The black plague killed more people, and was estimated to have kill...
"One compelling question emerges: can lessons from the 1918-1919 pa...
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There were three big waves of the 1918-1919 pandemic. ![Imgur](...
In 1918, NYC was considered a world leader in public health, and th...
"In dual-peaked cities, activation of nonpharmaceutical interventio...
“History is not a predictive science. There exist numerous well-doc...
"These findings contrast with the conventional wisdom that the 1918...
"Our study suggests that nonpharmaceutical interventions can play a...
ORIGINAL CONTRIBUTION
Nonpharmaceutical Interventions
Implemented by US Cities
During the 1918-1919 Influenza Pandemic
Howard Markel, MD, PhD
Harvey B. Lipman, PhD
J. Alexander Navarro, PhD
Alexandra Sloan, AB
Joseph R. Michalsen, BS
Alexandra Minna Stern, PhD
Martin S. Cetron, MD
T
HE INFLUENZA PANDEMIC OF
1918-1919 was the most deadly
contagious calamity in hu-
man history. Approximately 40
million individuals died worldwide, in-
cluding 550 000 individuals in the
United States.
1-4
The historical record
demonstrates that when faced with a
devastating pandemic, many nations,
communities, and individuals adopt
what they perceive to be effective so-
cial distancing measures or nonphar-
maceutical interventions including iso-
lation of those who are ill, quarantine
of those suspected of having contact
with those who are ill, school and se-
lected business closure, and public gath-
ering cancellations.
5,6
One compelling
question emerges: can lessons from the
1918-1919 pandemic be applied to con-
temporary pandemic planning efforts
to maximize public health benefit while
minimizing the disruptive social con-
sequences of the pandemic as well as
those accompanying public health re-
sponse measures?
7-10
Most pandemic influenza policy
makers agree that even the most rigor-
ous nonpharmaceutical interventions
are unlikely either to prevent a pan-
demic or change a population’s under-
lying biological susceptibility to the
pandemic virus. However, a growing
Author Affiliations: Center for the History of Medi-
cine, University of Michigan Medical School, Ann Ar-
bor (Drs Markel, Navarro, and Stern, and Ms Sloan
and Mr Michalsen); and Division of Global Migration
and Quarantine, Centers for Disease Control and Pre-
vention, Atlanta, Georgia (Drs Lipman and Cetron).
Corresponding Author: Martin S. Cetron, MD, Divi-
sion of Global Migration and Quarantine, Centers for
Disease Control and Prevention, 1600 Clifton Rd, Mail-
stop E-03, Atlanta, GA 30333 (mcetron@cdc.gov).
Context Acriticalquestioninpandemicinfluenzaplanningistherolenonpharmaceu-
tical interventions might play in delaying the temporal effects of a pandemic, reducing
the overall and peak attack rate, and reducing the number of cumulative deaths. Such
measures could potentially provide valuable time for pandemic-strain vaccine and anti-
viral medication production and distribution. Optimally, appropriate implementation of
nonpharmaceutical interventions would decrease the burden on health care services and
critical infrastructure.
Objectives To examine the implementation of nonpharmaceutical interventions for
epidemic mitigation in 43 cities in the continental United States from September 8,
1918, through February 22, 1919, and to determine whether city-to-city variation in
mortality was associated with the timing, duration, and combination of nonpharma-
ceutical interventions; altered population susceptibility associated with prior pan-
demic waves; age and sex distribution; and population size and density.
Design and Setting Historical archival research, and statistical and epidemiological
analyses. Nonpharmaceutical interventions were grouped into 3 major categories: school
closure; cancellation of public gatherings; and isolation and quarantine.
Main Outcome Measures Weekly excess death rate (EDR); time from the activation
of nonpharmaceutical interventions to the first peak EDR; the first peak weekly EDR; and
cumulative EDR during the entire 24-week study period.
Results There were 115 340 excess pneumonia and influenza deaths (EDR, 500/
100 000 population) in the 43 cities during the 24 weeks analyzed. Every city adopted
at least 1 of the 3 major categories of nonpharmaceutical interventions. School clo-
sure and public gathering bans activated concurrently represented the most common
combination implemented in 34 cities (79%); this combination had a median dura-
tion of 4 weeks (range, 1-10 weeks) and was significantly associated with reductions
in weekly EDR. The cities that implemented nonpharmaceutical interventions earlier
had greater delays in reaching peak mortality (Spearman r=0.74, P!.001), lower
peak mortality rates (Spearman r =0.31, P=.02), and lower total mortality (Spearman
r=0.37, P=.008). There was a statistically significant association between increased
duration of nonpharmaceutical interventions and a reduced total mortality burden (Spear-
man r=0.39, P=.005).
