influenza Other Respi Viruses 2009; 3(1): 37-49.
16. United States Census Bureau. Quick table (QT-P1A): age and sex for the total population: 1990. Washington, D.C.: US Census Bureau; 1990. Available from:
Link (<http://factfinder.census.gov/servlet/QTTable?_bm=y&-state=qt&-qr_name=DEC_1990_STF1_QTP1A&-ds_name=DEC_1990_STF1_&-redoLog=false&-_caller=geoselect&-geo_id=01000US&-format=&-_lang=en>.)
17. Public Health Agency of Canada. Cases of H1N1 flu virus in Canada. 26 June 2009; 2009. Available from:
<http://www.phac-aspc.gc.ca/alert-alerte/swine-porcine/surveillance-archive/20090626-eng.php>.
18. Milne GJ, Kelso JK, Kelly HA, Huband ST, McVernon J. A small community model for the transmission of infectious diseases: comparison of school closure as an intervention in individual-based models of an influenza pandemic. PLoS One 2008; 3(12): e4005.
19. Miller MA, Viboud C, Balinska M, Simonsen L. The signature features of
influenza pandemics--implications for policy. N Engl J Med 2009; 360(25): 2595-8.
20. Ghani AC, Donnelly CA, Cox DR, Griffin JT, Fraser C, Lam TH, et al.
Methods for estimating the case fatality ratio for a novel, emerging
infectious disease. Am J Epidemiol 2005; 162(5): 479-86.
21. Lipsitch M, Riley S, Cauchemez S, Ghani AC, Ferguson NM. Managing and reducing uncertainty in an emerging influenza pandemic. N Engl J Med 28 May 2009; [E-pub ahead of print].
--
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ProMED-mail
[The authors have indicated that their methods tended to focus on correcting for underascertainment of the denominator. All methods used have significant limitations, but they collectively suggest that infection with this particular pandemic strain is likely to cause illness with a relatively low CFR compared with an earlier estimate and also to historical standards. - Mod.CP]
******
[4] Tamiflu resistance - Japan
Date: Thu 2 Jul 2009
Source: Reuters News [edited]
Link (<http://www.reuters.com/article/internal_ReutersNewsRoom_ExclusivesAndWins_MOLT/idUSTRE5614TW20090702>)
Japan has confirmed its 1st case of a genetic mutation of the new H1N1
influenza that shows resistance to Tamiflu [oseltamivir], the main antiviral flu drug, a health ministry official said on Thursday [2 Jul 2009].
The World Health Organization has declared a global pandemic is under way from the virus, known as swine flu, which has so far been treatable with Tamiflu, made by Switzerland's Roche. Takeshi Enami, an official at Japan's health ministry, said that the patient's sensitivity to Tamiflu had yet to be tested.
The patient, who was confirmed in May 2009 with the H1N1 strain of the flu in the Osaka prefecture of western Japan, has since recovered, and no other cases of the new flu have been confirmed around the patient, Enami said. He could not confirm the age or the sex of the patient.
The 1st case of H1N1 that did not respond to Tamiflu was a patient in Denmark.
Earlier this week, WHO said that the case, revealed by Roche and Danish
officials on Monday [29 Jun 2009], was an isolated one and did not amplify the severity of the virus. Resistance to Tamiflu has been previously documented in the deadly bird flu virus H5N1 and seasonal H1N1 flu.
