Are US flu death figures more PR than science?

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