Are US flu death figures more PR than science?

Thompson et al. [1] highlight the correlation between “pneumonia and
influenza” estimated death rates and the percentage of samples positive
for influenza A(H3N2) viruses by week in United States from 1990 to 1998
(cf. Fig. 1, [1]). This correlation is not in itself inconsistent with the
hypothesis that other factors might substantially or even predominantly
contribute to the mortality seasonal burden. Apart from the respiratory
illnesses caused by the increase of environmental pollutants during the
winter season [2], it is worth remembering that “Cold weather alone causes
striking short term increases in mortality, mainly from thrombotic and
respiratory disease”, even without an influenza epidemic [3].

This is in agreement with the generally recognized circumstance that
“isolation of human influenza viruses in the blood has been reported only
rarely”[1] and that the immediate cause of death in almost all cases is
not the viral infection itself but an indirect “complication”, like
secondary bacterial pneumonia.

That there is a serious problem here for the conventional estimates
of the “pneumonia and flu” death rates is widely accepted. For instance,
one member of the Simonsen et al. team, Jonathan Dushoff, published a few
months ago a useful note emphasizing: “Approaching a consensus on the
health and mortality burden of influenza, and on the cause of winter
excess mortality in general, is an important scientific and public policy
goal. For this to happen, further progress is needed in several areas”,
and concluding: “The contribution of influenza to morbidity and mortality
– and, more broadly, cataloging the causes of daily and season excess
deaths and hospitalizations – remain as unresolved questions with
important scientific and public-health implications." ([4])

More should be done in the way of epidemiological research to assess
the relative weight of all plausible factors and to ascertain how
frequently the flu viruses are actually involved in the fatal outcomes.
Most importantly, it must be pointed out that the so-called
“complications” are also linked to influenza-like illness (ILI), which is
“clinically indistinguishable from influenza” [6]. ILI, defined as a
symptomatic syndrome, is in fact caused by hundreds of different agents,
including RSV (respiratory syncytial virus), picornaviruses,
parainfluenza, hMPV (human metapneumovirus), coronaviruses etc.(see e.g.
[5]).

Now, an important public health issue arises at this point, since
vaccine is protective only against two of the agents causing symptomatic,
clinical flu. It follows that even if clinical flu were the underlying
cause of seasonal differences in “pneumonia and influenza” death rates,
this would not in itself provide a solid ground for the mass flu
vaccination campaigns.

It is interesting that Doshi’s critics ([1], [9]) seem to evade the
crucial issue of the extent the flu vaccines are succeeding in preventing
clinical flu. The results of two recent meta-analyses are by no means
encouraging ([6], [7]). In [6], which deals with 65+ individuals (one of
the high priority groups for mass vaccination according to the CDC), it is
stated that “the usefulness of vaccines on the community [as opposed to
long-term care facilities] is modest”; in [7] the effectiveness of
vaccines in children younger than 2 (inactivated vaccines) or older than 2
(both inactivated and live attenuated vaccines) was found to be “low”. One
of the main reasons given to explain these disappointing results is that
“vaccines are specifically targeted at influenza viruses and are not
designed to prevent other causes of influenza-like illness”[7].

In an interview the senior author of [6] and [7], Dr. Tom Jefferson,
put the issue in a refreshingly explicit way: "The vaccine doesn't work
very well at all. [...] Vaccines are being used as an ideological weapon.
What you see every year as the flu is caused by 200 or 300 different
agents with a vaccine against two of them. That is simply nonsense."[8]

So it appears that the picture, not only at a theoretical level but
even as regards “public health efforts”[9], is much more complicated than
that provided by the NIH and CDC representatives.

References

[1] Thompson WW, Shay D, Weintraub E, Brammer L, Meltzer M, Cox N,
Bresee J. "Are estimates of influenza-associated deaths in the US really
just PR?". BMJ [rapid response] (18 Jan 2006)
<http://bmj.com/cgi/eletters/331/7529/1412#126308> (retrieved 23 Jan
2006).

[2] Crowe D. "The Peril of Correlation". BMJ [rapid response] (14 Jan
2006) <http://bmj.com/cgi/eletters/331/7529/1412#126100> (retrieved
23 Jan 2006).

[3] Donaldson G. C., W R Keatinge W. R., “Excess winter mortality:
influenza or cold stress? Observational study”, BMJ, Vol. 324, pp.89-90
(12 Jan 2002)
<http://bmj.bmjjournals.com/cgi/content/full/324/7329/89>

[4] Dushoff J. “Assessing influenza-related mortality: comment on
Zucs et al.”, Emerging Themes in Epidemiology, 2005, 2:7,
doi:10.1186/1742-7622-2-7
<http://www.ete-online.com/content/2/1/7>

[5] Kelly H., Birch C. “The causes and diagnosis of influenza-like
illness”, Australian Family Physician Vol. 33, No. 5, May 2004, pp. 305-9
<http://www.racgp.org.au/document.asp?id=12937>

[6] Jefferson T., Rivetti D., Rivetti A., Rudin M., Di Pietrantonj
C., Demicheli V., “Efficacy and effectiveness of influenza vaccines in
elderly people: a systematic review”, Lancet, Vol. 366, pp. 1165-74 (1 Oct
2005).