--
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ProMED-mail
[Dr Irene Lai of SOS International has provided the following information with regard to the 1st occurrence of Tamiflu-resistance (in Denmark). According to the press release from Denmark's State Serum Institute
(<http://www.ssi.dk/sw174.asp?PAGE=3D1&ArtNo=3D3651423>), the strain
isolated from the Danish patient remains sensitive to the alternate
neuraminidase inhibitor, zanamivir. In that case, the resistance arose in a person who was on post-exposure prophylaxis with Tamiflu [oseltamivir]. - Mod.CP]
************************************************** ****
A ProMED-mail post
In this update:
[1] Epidemic pneumonia
[2] Origins
[3] CFR estimations
[4] Tamiflu resistance - Japan
******
[1] Epidemic pneumonia
Date: Tue 29 Jun 2009
Source: The New England Journal of Medicine [edited]
<http://content.nejm.org/cgi/content/full/NEJMoa0904023>
[The following paper appeared in the 29 June issue of the New England
Journal of Medicine. - Mod.CP]
G Chowell, SM Bertozzi, MA Colchero, H Lopez-Gatell, C Alpuche-Aranda, M Hernandez, et al. Severe respiratory disease concurrent with the
circulation of H1N1 influenza. N Engl J Med 2009 (10.1056/NEJMoa0904023)
Abstract
--------
Background: In the spring of 2009, an outbreak of severe pneumonia was reported in conjunction with the concurrent isolation of a novel swine-origin influenza A (H1N1) virus (S-OIV), widely known as swine flu, in Mexico. Influenza A (H1N1) subtype viruses have rarely predominated since the 1957 pandemic. The analysis of epidemic pneumonia in the absence of routine diagnostic tests can provide information about risk factors for severe disease from this virus and prospects for its control.
Methods: From 24 Mar to 29 Apr 2009, a total of 2155 cases of severe
pneumonia, involving 821 hospitalizations and 100 deaths, were reported to
the Mexican Ministry of Health. During this period, of the 8817 nasopharyngeal specimens that were submitted to the National Epidemiological Reference Laboratory, 2582 were positive for S-OIV. We compared the age distribution of patients who were reported to have severe pneumonia with that during recent influenza epidemics to document an age shift in rates of death and illness.
Results: During the study period, 87 per cent of deaths and 71 per cent of cases of severe pneumonia involved patients between the ages of 5 and 59 years, as compared with average rates of 17 per cent and 32 per cent, respectively, in that age group during the referent periods. Features of this epidemic were similar to those of past influenza pandemics in that circulation of the new influenza virus was associated with an off-season wave of disease affecting a younger population.
Conclusions: During the early phase of this influenza pandemic, there was a sudden increase in the rate of severe pneumonia and a shift in the age distribution of patients with such illness, which was reminiscent of past pandemics and suggested relative protection for persons who were exposed to H1N1 strains during childhood before the 1957 pandemic. If resources or vaccine supplies are limited, these findings suggest a rationale for focusing prevention efforts on younger populations.
--
communicated by:
ProMED-mail rapporteur Mary Marshall
[The authors add the following in their Discussion. "Of note, during the study period, there was proportionately lower morbidity among persons who were 60 years of age or older, the age group in which all persons were born before the 1957 pandemic. With an annual influenza incidence of 15 to 20 per cent, most of these persons would have been 1st exposed to influenza A (H1N1) strains, which disappeared from circulation after the 1957 A (H2N2) influenza pandemic. Francis described the concept of "original antigenic sin," in which the immune response is greatest to antigens to which 1st exposure occurred in childhood. According to this concept, persons born before 1957 who were exposed in childhood to influenza A (H1N1) viruses might be better protected against this viral subtype than those who were 1st exposed to other influenza A subtypes, H2N2 and H3N2, at a later date. Age shifts in mortality to younger populations during pandemics have been described from the reemergence of a subtype. Although persons who were born after 1977 may have been 1st exposed to an influenza A (H1N1) subtype virus, such strains rarely predominate. In this data series, persons who were 60 years of age or older were proportionately less likely to have severe pneumonia, a consideration for future strategies for vaccine allocation.
