The NEW ENGLA ND JOURNAL of MEDICINE

Perspective february 14, 2013

Epidemic Influenza — Responding to the Expected

but Unpredictable
Joseph Bresee, M.D., and Frederick G. Hayden, M.D.

I n the United States, influenza viruses can be count-

ed on to cause outbreaks sometime between fall and
spring each year. However, the timing and severity of
text of this article at NEJM.org).
The number of cases of influenza-
like illness has already exceeded
the baseline for 7 weeks this sea-
these epidemics and the distribution of circulating son, and 48 states reported wide-
spread activity during the second
viruses are highly variable and or B viruses — predominated. week of January. Because indica-
difficult to predict (see figure). During an average influenza sea- tors of severe disease lag behind
For example, according to the son, there are 12 weeks during indicators of influenza activity in
Centers for Disease Control and which the rates of influenza-like general, it’s too early to know how
Prevention (CDC), the estimated illness exceed the level that the severe this season will be, but in-
number of influenza-associated CDC considers the national base- fluenza-associated hospitalizations
deaths varies from 3000 to 48,000 line, but during the 2011–2012 and deaths are already increasing
during a seasonal U.S. outbreak. season, there was only 1 week rapidly, particularly among per-
The past two seasons exem- when the rate reached the base- sons 65 years of age or older.
plify this unpredictability. The line level, and only four states re- We expect annual winter epi-
2011–2012 U.S. influenza season ported high levels of activity dur- demics in temperate regions, al-
was one of the mildest in the ing the season. This season, by though circulation patterns for
past two decades, even though contrast, the CDC is reporting the influenza virus are even more
influenza A(H3N2) viruses — a earliest influenza season since complex and prolonged in tropi-
subtype generally as- 2003–2004, when an antigeni- cal and subtropical parts of the
An interactive sociated with higher cally drifted seasonal H3N2 sub- world. The fundamental causes
graphic showing
regional rates of rates of complica- type influenza virus emerged as of seasonal epidemics, and of the
influenza is available tions and death than the dominant strain (see interac- variability in their timing and se-
at NEJM.org seasonal A(H1N1) tive graphic, available with the full verity, remain incompletely under-

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PERSPE C T I V E Epidemic Influenza — Expected but Unpredictable

8
No. of
Deaths
7 Predominant among
Influenza Season Virus Children
2012–2013 H3N2 29
6
Visits for Influenza-like Illness (%)

(current)
2011–2012 H3N2 34
5 (mild)
2009–2010 pH1N1 282
(pandemic)
4 2007–2008 H3N2 88
(moderately
severe)
3 2003–2004 H3N2 153
National baseline (moderately
severe)
2
2002–2003 B/H1N1 NA
(moderate)
1

0
40
42
44
46
48
50
52
2
4
6
8
10
12
14
16
18
20
22
24
26
28
30
32
34
36
38
40
Week

Percentages of Patient Visits for Influenza-like Illness and Number of Reported Deaths among Children for the 2012–2013 Season
to Date and for Selected Previous Seasons.
Data are from the U.S. Outpatient Influenza-like Illness Surveillance Network, Centers for Disease Control and Prevention (http://
www.cdc.gov/flu/weekly/fluactivitysurv.htm). Data for 2012–2013 are through January 12, 2013. NA denotes not available.

stood but probably include popula- fective), antiviral susceptibility, or es from other respiratory viruses.
tion factors (prevalence of specific other characteristics. On the vac- A recent meta-analysis showed that
immunity to circulating strains, cine front, in 2010, the United the median efficacy of seasonal
nutritional status, vitamin D lev- States adopted a policy recom- inactivated influenza vaccine in
els), behavioral factors (crowding, mending annual influenza-vaccine young and middle-aged adults was
school openings, air travel), viral administration for everyone 62%, but it varied considerably
factors (antigenicity, virulence, 6 months of age or older. Ontario, from season to season (range, 16
transmissibility), and environmen- Canada, initiated a universal in- to 76%).1 Live attenuated vaccine
tal factors (humidity, tempera- fluenza-vaccination program a de­ was shown to have greater efficacy
ture). Recent cases of swine-origin cade earlier, and ecologic studies in children, though not in adults.
A(H3N2)-variant infections in the have revealed benefits in terms of This season, circulating influ-
United States and of avian reduced mortality and indexes of enza strains are antigenically
A(H5N1) infections in other coun- health care utilization associated similar to the vaccine strains,
tries further highlight the chal- with seasonal influenza. Although except for one influenza B lin-
lenges of influenza prevention. influenza-vaccine coverage in the eage not in the vaccine: approxi-
We address influenza epidem- United States has increased, less mately 90% of strains character-
ics with both public health and than half the population receives ized by the CDC have been
specific pharmacologic interven- the vaccine every year, and each similar to the chosen vaccine vi-
tions, primarily vaccination and, season apparent vaccine failures ruses. Early data from a case–
for ill persons, treatment. Conse- are reported. Such failure proba- control study indicated that the
quently, a key question about sea- bly reflects the incomplete effec- estimated effectiveness of this
sonal outbreaks is whether the tiveness of current vaccines, the season’s vaccine was 62% (95%
circulating virus or viruses have high incidence of influenza infec- confidence interval, 51 to 71%)
changed, with regard to antige- tion in the population, and the overall.2 Since the current season
nicity (rendering vaccines less ef- presence in vaccinees of illness- may extend some months, increas-