[7] Jefferson T., Smith S., Harnden A., Rivetti A, Di Pietrantonj C.,
“Assessment of the efficacy and effectiveness of influenza vaccines in
healthy children: systematic review”, Lancet, Vol. 365, pp. 773-80 (26 Feb
2005).

[8] Gardner A., “Flu Vaccine Only Mildly Effective in Elderly”,
<http://www.healthfinder.gov/news/newsstory.asp?docID=528105>
(retrieved 24 Jan 2006)

[9] Simonsen L, Taylor R, Viboud C, Dushoff J, Miller M. "US Flu
Mortality Estimates Are Based on Solid Science". BMJ [rapid response]
(2006) <http://bmj.com/cgi/eletters/331/7529/1412#125778> (retrieved
11 Jan 2006).

Competing interests:
None declared

In the 10 December 2005 BMJ, Mr. Doshi states that estimates of
influenza-associated mortality made by the U.S. Centers for Disease
Control and Prevention (CDC) are flawed, and he suggests that they are
deliberately exaggerated in order to increase the use of influenza
vaccine. The author has misunderstood the methods used to estimate
influenza-associated deaths, and made several errors of fact we would like
to correct.

He correctly notes that estimates of U.S. deaths associated with the
1968-9 influenza A(H3N2) pandemic total 34,000 people [1], while current
annual estimates of influenza-associated mortality are ~36,000. [2] He
suggests that these estimates do not make sense, and he states that a
pandemic must result in more deaths than an average inter-pandemic
influenza season. This is not true because pandemics, like interpandemic
influenza seasons, vary in severity, by the age groups most affected, the
size of the populations affected and in their length. Therefore, it cannot
be assumed a priori that pandemics will cause more mortality than
interpandemic seasons. The author should be reminded that the 1968-9
pandemic was not particularly severe, with lower rates of mortality
compared with both the 1918 and the 1957-8 pandemics. Leading influenza
experts have postulated that reduced mortality during the 1968-9 pandemic
may have been due to pre-existing population immunity to the N2
neuraminidase of the pandemic virus. Since the last pandemic, ~90% of all
influenza-associated deaths have occurred among those aged >65 years.
Risk is not constant among the elderly. Those aged >85 years are 19
times more likely to suffer from an influenza-associated respiratory and
circulatory death compared with persons aged 65-69 years. [3] The steady
aging of the U.S. population along with the predominance of A(H3N2)
seasons during the 1990’s (i.e., six of the nine season were A(H3N2)
predominant seasons) and the increasing length of the influenza seasons
[2;4] have all contributed to the current estimates, with more influenza-
associated deaths occurring during annual influenza seasons than during
the 1968-9 pandemic.

Mr. Doshi suggests that the 12% increase among U.S. residents aged
>65 years from 1990 through 2000 indicates the aging of the population
could not be responsible for a significant increase in influenza-
associated deaths. However, an earlier estimate of 20,000 annual influenza
-associated deaths was made using data from 1972 through 1992 [5], while
our more recent estimate of 36,000 annual deaths is derived from an
analysis of deaths from 1990-1999. (2) From 1972 through 1999, the number
of persons aged >65 years increased 64% and the number of persons aged
>85 years more than doubled. [6] Thus, the rapid aging of the US
population between these periods can indeed explain, in part, why
influenza-associated deaths have increased.

We estimate that ~36,000 influenza-associated deaths occurred from
the 1990-91 through the 1998-99 influenza seasons among those with an
underlying cause of death listed as a respiratory or a circulatory
disease. Of these deaths, we estimate that ~8100 occurred among those with
an underlying cause of death categorized as pneumonia and influenza. Thus,
pneumonia and influenza deaths are a subset of respiratory and circulatory
deaths. Influenza may precipitate deaths from other causes, such as
cardiovascular diseases, as first appreciated during the 1957-8 pandemic.
[7] It has been recognized for many years that influenza is infrequently
listed on death certificates [8] and testing for influenza infections has
been rare, particularly among the elderly at greatest risk. In addition,
some deaths, particularly in the elderly, are associated with secondary
complications of influenza (including bacterial pneumonias). For these
reasons, statistical modeling strategies have been used to estimate
influenza associated deaths for many decades, both in the United States
and the United Kingdom [2;5;9-13]. It is also important to recognize the
variability of influenza seasons; during the period over which 36,000
annual deaths were estimated, on average, the range in annual estimates
was from 17,000 to 51,000 deaths.