"Our outline of the age-stratification profile of risk provides a possible foundation for control strategies on the basis of the biologic plausibility of partial protection from earlier exposure. Further studies are under way in Mexico to elucidate other potential risk factors for severity of S-OIV infection to guide targeted control efforts." - Mod.CP]
******
[2] Origins
Date: Mon 29 Jun 2009
Source: ScienceDaily, News [edited]
<http://www.sciencedaily.com/releases/2009/06/090629200641.htm>
The current H1N1 swine flu strain has genetic roots in an illness that sickened pigs at the 1918 Cedar Rapids Swine Show in Iowa, report infectious disease experts at the University of Pittsburgh Graduate School of Public Health in the New England Journal of Medicine. Their paper, published online 29 Jun 2009 and slated for the 16 Jul 2009 print issue, describes H1N1's nearly century-long and often convoluted journey, which may include the accidental resurrection of an extinct strain.
"At the same time the 1918 flu pandemic was rapidly spreading among humans, pigs were hit with a respiratory illness that closely resembled symptoms seen in people," said senior author Donald S Burke, MD, dean, University of Pittsburgh Graduate School of Public Health. "Early experiments confirmed that this 1918 swine virus and a human strain emerged about the same time.
Since then, this ancestor virus has re-assorted genetically with other influenza strains at least 4 times, leading to the emergence of the new 2009 strain, which has retained some similarities to the original virus."
In the paper, Dr Burke and lead author Shanta M Zimmer, MD, assistant professor, University of Pittsburgh School of Medicine, describe the temporary "extinction" of the H1N1 virus from humans in 1957 and its subsequent re-emergence 20 years later. They note a small 230 person outbreak of H1N1 in 1976 among soldiers in Fort Dix, New Jersey that did not extend outside the military base. Then, H1N1 influenza re-emerged in 1977 among people in the former Soviet Union, Hong Kong and north eastern China. Careful study of the genetic origin of the 1977 strain showed that it was not the Fort Dix strain, but, surprisingly, was related closely to a 1950 human strain. Given the genetic similarity of these strains, re-emergence was likely due to an accidental release during laboratory studies of the 1950 strain that had been preserved as a "freezer" virus, they said.
The authors hypothesize that concerns about the Fort Dix outbreak stimulated a flurry of research on H1N1 viruses in 1976, which led to an accidental release and re-emergence of the previously extinct virus a year later. The re-emerged 1977 H1N1 strain has continued to circulate among humans as seasonal flu for the past 32 years.
Although originally traced to Mexico, the exact physical origins of the 2009 H1N1 pandemic virus are unknown. Because the current strain shares
common ancestry with older flu strains, it is possible that portions of the population may have partial immunity to the new pandemic virus.
The authors also go on to explain that the danger posed by a virus isn't based solely on its lethality but also on its transmissibility, which is the ability to jump from animals to humans and to survive by mutating to adapt to its new human host. H1N1 influenza viruses have demonstrated this ability throughout their history.
"Studying the history of emergence and evolution of flu viruses doesn't provide us with a blueprint for the future, but it does reveal general patterns, and this kind of information is critical if we are to be as prepared as possible," said Dr Burke.
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communicated by:
ProMED-mail rapporteur Susan Baekeland
*****
[3] CFR estimations
Date: Thu 2 Jul 2009
Source: Eurosurveillance, Volume 14, Issue 26, 2009 [edited]
<http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=19255>
The emerging influenza pandemic: estimating the case fatality ratio
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By: N Wilson, M G Baker (Department of Public Health, University of Otago, Wellington, New Zealand)
To determine appropriate influenza pandemic containment and mitigation
measures, health authorities need to know the approximate case fatality
ratio (CFR) for this new infection. We present 4 different methods for very provisionally estimating the plausible range of the CFR for symptomatic infection by this pandemic strain in developed countries. All of the methods produce substantially lower values (range 0.06 percent to 0.0004 percent) than a previously published estimate for Mexico (0.4 percent). As these results have many limitations, improved surveillance and serological surveys are needed in both developed and developing countries to produce more accurate estimates.