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The New England Journal of Medicine

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PERSPECTIVE
ing immunization coverage now
with a vaccine providing moderate
protection should mitigate the ef-
fects of the epidemic.
Various strategies have been
employed to enhance the effec-
tiveness of seasonal inactivated
vaccine, especially in elderly and
other high-risk groups. These in-
clude the recent approval by the
Food and Drug Administration
(FDA) of quadrivalent vaccines
containing two B strains (one
from each lineage); these vaccines
are expected to be introduced into
clinical practice next season. In
addition, vaccine immunogenicity
can be enhanced by use of oil-
in-water adjuvants such as MF59
or AS03. These adjuvants were
incorporated into monovalent
A(H1N1)pdm09 vaccines in other
countries, and an MF59-adjuvant-
ed seasonal vaccine was shown to
have greater efficacy in infants
than nonadjuvanted vaccine.3 An
AS03-adjuvanted A(H5N1) vaccine
has been submitted for approval
in the United States. Immunoge-
nicity can also be enhanced by
increasing a vaccine’s hemagglu-
tinin antigen content. One vac-
cine with quadruple the standard
hemagglutinin content is approved
in the United States for persons
65 years of age or older, and an
ongoing study will determine
whether the increased antibody
responses it elicits are associated
with increased protection.
The increasing variety of ap-
proved seasonal vaccines also in-
cludes one intradermally admin-
istered vaccine that’s particularly
useful in persons averse to intra-
muscular injections and two cell-
culture–produced vaccines (one
expressing recombinant hemag-
glutinin), which may be espe-
cially useful for persons con-
cerned about egg allergies. These
n engl j med 368;7  nejm.org  february 14, 2013
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Epidemic Influenza — Expected but Unpredictable
advances could incrementally hospitalized with A(H1N1)pdm09,
improve influenza control over seasonal, or avian H5N1 influ-
the next several years. Multiple enza, who benefited from treat-
investigational vaccines offering ment even if it was delayed up to
broader-spectrum and more dura- 4 to 5 days after symptom onset.5
ble immune responses, including Current guidance from the CDC
responses to conserved epitopes, and the World Health Organiza-
are in various stages of develop- tion emphasizes the importance
ment, and the use of such vac- of initiating antiviral therapy as
cines might result in substan- early as possible in patients who
tially improved influenza-control are hospitalized with severe or
measures in the future. progressive illness caused by sus-
On the treatment front, unlike pected influenza and in high-risk
the 2008–2009 season, when osel- outpatients, regardless of wheth-
tamivir-resistant seasonal H1N1 er they were vaccinated or have
virus circulated globally, the cur- been sick for more than 2 days.
rent season is dominated by in- FDA approval of oseltamivir was
fluenza A and B strains suscep- recently extended to infants as
tible to neuraminidase inhibitors. young as 2 weeks.
Observational studies during the Surveys have shown that use
2009 pandemic confirmed that of antiviral medications has de-
In seriously ill or immunocompromised patients,
protracted viral replication sometimes occurs
despite oseltamivir treatment. Such findings
and the occurrence of deaths despite early
antiviral therapy emphasize the importance
of developing more potent antiviral regimens
for such patients.
timely antiviral treatment could creased since the 2009 pandemic,
reduce the duration of illness which could result in worsened
and functional disability in ambu- outcomes. Furthermore, more pro-
latory patients and severe out- longed treatment appears warrant-
comes in hospitalized patients. ed in seriously ill or immunocom-
A meta-analysis of 90 observation- promised patients, particularly
al studies, most of which covered those with severe viral pneumo-
A(H1N1)pdm09 infections, showed nia, in whom protracted viral rep-
that antiviral therapy, principally lication sometimes occurs despite
with oseltamivir, initiated within oseltamivir treatment. Such viro-
48 hours after symptom onset re- logic findings and the occurrence
duced the likelihood of both ad- of deaths despite early anti­viral
mission to the critical care unit therapy emphasize the importance
and death.4 This finding confirms of developing more potent anti-
those of observational studies re- viral regimens for such patients,
vealing reduced mortality with particularly intravenous antivirals
oseltamivir therapy among patients and combinations. Intravenous za-
591
PERSPE C T I V E
namivir, which is the focus of an
ongoing phase 3 trial and avail-
able on compassionate-use basis,
currently appears to be the anti-
viral of choice for treating hospi-