Conclusions These findings demonstrate a strong association between early, sus-
tained, and layered application of nonpharmaceutical interventions and mitigating the
consequences of the 1918-1919 influenza pandemic in the United States. In planning
for future severe influenza pandemics, nonpharmaceutical interventions should be con-
sidered for inclusion as companion measures to developing effective vaccines and medi-
cations for prophylaxis and treatment.
JAMA. 2007;298(6):644-654 www.jama.com
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body of theoretical modeling research
suggests that nonpharmaceutical inter-
ventions might play a salubrious role
in delaying the temporal effect of a pan-
demic; reducing the overall and peak
attack rate; and reducing the number
of cumulative deaths.
11-15
Such mea-
sures could potentially provide valu-
able time for production and distribu-
tion of pandemic-strain vaccine and
antiviral medication. Optimally, appro-
priate implementation of nonpharma-
ceutical interventions would decrease
the burden on health care services and
critical infrastructure.
The historical record of the 1918-
1919 influenza pandemic in the United
States constitutes one of the largest re-
corded experiences with the use of non-
pharmaceutical interventions to miti-
gate an easily spread, high mortality and
morbidity influenza virus strain (ie, a cat-
egory 4-5 pandemic using the Centers for
Disease Control and Prevention Febru-
ary 2007 Interim Pre-Pandemic Planning
Guidance).
16
Our study focused on this
data set by assessing the nonpharmaceu-
tical interventions implemented in 43 cit-
ies in the continental United States from
September 8, 1918, through February 22,
1919, a period that encompasses all of
the second pandemic wave (September-
December 1918) and the first 2 months
of the third wave (January-April 1919)
and represents the principal time span
of activation and deactivation of non-
pharmaceutical interventions. The pur-
pose was to determine whether city-to-
city variation in mortality was associated
with the timing, duration, and combi-
nation (or layering) of nonpharmaceu-
tical interventions; altered population
susceptibility associated with prior pan-
demic waves; age and sex distribution;
and population size and density.
METHODS
Data Collection
We combined systematic historical data
collection and contemporary epidemio-
logical and statistical analytic tools. Mor-
tality data wereobtained fromthe USCen-
sus Bureau’s Weekly Health Index
17
for
1918-1919, a series of reports listingtotal
deaths and death rates for 43 large US cit-
ies. These 43 cities were among the 66
most populous urban centers according
to the 1920 census, and all had a popu-
lation greater than 100 000. Of the 66
most populous cities, the remaining 23
hadincomplete archivaland mortality rec-
ords. No city with a comprehensive ar-
chival record of nonpharmaceutical in-
terventions was excluded. The Weekly
Health Index is the most complete extant
compilation of weekly pneumonia and
influenza mortality data inUS urbanareas
during the 1918-1919 pandemic.
In addition, we captured all of the
available public health documents on
nonpharmaceutical interventions imple-
mented by these 43 citiesduring the1918-
1919 pandemic, including municipal
public health department annual and
monthly reports and weekly bulletins;
every state and federalreport onthe 1918-
1919 influenza pandemic published be-
tween 1917 and 1922; US Census pneu-
monia and influenza mortality data from
1910-1920; the corpus of published his-
torical, medical, and public health litera-
ture on the 1918-1919 pandemic; 86 dif-
ferent newspapers from the 43 different
cities; records of US military installations
between 1917-1920; and additionalhold-
ings housedin several major libraries and
archival repositories (the complete bib-
liography of the 1144 primary and sec-
ondary sources is available as an online
supplement at http://www.cdc.gov
/ncidod/dq/index.htm).