Contrary to the suggestion that the number of influenza-associated
deaths has been exaggerated, CDC’s models provide a conservative estimate
of such deaths. Our estimate of 36,000 influenza-associated deaths with an
underlying respiratory or circulatory cause represents <_3 of="of" all="all" these="these" deaths.="deaths." we="we" control="control" for="for" seasonal="seasonal" variations="variations" in="in" deaths="deaths" and="and" the="the" circulation="circulation" respiratory="respiratory" syncytial="syncytial" virus="virus" a="a" viral="viral" pathogen="pathogen" that="that" has="has" increasingly="increasingly" been="been" recognized="recognized" as="as" an="an" important="important" cause="cause" wintertime="wintertime" morbidity="morbidity" mortality.="mortality." _14="_14" consistent="consistent" relationship="relationship" between="between" influenza="influenza" weekly="weekly" peaks="peaks" mortality="mortality" is="is" impossible="impossible" to="to" ignore="ignore" explaining="explaining" decades="decades" research="research" using="using" statistical="statistical" methods="methods" estimate="estimate" p="p"/> Finally, Dr. Rosenthal of Harvard University Health Services is
quoted as suggesting that individuals infected with influenza die of
secondary bacterial pneumonias, and not viremia. We agree that individuals
infected with influenza typically do not die of viremia. Isolation of
human influenza viruses in the blood has been reported only rarely. [15]
However, elderly individuals in particular are at risk of serious
morbidity from bacterial pneumonias and many other direct and indirect
complications after influenza infections. Furthermore, a recent report
documented that 153 children died with laboratory-confirmed influenza
virus infections in the United States during the 2003-04 influenza season.
[16] Approximately half of these children did not receive a clinical or
autopsy diagnosis of pneumonia. Their deaths may have resulted from direct
effects of viral pathogenicity, host responses to infection, or a
combination of factors, including exacerbation of a variety of underlying
conditions, including chronic neurologic diseases. [17]

We stand by our estimate that during recent influenza seasons,
approximately 36,000 influenza-associated deaths occur annually in the
United States. Similar estimates were published by the National Institutes
of Health and academic investigators using different statistical
methods.[2;13] Influenza remains the most important cause of vaccine-
preventable deaths in the United States. Developing improved prevention
strategies for influenza depends on reasonable and well-documented disease
burden estimates. We encourage constructive dialogue on how best to refine
these estimates.

Figure 1. Pneumonia and Influenza Death Rates and Percent of Samples Positive for Influenza A(H3N2) viruses by Week in United States, 1990-1998

William W. Thompson, David K. Shay, Eric Weintraub, Lynnette Brammer,
Martin Meltzer, Nancy J. Cox, and Joseph S. Bresee, US Centers for Disease
Control and Prevention, Atlanta, GA 30333.

Reference List

[1] Noble GR. Epidemiogical and clinical aspects of influenza. Basic
and Applied Influenza Research. Boca Raton, FL: CRC Press, 1982: 11-50.

[2] Thompson WW, Shay DK, Weintraub E, Brammer L, Cox N, Anderson LJ
et al. Mortality associated with influenza and respiratory syncytial virus
in the United States. JAMA 2003; 289(2):179-186.

[3] Thompson WW, Shay DK, Weintraub E, Brammer L, Cox NJ, Fukuda K.
Age-specific estimates of US influenza-associated deaths and
hospitalizations. In: Kawaoka Y, editor. Amsterdam: Elsevier Science,
2004: 316-320.

[4] Thompson WW, Shay DK, Weintraub E, Brammer L, Cox N, Anderson LJ
et al. In Reply to Letters. JAMA 2003; 289(19):2500-2502.

[5] Simonsen L, Clarke MJ, Williamson GD, Stroup DF, Arden NH,
Schonberger LB. The impact of influenza epidemics on mortality:
introducing a severity index. Am J Public Health 1997; 87(12):1944-1950.

[6] U.S.Bureau of the Census. Intercensal Estimates of the Population
by Age, Sex, and Race: 1970-2000. Washington DC: 2005.

[7] Eickoff TC, Sherman IL, Serfling RE. Observations on excess
mortality associated with epidemic influenza. JAMA 1961; 176:776-782.

[8] Wiselka M. Influenza: diagnosis, management, and prophlaxis. BMJ
1994; 308:1341-1345.

[9] Serfling RE. Methods for Current Statistical Analysis of Excess
Pneumonia-Influenza Deaths. Public Health Rep 1963; 78(6):494-505.