talized or immunocompromised
patients with serious influenza
caused by most oseltamivir-resis-
tant variants, including H1N1-
subtype viruses harboring the
H275Y mutation. However, one
U.S. government–sponsored ran-
domized trial of intravenous pera-
mivir in hospitalized patients was
recently terminated by its data and
safety monitoring board because
of futility with regard to reach-
ing its primary end point. Such
findings highlight the impor-
The Cure for Cholera — Improving Access to Safe Water
and Sanitation
Ronald J. Waldman, M.D., M.P.H, Eric D. Mintz, M.D., M.P.H., and Heather E. Papowitz, M.D., M.P.H.
W henever epidemics of chol-
era occur, the global pub-
lic health community is energized.
Experts meet, guidelines for con-
trol are reviewed and reissued,
and new and modified interven-
tions are proposed and promoted.
In the past two decades, these
things happened after cholera
appeared in Latin America in
1991, in the wake of the Rwan-
dan genocide and the ensuing
refugee crisis in Zaire (now Dem-
ocratic Republic of Congo) in
1994, in Zimbabwe in 2008, and
in October 2010, at the onset of
the ongoing epidemic in Haiti
(see article by Barzilay et al.).
But even when it is not covered
in the news or noticed by the
public, cholera occurs regularly
in the developing world, and the
annual number of cases reported
to the World Health Organization
592
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Copyright © 2013 Massachusetts Medical Society. All rights reserved.
Epidemic Influenza — Expected but Unpredictable
tance of developing antiviral
agents with new mechanisms of
action, and ongoing work on
new inhibitors directed against
influenza polymerase, hemagglu-
tinin, M gene, and other targets
offers promise.
Disclosure forms provided by the authors
are available with the full text of this article
at NEJM.org.
From the Epidemiology and Prevention
Branch, Influenza Division, Centers for Dis-
ease Control and Prevention, Atlanta (J.B.);
and the Division of Infectious Diseases and
International Health, University of Virginia
School of Medicine, Charlottesville (F.G.H.).
This article was published on January 23,
2013, at NEJM.org.
1. Osterholm MT, Kelley NS, Sommer A, Be-
longia EA. Efficacy and effectiveness of in-
(WHO) has increased over the
past few years to more than half
a million cases and 7816 related
deaths reported from all regions
in 2011 (see map).1 Moreover,
these reported numbers grossly
underestimate the actual global
burden of cholera: the WHO esti-
mates that 3 million to 5 million
cases and 100,000 to 200,000
deaths due to cholera occur an-
nually.
Among the latest developments
in cholera control are the recom-
mendations that antibiotic agents
be given to patients with moder-
ate dehydration, as well as to
those with severe dehydration (al-
ways in conjunction with ag-
gressive oral or parenteral rehydra-
tion), that all patients be treated
with zinc, and that use of an
improved two-dose oral cholera
vaccine be expanded. The vaccine
n engl j med 368;7  nejm.org  february 14, 2013
The New England Journal of Medicine
fluenza vaccines: a systematic review and
meta-analysis. Lancet Infect Dis 2012;12:36-
44. [Erratum, Lancet Infect Dis 2012;12:655.]
2. Early estimates of seasonal influenza vac-
cine effectiveness — United States, January
2013. MMWR Morb Mortal Wkly Rep 2013;
62:32-5.
3. Vesikari T, Knuf M, Wutzler P, et al. Oil-in-
water emulsion adjuvant with influenza vac-
cine in young children. N Engl J Med 2011;
365:1406-16.
4. Muthuri SG, Myles PR, Venkatesan S,
Leonardi-Bee J, Nguyen-Van-Tam JS. Impact
of neuraminidase inhibitor treatment on out-
comes of public health importance during
the 2009-10 influenza A(H1N1) pandemic: a
systematic review and meta-analysis in hos-
pitalized patients. J Infect Dis 2013 January
11 (Epub ahead of print).
5. Louie JK, Yang S, Acosta M, et al. Treat-
ment with neuraminidase inhibitors for criti-
cally ill patients with influenza A (H1N1)
pdm09. Clin Infect Dis 2012;55:1198-204.
DOI: 10.1056/NEJMp1300375
Copyright © 2013 Massachusetts Medical Society.
has been administered success-
fully in pilot trials in a number
of locations where cholera is en-
demic and, in 2012, during epi-
demics in Haiti and Guinea. The
WHO recently agreed to establish
a vaccine stockpile for emergency
use to encourage greater produc-
tion at lower cost. These devel-
opments are welcome additions
to the anticholera armamentari-
um, but public health profession-
als know that they do not address
the underlying problem.
The best intervention for long-
term cholera control and, for that
matter, for the control of the
great majority of diarrheal dis-
eases is the strategy that elimi-
nated epidemic cholera from the
United States and Northern Eu-
rope long before either marketed
antibiotics or effective vaccines
existed. The development and