17-23
Data Analysis
From the census reports, we extracted
the weekly pneumonia and influenza
mortality data covering the 24 weeks
from September 8, 1918, through Feb-
ruary 22, 1919, for the 43 US cities. In
1920, these 43 cities had a combined
population of approximately 23 mil-
lion (22% of the total US population). A
small number of missing values (846
[0.6%] of 136 563 deaths) was im-
puted. Using estimated weekly baseline
pneumonia and influenza death rates
generated from the 1910-1916 median
monthly values found by Collins et al,
18
weekly excess death rates (EDR) were
computed. Based on available mortality
data and epidemiological reports from
that era, as well as a recent retrospec-
tive statistical analysis, we estimated that
those who succumbed to influenza con-
tracted it 10 days earlier.
3,24-27
The onset of the epidemic in a par-
ticular city was estimated as either the
day of the first reported pneumonia and
influenza case, or the calendar day of
the first recorded pneumonia and in-
fluenza death minus 10 days, which-
ever was earlier. Information on non-
pharmaceutical interventions was
captured by reviewing at least 2 daily,
high-circulation newspapers for each
city and available municipal or state
health reports. Nonpharmaceutical in-
terventions were grouped into 3 ma-
jor categories: school closure; public
gathering bans; and isolation and quar-
antine. We also considered an addi-
tional general category of ancillary non-
pharmaceutical interventions (eg,
altering work schedules, limited clo-
sure or regulations of businesses, trans-
portation restrictions, public risk com-
munications, face mask ordinances).
Nonpharmaceutical interventions
were considered either activated (“on”)
or deactivated (“off”), according to data
culled from the historical record and
daily newspaper accounts. Specifi-
cally, these nonpharmaceutical inter-
ventions were legally enforced and af-
fected large segments of the city’s
population. Isolation of ill persons and
quarantine of those suspected of hav-
ing contact with ill persons refers only
to mandatory orders as opposed to vol-
untary quarantines being discussed in
our present era. School closure was con-
sidered activated when the city offi-
cials closed public schools (grade school
through high school); in most, but not
all cases, private and parochial schools
followed suit. Public gathering bans
typically meant the closure of saloons,
public entertainment venues, sport-
ing events, and indoor gatherings were
banned or moved outdoors; outdoor
gatherings were not always canceled
during this period (eg, Liberty bond pa-
rades); there were no recorded bans on
shopping in grocery and drug stores.
Based on an estimated 10-day time
frame between disease onset and death,
INTERVENTIONS DURING 1918-1919 INFLUENZA PANDEMIC
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we estimated that the association of
nonpharmaceutical interventions with
reductions in EDR occurred 10 days
after their actual date of implemen-
tation.
3,24-27
To test the association of the layering
and timing of nonpharmaceutical inter-
ventions with mortality, an analysis of
variance (ANOVA) model was con-
structed with weekly EDR as the depen-
dent variable and epidemiological week,
city, andthe status (on/off ) of everycom-
bination ofnonpharmaceutical interven-
tions as the independent variables. Inthe
ANOVA model, each possible combina-
tion ofnonpharmaceutical interventions
was treated as an independent variable
to testfor layering effects. Any factorwith
a P value of less than .10 was included
in the model. Because there is ambigu-
ity overthe rigor withwhich the category
of ancillary nonpharmaceutical interven-
tions was applied, enforced, and deac-
tivated, we focused primarily on the 3
major categories of nonpharmaceutical
interventions discussed above and we
included the ancillary nonpharmaceu-
tical interventions in the multivariate
model for purposes of completeness.
We defined additional outcome (de-
pendent) variables: (1) the time to first
peak as the time in days from the acti-
vation of the first major category of non-
pharmaceutical interventions to the date
of the first peak EDR; (2) the magni-
tude of the first peak as the first peak
weekly EDR; and (3) the mortality bur-
den as the cumulative EDR during the
entire 24-week study period.
We also defined the following inde-
pendent variables. The first was the
public health response time (PHRT) as
the time in days (either positive or nega-
tive) between the date when weekly
EDR first exceeds twice the baseline
pneumonia and influenza death rate
(2"baseline; ie, when the mortality rate
begins to accelerate) and the activa-
tion of the first major nonpharmaceu-
tical interventions. Interventions that
occurred prior to this reference point
are recorded as negative PHRT values,
indicating that public health officials re-
sponded to events prior to the accel-
eration of weekly death rates. How-
ever, most cities had positive PHRT in
that they reacted after the 2" baseline
mortality threshold, indicating that the
epidemic had already entered its accel-
eration phase. The second indepen-
dent variable was total days of non-
pharmaceutical interventions, which
was defined as the total cumulative
number of days that nonpharmaceuti-
cal interventions from the 3 major cat-
egories were activated during the en-
tire 24-week study period.