Introduction
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The 1st published estimate of the case fatality ratio (CFR) for those infected by the influenza A(H1N1)v pandemic strain was based on data from Mexico [1]. This work estimated the CFR to be 0.4 per cent (range 0.3 per cent to 1.5 per cent) based on confirmed and suspected influenza A(H1N1)v-related deaths reported up to late April 2009. Since that date, the new pandemic strain has spread globally, and new impact data are available, but we were unable to identify new estimates of the CFR in the literature. Yet this figure is critical if health authorities are to produce reasonable estimates of the likely impact of the pandemic in their particular countries. The estimated mortality burden is particularly useful for calibrating appropriate containment and mitigation measures that balance the likely health gains from interventions against their social and economic costs.
Methods
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We considered 4 different ways to provide provisional estimates for plausible ranges of CFRs in developed countries for this pandemic.
1. Multiplier method: This method used confirmed deaths and cases reported to the World Health Organization (WHO), but with a range of multipliers for the latter to adjust for under-ascertainment. These multipliers were based on expert judgment that most symptomatic cases of the new pandemic involve relatively mild symptoms and that the great majority of cases were not being identified and reported. For example, spokespeople from the United States (US) Centers for Disease Control and Prevention (CDC) have announced "hundreds of thousands of cases that have occurred in the US" in late May and mid-June 2009 [2,3]. Similarly, one estimate for the United Kingdom was 30 000 cases in the community in May 2009 [4]. Regarding the choice of a multiplier to adjust data on laboratory-confirmed cases of pandemic influenza, we considered the above assessments, which are specific to the current pandemic, to be more informative than past experience with seasonal influenza, which only provides very broad estimates of a potential multiplier. For example, it has been estimated for seasonal influenza in the US that there are 2.3 influenza cases in the community for every outpatient consultation, and 84.1 for every case that is hospitalised (derived from Molinari et al. [5]). But during a pandemic, patients are encouraged to remain at home unless they have "severe illness" or are "at high risk for influenza complications." In addition, laboratory testing capacity can be quickly saturated in a pandemic, and priority is given to those who require hospitalisation or are at high risk for severe disease [6]. These processes will tend to push the ratio of community cases to laboratory-confirmed cases upwards to the multiplier in the range of 10-30 that we judged reasonable for this analysis.
In the calculations, we used WHO data for cumulative cases and deaths as of 26 Jun 2009 [7] for all member countries of the Organisation for Economic Cooperation and Development (OECD), but excluding data from Mexico. The reason for this exclusion was that the epidemic appeared to have started in Mexico, and we were concerned about the quality and sensitivity of numerator data in the early stages of the epidemic there -- that is, when it was not recognised that the new pandemic strain was spreading.
2. Community survey method: This method used an estimate for community
cases from a telephone survey done by the New York City Department of
Health [8]. It reported that 6.9 per cent of New Yorkers had symptoms of influenza-like illness (ILI) between 1 and 20 May 2009. The report on this survey did not publish confidence intervals, so we calculated these to be 5.6 per cent to 8.5 per cent (for the survey of 1005 households). Furthermore, at the time of this survey, only 90 per cent of the influenza samples tested in the city were of the current pandemic strain [9], and so we adjusted the CFR estimate accordingly by this proportion. We conservatively used the cumulative death toll for New York City at 3 weeks after the time period used in this survey (when it was n=12) to allow for a lag in illness progression and then in reporting fatalities to health authorities [10]. We identified that there were no pandemic influenza deaths prior to May 2009 [11], and the New York City population of 8 274 500 used in our calculations was that for 2007 [12].
3. Method extrapolating from seasonal influenza mortality: This method was based on evidence that the elderly population appear to have a relatively low mortality rate compared to other age groups in this pandemic. Data from Canada on hospitalisations and deaths [13] and US data indicate a median age of hospitalisation at 19 years and of death at 37 years [14]. Hence, we assumed that a CFR for seasonal influenza in the age group of under 65 years could provide a crude approximation for the CFR of the new pandemic strain. To obtain this value, we used the full range estimates that could be derived from a detailed US study [15] that used 7 models for determining excess mortality attributable to influenza. [These data are presented as a table in the original text].
