Published Date: 2009-05-15 19:00:11
Subject: PRO/AH/EDR> Influenza A (H1N1) - worldwide (29)
Archive Number: 20090515.1824
INFLUENZA A (H1N1) - WORLDWIDE (29)
A ProMED-mail post
ProMED-mail is a program of the
International Society for Infectious Diseases
 Swine H1N1 clarification
 WHO decline to assign severity scale
 Reproductive rate estimate
 Swine H1N1 clarification
Date: Thu 14 May 2009
From: Ian Brown
re: Pathogenesis of swine influenza virus reported as part  of Influenza
A (H1N1) - worldwide (26), archived as 20090514.1798.
The above post quotes a study with H1N1 in pigs conducted by Sreta D,
Kedkovid R, Tuamsang S, Kitikoon P,Thanawongnuwech R. Pathogenesis of swine
influenza virus (Thai isolates) in weanling pigs: an experimental trial.
It should be clarified that the H1N1 virus used in this study is a local
strain from 2005 with a haemagglutinin gene derived from classical swine
H1N1 virus. Therefore whilst there may be some genetic characteristics in
this virus, with some similarity to the current emergent influenza (A) H1N1
human virus, it is not the same. The study whilst of interest does confirm
symptoms and pathology consistent with numerous other published studies
using this virus subtype in pigs.
Veterinary Laboratories Agency (VLA)
[ProMED-mail thanks Ian Brown for this clarification. - Mod.CP]
 WHO declines to assign severity scale
Date: Wed 13 May 2009
Source: Medscape Infectious Diseases [edited]
<http://www.medscape.com/viewarticle/702773?src=rss> [membership required]
WHO declines to assign severity scale
The World Health Organization (WHO) said today that it is unable to assign
a severity scale to the influenza A (H1N1) epidemic for the reason that
disease characteristics and responses of countries vary. Dr Sylvie Briand,
with the WHO Global Influenza Programme, spoke today [13 May 2009] at a
media briefing in Geneva. According to Dr Briand, the WHO pandemic alert
level phases are mainly based on the transmission of the virus and its
geographical spread, while "the severity itself is assessed by other
means." Currently, the pandemic alert level has remained at level 5 out of
6, indicating community-based outbreaks in a single WHO region.
The severity of a potential pandemic is based on 3 factors: "the
[characteristics of the] virus, the vulnerability of the population, and
the intervention we can put in place to reduce the impact of severe
disease," Dr Briand said. Assessing severity is important for helping
countries determine their response to an outbreak, but at a global level, a
severity index is "not very helpful" because "severity will vary from place
to place," she said. Dr Briand pointed out that while wealthier countries
may have the resources to mount a more effective response to an outbreak,
some developing parts of the world such as West Africa are already used to
coping with epidemics and may be at an advantage due to having healthcare
systems in place. This is referred to as the "resilience" of a country, she
Dr Briand also emphasized that oseltamivir and zanamivir are effective
against this novel H1N1 strain, which is in contrast to the seasonal
influenza strain, which is resistant to these antiviral drugs.
News reports are circulating regarding a claim by an eminent Australian
influenza researcher that human error may have been involved in creating
this strain. Adrian Gibbs, 75, said in an interview that he intends to
publish a report suggesting the new strain may have accidentally evolved in
eggs that scientists use to grow viruses and drugmakers use to make
vaccines. WHO spokesperson Gregory Hartl said the WHO is looking into
evidence regarding these claims, but "it is way too soon to say anything."
He added that the WHO's main task is to assess the current risk level and
to "help member states to be prepared to respond."
Yesterday CDC issued a dispatch in the Morbidity and Mortality Weekly
Report on novel influenza A (H1N1) virus infections in pregnant women. As
of 10 May 2009, 20 probable or confirmed cases had been reported in
pregnant women. Of the women, 3 have been hospitalized and 1 woman died.
The CDC is recommending that pregnant women with confirmed, probable, or
suspected novel influenza A (H1N1) virus infection should receive antiviral
treatment for 5 days. Interim guidance on issues specific to pregnant women
and the novel influenza A (H1N1) virus is available at
[byline: Emma Hitt]
 Reproductive rate estimate
Date: Thu 14 May 2009 [edited]
Source: Eurosurveillance, Vol. 14, Issue 19 [edited]
A preliminary estimation of the reproduction ratio for new influenza
A(H1N1) from the outbreak in in Mexico, March-April 2009
As of 12 May 2009, 5251 cases of the new influenza A(H1N1) have been
officially reported to the World Health Organization (WHO) from 30
countries, with most of the identified cases exported from Mexico where a
local epidemic has been going on for the last 2 months. Sustained
human-to-human transmission is necessary to trigger influenza pandemic and
estimating the reproduction ratio (average number of secondary cases per
primary case) is necessary for forecasting the spread of infection. We use
2 methods to estimate the reproduction ratio from the epidemic curve in
Mexico using 3 plausible generation intervals (the time between primary and
secondary case infection). As expected, the reproduction ratio estimates
were highly sensitive to assumptions regarding the generation interval,
which remains to be estimated for the current epidemic. Here, we suggest
that the reproduction ratio was less than 2.2 3.1 in Mexico, depending on
the generation interval. Monitoring and updating the reproduction ratio
estimate as the epidemic spreads outside Mexico into different settings
should remain a priority for assessing the situation and helping to plan
public health interventions.