The ANOVA models were based on
the study design of a 43 (city)" 24
(week) factorial design without replica-
tion. Because there is no replication, the
city" week interaction term was treated
as the error term in the multivariate analy-
sis. We considered 4 different nonphar-
maceutical interventions. Hence, there
are 15 different combinations of these
interventions (excluding the no inter-
vention combination). Each of these 15
combinations was either implemented
(on) or not implemented (off) in each
city for each week. Thus, the effects of
each of these combinations of nonphar-
maceutical interventions are included in
the city" week interaction term. Each of
these terms (along with their " city and
"week interaction terms) were extracted
from the original city" week interac-
tion term. The remaining unexplained
variation was used as the error term in
the ANOVA model. The remaining error
term is likely to be larger than a true error
term generated through replication so the
analysis of any effects using this error
term can be expected to be conserva-
tive. Such a factorial model without rep-
lication can be used to test hypotheses
but the lack of natural error in the model
makes estimates or predictions from the
model such as effect size measures and
confidence intervals nonestimable.
We also generated scatterplots and
Spearman rank correlation coefficients
to explore the associations between
PHRT and each of the 2 additional de-
pendent variables and associations be-
tween total days of nonpharmaceutical
interventions and mortality burden. We
further investigated these associations by
using box plots and Wilcoxon rank sum
tests to compare the outcomes for the cit-
ies above and below the median of each
independent variable.
We also generated scatterplots and
Spearman rank correlation coefficients
to explore other potential or confound-
ing associations (as independent deter-
minants): (1) EDR in the 4 successive
waves of the pandemic; (2) city-specific
population size vs EDR; (3) city-
specific population density vs EDR; (4)
city-specific population age distribu-
tion vs EDR; and (5) city-specific sex dis-
tribution vs EDR. Analyses were per-
formed using SAS statistical software
version 9.1 (SAS Institute Inc, Cary, NC).
RESULTS
There were 115 340 excess pneumonia
and influenza deaths (EDR, 500/
100 000 population) in the 43 cities dur-
ing the 24 weeks analyzed. T
ABLE 1
shows considerable city-to-city varia-
tion in mortality profiles and interven-
tion characteristics; lists the earliest re-
ported dates of the first pneumonia and
influenza cases by city, mortality accel-
eration (2" baseline EDR), first imple-
mentation of nonpharmaceutical inter-
ventions, and first peak EDR; and lists
the values for each of the independent
and outcome variables described above.
T
ABLE 2 shows the categories of non-
pharmaceutical intervention combina-
tions, the number of cities implement-
ing those combinations, and the median
and range of duration of implementa-
tion by each of the 43 cities during the
study period. Every city adopted at least
1ofthe3majorcategoriesofnonphar-
maceutical interventions; 15 applied all
3 categories of nonpharmaceutical in-
terventions concurrently. School clo-
sure concurrently combined with pub-
lic gathering bans represented the most
common combination, implemented in
34 cities (79%) for a median duration
of 4 weeks (range, 1-10 weeks). School
closure was ultimately used in some
combination with the other categories
of nonpharmaceutical interventions by
40 cities (93%). Three cities never of-
ficially closed their schools (New York
City, New York, New Haven, Connecti-
cut, and Chicago, Illinois, although the
latter reported a student absenteeism
INTERVENTIONS DURING 1918-1919 INFLUENZA PANDEMIC
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rate of #45% at the peak of its epi-
demic); 25 cities closed their schools
once, 14 closed them twice, and 1 (Kan-
sas City, Missouri) closed its schools 3
times. Schools were officially closed a
median of 6 weeks (range, 0-15 weeks).