4. Method extrapolating from a more "mature" epidemic: This method was
restricted to data from Canada and assumed that the epidemic there was
relatively advanced in that the trend data for cases and hospitalisations were suggestive of a peak in early June 2009 with a subsequent waning of the epidemic in the following 3 weeks [17]. To calculate the CFR, we assumed that the epidemic in Canada was half complete in terms of cumulative deaths (with n=21 deaths confirmed as of 26 Jun 2009 [17]), which is possibly a conservative assumption given the low level of new hospitalisations in late June 2009. We also assumed that the cumulative total of symptomatic cases would ultimately reach between 5 per cent of the total population (which is within the range of seasonal influenza) and around 30 per cent (which is about the value predicted by modelling for a pandemic with an R0 value of 1.5 [18] as estimated for the current pandemic using the Mexican data [1]).
Results
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The 4 different methods produced a wide range of estimates for the CFR in developed countries, from 0.0004 per cent to 0.06 per cent, a range of 150-fold (table 2). The ranges for each model overlapped with at least one other model. When these CFR estimates were applied to a country with a population of 10 million that ultimately experienced a cumulative incidence of symptomatic infection with the pandemic strain of 30 per cent, the total number of deaths would range from 12 to 1800.
Table: Case fatality ratio for symptomatic infection with influenza A(H1N1)v pandemic strain in developed countries, estimated by 4 different methods [abbreviated]:
Method / Range of CFR (per cent) / Projected number of deaths in developed country of 10 million inhabitants
1 / 0.004 - 0.06 / 120 - 1800
2 / 0.01 - 0.03 / 300 - 900
3 / 0.002 - 0.003 / 60 - 90
4 / 0.0004 - 0.003 / 12 - 90
Discussion
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All these estimated CFRs are substantially lower than the previously
published estimate (0.4 per cent for Mexico). They also differ markedly
from the simplistic estimate that would be derived from using surveillance data available only for confirmed cases reported to WHO (that is, CFR = 0.29 per cent, based on 110 deaths in 38 409 cases for the 29 OECD countries used in this analysis [7]). A low CFR would be consistent with the mild 1st wave seen in previous pandemics which caused widespread infection but low mortality [19]. It could also be related to the relatively young age of the majority of cases and the use of highly effective modern treatment for those who are seriously ill.
Although based on the most current data possible, all the methods used
still have substantial limitations. The multiplier method merely relied on the judgment (from other experts as well as ours) of widespread and relatively mild disease that is not being reported. Nevertheless, the suggestion of widespread community spread in the US is broadly consistent with the community survey in New York City and another community survey in the US with around 6 per cent cumulative incidence of ILI [14].
The New York City survey was limited by asking only about ILI that occurred during a 20 day period in May 2009 and by ignoring illness in April 2009 even though there were hospitalisations in New York City in that month. Therefore, the method using this survey could have overestimated the CFR, although the opposite could have occurred if some of the reported ILI symptoms were due to other respiratory infections and allergic conditions such as hay fever.
The method that extrapolated from seasonal influenza mortality data in
people under 65 years of age was limited in that it effectively considered no aspects of the epidemiology of the new pandemic influenza virus other than the age distribution -- that is, that it seems to affect younger age groups more than older age groups. Yet there is little information comparing the current pandemic strain with seasonal influenza strains in terms of mortality risk in this younger age group. Furthermore, the data from which the estimated range was derived may be outdated in that modern medical care has progressed since the early part of the period used in the particular US study [15] that the estimates were based on.
Although the Canadian epidemic appears to be waning, the method using the crude extrapolation of the course of this epidemic was very simplistic. Indeed, rather than being half complete, this epidemic wave could continue throughout the northern hemisphere summer and beyond.