As of 12 May 2009, 5251 cases of the new influenza A(H1N1) have been
officially reported to WHO from 30 countries [1,2]. 2 parameters must be
estimated for this new virus using mathematical and computational models:
the reproduction ratio (R), which measures the average number of secondary
cases per primary case; and the generation interval, which measures the
average time between infection in a primary case and its secondary cases.
The larger the reproduction ratio, the higher the required efficacy of
public health interventions . Here we use 2 different methods to provide
preliminary estimates of R for the outbreak in Mexico.
We used the daily incidence data from 11 March to 2 May 2009 as reported by
the Mexican health authorities 
The data consisted in 1364 confirmed cases given as daily counts.
2 different approaches were used to estimate R:
(1) M1 - intrinsic growth rate : the growth rate of the epidemic is
estimated by Poisson regression over a given time interval and transformed
to R using Laplace transform of the generation interval distribution. The
assumptions are the exponential growth of the epidemic and known generation
interval. After visual inspection of the epidemic curve, all periods
starting before 20 Apr 2009 and ending after this date, more than 5 days
long, were explored. Goodness of fit of the exponential model was judged by
the deviance Rsquared measure.
(2) M2 - real time estimation : a daily reproduction ratio R(t) is
determined by averaging the number of secondary cases over all possible
chains of transmissions compatible with the epidemic curve. This approach
assumes no imported cases, equiprobability of all chains of transmission
compatible with the data and known generation interval. The 2 methods
require full specification of the generation interval distribution.
As no information regarding the actual generation interval in Mexico is
available, we used 3 plausible candidate values of the generation interval
(denoted GI) derived from different approaches: one (denoted as PAN)
obtained from household studies from the 1957 and 1968 pandemics , one
derived from viral excretion in experimental influenza infection (denoted
as VIR) , and a hypothetical distribution introduced in Elveback
(denoted ELV) . Their values with mean standard deviation (SD) were the
following: PAN = 3.1 +/- 1.9 days; VIR = 2.6 +/- 1 day; ELV = 4.6 +/- 1.5 days.
When using M1, the period starting on 9 Apr 2009 and ending on 24 Apr 2009
yielded the best fit for exponential growth, with daily rate r = 0.30 [CI95
per cent 0.28-0.34]. [The Epidemic curve of the outbreak of new influenza
A(H1N1) in Mexico and fitted exponential growth over the period 9 to 24 Apr
2009 is illustrated as a figure in the original text]. The corresponding R
was 2.2 [2.1, 2.4] for the PAN GI; 2.6 [2.4, 2.8] for the VIR GI; and 3.1
[2.9, 3.5] for the ELV GI. Overall, the differences in goodness of fit were
small. The reproduction ratio decreased as the duration of the period used
to estimate the growth rate increased: for the PAN GI, the maximum was 2.7
(8 days) and the minimum 2.0 (17 days).
With method M2, all 3 generation intervals led to similar profiles of R(t)
with time: R(t) was around 1 up to 8 Apr 2009 then increased rapidly during
the 2 following weeks. [Estimates of the daily reproduction ratio R(t) in
the outbreak of new influenza A(H1N1) in Mexico is illustrated in the text
by a figure]. The magnitude of R depended on the generation interval: the
maximum value was 2.1 (18 April) for the PAN GI; 4.0 (11 April) for the VIR
GI; and 3.2 (17 April) for the ELV GI.
[The epidemic growth rates estimated for the new influenza A(H1N1) epidemic
in Mexico and corresponding reproduction ratio estimates calculated with
method M1 are presented as a table in the original text.]
Obtaining timely estimates of the reproduction ratio is crucial for
deciding on public health interventions in case of a pandemic. In this
respect, our analysis suggests that the maximum reproduction ratio was <
2.2 (for PAN GI); < 2.6 (for VIR GI) and < 3.1 (for ELV GI) during the
outbreak in Mexico, subject to the following limitations.
Firstly, the epidemic curve was obtained by retrospective testing of
samples, so that new cases may still be added. Indeed, for the same period
(11 Mar 2009 to 26 Apr 2009), there were 97 confirmed cases in the report
published on 1 May 2009, 682 in the 5 May 2009 report, and 803 in the 8 May
2009 report. With each new version of the epidemic curve, the reproduction
ratio estimates grew smaller. The increase in the epidemic curve coincided
with the setup of enhanced surveillance (starting from 16 Apr 2009),
suggesting improved case-finding with time. This notification/surveillance
bias leads to overestimation of the reproduction ratio, as a larger number
of late cases would be attributed to fewer earlier cases; on the other
hand, however, the effect of public health interventions (closure of
schools, restaurants and other public places, etc.) may affect the results
in the opposite direction.