[10] Nicholson KG. Impact of influenza and respiratory syncytial
virus on mortality in England and Wales from January 1975 to December
1990. Epidemiol Infect 1996; 116(1):51-63.

[11] Tillett HE, Smith JW, Clifford RE. Excess morbidity and
mortality associated with influenza in England and Wales. Lancet 1980;
1(8172):793-795.

[12] Dushoff J, Plotkin JB, Viboud C, Earn DJ, Simonsen L. Mortality
due to Influenza in the United States--An Annualized Regression Approach
Using Multiple-Cause Mortality Data. Am J Epidemiol 2005.

[13] Simonsen L, Reichert TA, Viboud C, Blackwelder WC, Taylor RJ,
Miller MA. Impact of Influenza Vaccination on Seasonal Mortality in the US
Elderly Population. Arch Intern Med 2005; 165(3):265-272.

[14] Falsey AR, Hennessey PA, Formica MA, Cox C, Walsh EE.
Respiratory syncytial virus infection in elderly and high-risk adults. N
Engl J Med 2005; 352(17):1749-1759.

[15] Stanley ED, Jackson GG. Viremia in asian influenza. Trans Assoc
Am Physicians 1966; 79:376-387.

[16] Bhat N, Wright J, Broder K, et al. Influenza-associated deaths
among children in the United States, 2003-2004. N Engl J Med 2005;
353:2559-2567.

[17] Dolin R. Influenza-interpandemic as well as pandemic disease. N
Engl J Med 2005; 353:2535-2537.

Competing interests:
None declared

The influenza virus just don't get no respect, at least according to its
afficionados at the RKI and CDC. There are many flaws with their argument,
however, that 'surplus' deaths at times when flu is common are due to the flu.
There may be a correlation, but there may not be causation.

Epidemics of respiratory disease tend to occur in winter months, making
the weather a plausible confounding factor. Winter conditions vary from year
to year, and bad winters will increase the use of fossil fuels, and will result in
automobiles being driven in cold weather more often, resulting in less
efficient combustion. People will also spend more time indoors.

The Zucs et al analysis of excess mortality in Germany cited by RKI (1)
ignores any such non-infectious factors that might lead to the increased
deaths. The definition of ‘flu seasons’ as an excess incidence of
doctor visits and hospitalizations due to acute respiratory
‘infections’ (in the absence of testing for viral causation in the
vast majority of cases) leads to a tautology. More illness will almost certainly
be associated with more deaths, but there is no proof that the excess deaths
are due to the flu or infectious diseases. Just calling it an ‘Influenza
Season’ does not make it one.

Furthermore, the choice of samples by private physicians performing
surveillance for the RKI are not random (1). The perception of doctors that
there is a lot of flu around might well be influenced by newspaper reports and
the RKI itself, perhaps even by the weather. This might lead to the submission
of more samples, resulting in an amplification of concern.

That there might be a hidden epidemic of pollution-induced respiratory
disease is plausible when we consider that Dr. Peter Joseph of the University
of Pennsylvania found higher levels of MTBE (an oxygenate) mixed into
gasoline in Philadelphia in the winters of the early 1990s was associated with
large increases in physician visits for a variety of respiratory conditions,
including upper respiratory infections (compared with earlier years and
summers, when rates of MTBE in gasoline are lower). Rates of other
conditions did not change dramatically. (2)

Changes in the formulation of gasoline are easily overlooked. But the
Philadelphia study shows that they may have a large impact on human health,
especially when combined with weather factors (e.g. higher or lower winds
than normal, temperature inversions, extremely low temperatures).

The German excess mortality study (1) does not consider any
environmental causes for peaks in mortality, particularly in the winters of
1989/90 and 1995/96. Information on air quality factors such as
SO₂, CO, O₃, NO₂ and other
common air pollutants (3) (4) should have been included in a multi-variate
analysis.

Flu scientists have no qualms about claiming that their favourite virus is
really the underlying cause responsible for the deaths of many people with
certificates stating bacterial pneumonia, but they seem loath to consider that
upper respiratory tract infections (if they are even infections at all) could have
a non-infectious underlying cause.

1. Zucs P, Buchholz U, Haas W, Uphoff H. Influenza associated excess
   mortality in Germany, 1985-2001. Emerging Themes in Epidemiology
   2005;21;2(1):6.
2. Joseph PM et al. Visits to physicians after the oxygenation of gasoline in
   Philadelphia. Arch Environ Health. 2002 Mar-Apr; 57(2): 137-54.
3. What causes air pollution? UK National Air Quality Information Archive.
   http://
   www.airquality.co.uk/archive/what_causes.php
4. Six Principal Pollutants. US Environmental Protection Agency. http://www.epa.gov/
   airtrends/sixpoll.html

Competing interests:
None declared