The ANOVA multivariate model had
an r
2
of 86.7% (P! .001). Nonpharma-
ceutical interventions were a significant
Table 1. Characteristics of Influenza Pandemic for 43 US Cities Between September 8, 1918, and February 22, 1919
City
First
Case
Date
Mortality
Acceleration
Date
a
Date of First
Nonpharmaceutical
Intervention
Public
Health
Response
Time, d
b
Total No. of Days of
Nonpharmaceutical
Interventions
Date of
Peak
Excess
Death
Rate
Time to
Peak, d
Magnitude of
First Peak,
Excess
Deaths/
100 000
Population
c
Excess
Pneumonia
and
Influenza
Mortality,
Deaths/
100 000
Population
d
Albany, NY 9/27 10/6 10/9 3 47 10/24 15 161.8 553.2
Baltimore, MD 9/18 9/29 10/9 10 43 10/18 9 182.1 559.3
Birmingham, AL 9/24 9/30 10/9 9 48 10/22 13 70.9 591.8
Boston, MA 9/4 9/12 9/25 13 50 10/3 8 159.9 710.0
Buffalo, NY 9/24 9/28 10/10 12 49 10/22 12 140.9 529.5
Cambridge, MA 9/4 9/11 9/25 14 49 10/3 8 125.5 541.0
Chicago, IL 9/17 9/28 9/26 2 68 10/21 25 84.8 373.2
Cincinnati, OH 9/24 10/4 10/6 2 123 10/24 18 67.6 451.2
Cleveland, OH 9/20 10/7 10/5 2 99 10/31 26 83.6 474.0
Columbus, OH 9/20 10/6 10/11 5 147 10/24 13 47.3 311.7
Dayton, OH 9/20 10/5 9/30 5 156 10/20 20 87.8 410.0
Denver, CO 9/17 9/27 10/6 9 151 10/20 14 55.0 630.9
Fall River, MA 9/9 9/16 9/26 10 60 10/12 16 165.2 621.3
Grand Rapids, MI 9/23 10/2 10/19 17 62 10/25 6 15.0 210.5
Indianapolis, IN 9/22 9/30 10/7 7 82 10/18 11 38.8 290.0
Kansas City, MO 9/20 9/26 9/26 0 170 10/27 31 58.1 579.8
Los Angeles, CA 9/27 10/6 10/11 5 154 10/30 19 64.2 493.8
Louisville, KY 9/13 10/1 10/7 6 145 10/20 13 74.8 406.4
Lowell, MA 9/9 9/16 9/27 11 59 10/10 13 123.1 522.9
Milwaukee, WI 9/14 10/6 10/11 5 132 10/23 12 36.4 291.5
Minneapolis, MN 9/21 10/6 10/12 6 116 10/24 18 37.6 267.1
Nashville, TN 9/21 10/6 10/7 1 55 10/16 9 160.1 610.4
New Haven, CT 9/14 9/23 10/15 22 39 10/24 9 109.5 586.5
New Orleans, LA 9/10 10/1 10/8 7 78 10/20 12 172.9 734.0
New York City, NY 9/5 9/29 9/18 11 73 10/23 35 90.1 452.3
Newark, NJ 9/6 9/30 10/10 10 33 10/22 12 101.5 533.0
Oakland, CA 10/1 10/8 10/12 4 127 10/30 18 107.0 506.2
Omaha, NE 9/18 10/4 10/5 1 140 10/18 13 81.7 554.0
Philadelphia, PA 8/27 9/25 10/3 8 51 10/16 13 249.7 748.4
Pittsburgh, PA 9/4 9/27 10/4 7 53 11/5 32 130.7 806.8
Portland, OR 10/2 10/7 10/11 4 162 11/2 22 59.4 505.2
Providence, RI 9/8 9/17 10/6 19 42 10/17 11 105.2 574.2
Richmond, VA 9/21 9/29 10/6 7 60 10/16 10 112.2 508.3
Rochester, NY 9/22 10/6 10/9 3 54 10/26 17 70.2 359.1
St Louis, MO 9/23 10/7 10/8 1 143 10/29 21 30.0 358.0
St Paul, MN 9/21 10/2 11/6 35 28 11/12 6 55.6 413.2
San Francisco, CA 9/24 10/7 10/18 11 67 10/29 11 143.0 672.7
Seattle, WA 9/24 10/1 10/6 5 168 10/23 17 49.5 414.1
Spokane, WA 9/28 10/9 10/10 1 164 11/5 26 66.0 481.8
Syracuse, NY 9/12 9/18 10/7 19 39 10/14 7 145.4 541.4
Toledo, OH 9/21 10/13 10/15 2 102 10/25 10 54.8 294.5
Washington, DC 9/11 9/23 10/3 10 64 10/15 12 140.1 607.6
Worcester, MA 9/9 9/12 9/27 15 44 10/7 10 126.1 654.7
a
Defined as 2 " baseline death rate.
b
Defined as days between 2 " baseline death rate and first nonpharmaceutical intervention.
c
Weekly excess death rate.
d
Total excess death rate through 24 weeks.