The assumptions required to estimate the reproduction ratio must also be
taken into account. As already mentioned, the generation interval is
unknown for the outbreak in Mexico, but of major importance for
quantitative estimates. This illustrates the importance of estimating as
soon as possible the generation time distribution to calibrate estimates of
R . As expected, longer generation time generally led to larger
estimated R . We believe the PAN GI should be favoured in the
interpretation of the results, as it was determined from household data
during past influenza pandemics.
A 2nd limitation arises from arbitrary deciding which part of the epidemic
curve displayed exponential growth, namely a minimum duration (5 days), a
starting and ending date. Stochastic variations, especially in small time
series, may cause large uncertainties in the estimates . Observing that
the real time reproduction ratio M2, which does not rely on the exponential
growth assumption, yielded smaller reproduction ratio estimates, suggests
that method M1 yielded upper bound estimates.
A comprehensive analysis of all available data has independently led to the
range 1.4-1.6 for the reproduction ratio . At least 2 factors
contribute to this substantially lower estimate: underreporting was
explicitly taken into account and reduced the reproduction ratio, and the
generation interval, estimated from the actual epidemic, seems to have been
much shorter than considered here (mean 1.9 days).
Although sensitive to all uncertainties discussed above, our early
estimates show that the reproduction ratio in Mexico was in a range similar
to that of past influenza pandemics [12,13].
1. WHO. Influenza A(H1N1) - update 25. 12 May 2009. Available from:
2. European Centre for Disease Prevention and Control. ECDC Situation
Report. Influenza A(H1N1) infection. 12 May 2009. Available from:
3. Ferguson NM, Cummings DA, Fraser C, Cajka JC, Cooley PC, Burke DS.
Strategies for mitigating an influenza pandemic. Nature 2006; 442(7101):
4. Ministry of Health of Mexico. Situación actual de la epidemia [Current
epidemic situation]. 8 May 2009. Available from:
[at the time of posting (15 May 2009) this URL is unavailable, but a
current bulletin can be accessed
5. Wallinga J, Lipsitch M. How generation intervals shape the relationship
between growth rates and reproductive numbers. Proc Biol Sci 2007;
6. Cauchemez S, Boelle PY, Donnelly CA, Ferguson NM, Thomas G, Leung GM, et
al. Real-time estimates in early detection of SARS. Emerg Infect Dis 2006;
7. Ansart S, Boelle PY, Cauchemez S, Legrand J, Carrat F, Ferguson N, et
al. Generation interval and reproduction number for influenza: a review.
Technical report. Universite Pierre et Marie Curie: Paris; 24 April 2009.
8. Carrat F, Vergu E, Ferguson NM, Lemaitre M, Cauchemez S, Leach S, et al.
Time lines of infection and disease in human influenza: a review of
volunteer challenge studies. Am J Epidemiol 2008; 167(7): 775-85.
9. Elveback LR, Fox JP, Ackerman E, Langworthy A, Boyd M, Gatewood L. An
influenza simulation model for immunization studies. Am J Epidemiol 1976;
10. Chowell G, Nishiura H, Bettencourt LM. Comparative estimation of the
reproduction number for pandemic influenza from daily case notification
data. J R Soc Interface 2007; 4(12): 155-66.
11. Fraser C, Donnelly CA, Cauchelmes S, Hanage WP, Van Kerkhove MD,
Hollingsworth TD, et al. Pandemic potential of a strain of influenza A
(H1N1): early findings. Published 11 May 2009 on Science Express. DOI:
10.1126/science.1176062. Available from:
12. Mills CE, Robins JM, Lipsitch M. Transmissibility of 1918 pandemic
influenza. Nature 2004; 432(7019): 904-6.
13. Gani R, Hughes H, Fleming D, Griffin T, Medlock J, Leach S. Potential
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[byline: P Y Boelle1,2, P Bernillon3, J C Desenclos3, At:
1) INSERM, Institut national de la sante et de la recherche medicale
(National Institute of Health and Medical Research), U707, Paris, France
2) Universite Pierre et Marie Curie - Paris 6, UMR S 707, Paris, France
3) Institut National de Veille Sanitaire (Institute for Public Health
Surveillance, InVS), Saint-Maurice, France
[The estimate of the reproduction ratio arrived at by Boelle and colleagues
is somewhat higher than that of Fraser and colleagues reported previously
in ProMED-mail (see: part  of Influenza A (H1N1) - worldwide (23)
archived as 20090511.1764), but is in line with that observed in past
influenza virus pandemics. Further refinement of these analyses is
essential and must remain a priority for assessing the epidemic situation
and helping to plan public health interventions. - Mod.CP]