These methods tended to focus on correcting for under-ascertainment of the denominator, yet there is also a potential bias from underascertainment of the numerator of the CFR. Particularly in the early stages of an epidemic, there will be a lag in reported deaths and other severe outcomes. Sophisticated statistical methods have been proposed for obtaining adjusted CFR estimates using data from the early phase of an epidemic [20], and these result in adjustment for various time lags and an upward shift of the CFR. However, such adjustments would probably have little effect on the estimates presented in this article which are based on data from country epidemics which have progressed well beyond their early stages (for example, the Canadian data). There is also the potential for under-recognition of deaths attributable to influenza in those with serious co-morbidities, but this can only be addressed by careful research studies and post-epidemic modelling to determine total excess deaths. Nevertheless, this bias might be relatively smaller in this pandemic where more deaths involve young people. Also, once the new influenza A(H1N1)v strain was recognised, there is likely to have been increased sensitivity for diagnosing influenza-related deaths (at least in developed countries where hospitalisation is likely to precede influenza-related death).
All of the presented methods have limitations and could be refined using additional data to provide more robust estimates. Ultimately, such estimates require enhanced surveillance, outbreak investigations in a range of settings, and carefully designed population studies, ideally with serological testing [21]. Additionally, the ranges of CFRs for disadvantaged populations in developed countries and for most of the population in developing countries are likely to be much higher than those estimated here, given likely differences in disease transmission, co-morbidity, access to antivirals and standards of medical care.
Conclusion
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We present several methods for provisionally estimating the plausible range for the CFR of the emerging influenza pandemic in developed countries. All methods used have significant limitations, but they collectively suggest that infection with this particular pandemic strain is likely to cause illness with a relatively low CFR compared to an earlier estimate and also to historical standards. A further reason for presenting this range of methods is to encourage data collection that can start to reduce the uncertainty around this important pandemic parameter.
References
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1. Fraser C, Donnelly CA, Cauchemez S, Hanage WP, Van Kerkhove MD,
Hollingsworth TD, et al. Pandemic potential of a strain of influenza A
(H1N1): early findings. Science 2009; 324(5934): 1557-61.
2. CDC. CDC telebriefing on investigation of human cases of novel influenza A (H1N1). 18 June 2009. Atlanta: CDC; 2009. Available from:
<http://www.cdc.gov/media/transcripts/2009/t090618.htm>.
3. CDC. Update on the novel influenza A H1N1 virus and new findings
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4. Lean G. UK swine flu toll is really 30 000, says leading scientist.
London: The Independent; 24 May 2009. Available from:
Link (<http://www.independent.co.uk/life-style/health-and-families/health-news/uk-swine-flu-toll-is-really-30000-says-leading-scientist-1690130.html>.)
5. Molinari NA, Ortega-Sanchez IR, Messonnier ML, Thompson WW, Wortley PM, Weintraub E, et al. The annual impact of seasonal influenza in the US: measuring disease burden and costs. Vaccine 2007; 25(27): 5086-96.
6. CDC. Interim guidance for clinicians on identifying and caring for
patients with swine-origin influenza A (H1N1) virus infection (4 May). Atlanta: CDC; 2009. Available from: <http://www.cdc.gov/h1n1flu/identifyingpatients.htm>.
7 WHO. Influenza A(H1N1) - update 54. 26 June 2009. Geneva: WHO; 2009.
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10. NYCDHMH. Health Department survey suggests that 7 per cent of New
Yorkers had flu-like illness in May (press release 10 June 2009). New York: NYCDHMH; 2009. Available from:
<http://www.nyc.gov/html/doh/html/pr2009/pr041-09.shtml>.
11. NYCDHMH. Health Department updates flu status (press release, 2 May
2009). New York: NYCDHMH; 2009. Available from:
<http://www.nyc.gov/html/doh/html/pr2009/pr021-09.shtml>.
12. United States Census Bureau. Population finder. Washington DC: US
Census Bureau; 2009. Available from:
<http://factfinder.census.gov/servlet/SAFFPopulation?_submenuId=population_0&_sse=on>.
13. Public Health Agency of Canada. FluWatch: June 14, 2009 to June 20,
2009 (Week 24). Public Health Agency of Canada. Ottawa; 2009. Available
from: <http://www.phac-aspc.gc.ca/fluwatch/08-09/w24_09/index-eng.php>.
14. CDC. CDC telebriefing on investigation of human cases of novel
influenza A (H1N1). 26 June 2009. Atlanta: CDC; 2009. Available from:
<http://www.cdc.gov/media/transcripts/2009/t090626.htm>.
15. Thompson WW, Weintraub E, Dhankhar P, Cheng PY, Brammer L, Meltzer MI, et al. Estimates of US influenza-associated deaths made using four
different methods. Influenza Other Respi Viruses 2009; 3(1): 37-49.
16. United States Census Bureau. Quick table (QT-P1A): age and sex for the total population: 1990. Washington, D.C.: US Census Bureau; 1990. Available from:
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17. Public Health Agency of Canada. Cases of H1N1 flu virus in Canada. 26 June 2009; 2009. Available from:
<http://www.phac-aspc.gc.ca/alert-alerte/swine-porcine/surveillance-archive/20090626-eng.php>.
18. Milne GJ, Kelso JK, Kelly HA, Huband ST, McVernon J. A small community model for the transmission of infectious diseases: comparison of school closure as an intervention in individual-based models of an influenza pandemic. PLoS One 2008; 3(12): e4005.
19. Miller MA, Viboud C, Balinska M, Simonsen L. The signature features of
influenza pandemics--implications for policy. N Engl J Med 2009; 360(25): 2595-8.
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Methods for estimating the case fatality ratio for a novel, emerging
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21. Lipsitch M, Riley S, Cauchemez S, Ghani AC, Ferguson NM. Managing and reducing uncertainty in an emerging influenza pandemic. N Engl J Med 28 May 2009; [E-pub ahead of print].
--
communicated by:
ProMED-mail
[The authors have indicated that their methods tended to focus on correcting for underascertainment of the denominator. All methods used have significant limitations, but they collectively suggest that infection with this particular pandemic strain is likely to cause illness with a relatively low CFR compared with an earlier estimate and also to historical standards. - Mod.CP]
******
[4] Tamiflu resistance - Japan
Date: Thu 2 Jul 2009
Source: Reuters News [edited]
Link (<http://www.reuters.com/article/internal_ReutersNewsRoom_ExclusivesAndWins_MOLT/idUSTRE5614TW20090702>)
Japan has confirmed its 1st case of a genetic mutation of the new H1N1
influenza that shows resistance to Tamiflu [oseltamivir], the main antiviral flu drug, a health ministry official said on Thursday [2 Jul 2009].
The World Health Organization has declared a global pandemic is under way from the virus, known as swine flu, which has so far been treatable with Tamiflu, made by Switzerland's Roche. Takeshi Enami, an official at Japan's health ministry, said that the patient's sensitivity to Tamiflu had yet to be tested.
The patient, who was confirmed in May 2009 with the H1N1 strain of the flu in the Osaka prefecture of western Japan, has since recovered, and no other cases of the new flu have been confirmed around the patient, Enami said. He could not confirm the age or the sex of the patient.
The 1st case of H1N1 that did not respond to Tamiflu was a patient in Denmark.
Earlier this week, WHO said that the case, revealed by Roche and Danish
officials on Monday [29 Jun 2009], was an isolated one and did not amplify the severity of the virus. Resistance to Tamiflu has been previously documented in the deadly bird flu virus H5N1 and seasonal H1N1 flu.
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communicated by:
ProMED-mail
[Dr Irene Lai of SOS International has provided the following information with regard to the 1st occurrence of Tamiflu-resistance (in Denmark). According to the press release from Denmark's State Serum Institute
(<http://www.ssi.dk/sw174.asp?PAGE=3D1&ArtNo=3D3651423>), the strain
isolated from the Danish patient remains sensitive to the alternate
neuraminidase inhibitor, zanamivir. In that case, the resistance arose in a person who was on post-exposure prophylaxis with Tamiflu [oseltamivir]. - Mod.CP]