INTERVENTIONS DURING 1918-1919 INFLUENZA PANDEMIC
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source of the variation in the weekly
EDRs within and between the cities. The
ANOVA results are shown in T
ABLE 3.
The multivariate model demonstrates
that layered nonpharmaceutical inter-
ventions generally had a more signifi-
cant association with weekly EDR than
individual nonpharmaceutical interven-
tions. Specifically, combinations of non-
pharmaceutical interventions includ-
ing school closure and public gathering
bans appeared to have the most signifi-
cant association with weekly EDR (ie, the
lowest P values, most were P!.001). The
large number of significant nonpharma-
ceutical interventions" week interac-
tions in the model confirms that the tim-
ing of the implementation of a given
combination of nonpharmaceutical inter-
ventions was a significant factor in reduc-
ing mortality. One caveat is persistent
nonpharmaceutical interventions" city
interactions, meaning that the success of
astrategyofnonpharmaceuticalinter-
ventions in a particular city does not uni-
formly translate to all other cities. The 2
outlier cities in our study, Grand Rap-
ids, Michigan, and St Paul, Minnesota,
exemplify this point.
The scatterplots in F
IGURE 1A,
Figure 1B, and Figure 1C display the
associations between the PHRT and
each of the 3 dependent variables.
Figure 1A displays the association be-
tween PHRT in days and time to first
peak EDR; cities that implemented non-
pharmaceutical interventions earlier
had greater delays in reaching peak
mortality (Spearman r =0.74,
P! .001). Figure 1B shows the asso-
ciation between PHRT and the magni-
tude of the first peak EDR; cities that
implemented nonpharmaceutical in-
terventions earlier had lower peak mor-
tality rates (Spearman r=0.31, P=.02).
Figure 1C depicts the association be-
tween PHRT and total mortality bur-
den; cities that implemented nonphar-
maceutical interventions earlier
experienced a lower total mortality
(Spearman r=0.37, P =.008). In sum-
mary, when comparing the 21 cities
with earlier (less than the median)
PHRT with the 21 cities with the later
(greater than the median) PHRT, there
are statistically significant differences
for each of the outcome measures
(P$ .001; T
ABLE 4).
Figures 1C and 1D show the associa-
tion betweenearly, sustained, and layered
application of nonpharmaceutical inter-
ventions and total excess pneumonia and
influenza mortality burden in 43 cities.
Figure 1C shows the statistically signifi-
cant association between PHRT and total
mortality burden. Figure 1D shows a sta-
tistically significant association between
increased duration of nonpharmaceuti-
cal interventions and a reduced total
mortality burden (Spearman r=0.39,
P=.005).Insummary,the 21 citiesthat
hadearlier PHRT(ie, less thanthe median)
and the most sustained and most days of
nonpharmaceutical interventions had a
statistically significant reduction inexcess
pneumonia and influenza mortality rates
compared with the 21 cities that had later
PHRT and fewer days of nonpharmaceu-
tical interventions (Table 4).
F
IGURE 2 shows the aggregate city
mortality curves by region (East, Mid-
west and South, and West). F
IGURE 3
displays 4 city-specific mortality curves,
including weekly EDR and the non-
pharmaceutical interventions imple-
mented as well as their activation and
deactivation dates for St Louis, Mis-
souri, New York City, Denver, Colo-
rado, and Pittsburgh, Pennsylvania.
These 4 cities were chosen because they
indicate the broad spectrum of out-
comes seen in the 43 cities studied as
well as for their geographical and so-
cial diversity. (The mortality curves for
all 43 cities are available at http://www
.cdc.gov/ncidod/dq/index.htm.) Over-
all, cities that implemented nonphar-
maceutical interventions earlier
experienced associated delays in the
time to peak mortality, reductions in the
magnitude of the peak mortality, and
decreases in the total mortality burden.
In exploring alternative and poten-
tially confounding explanations for varia-
tion in city-specific EDR, we used a scat-
terplot to compare the cumulative EDR
of the 43 cities during pandemic waves
1(February-May1918),2(September-
December 1918), 3 ( January-April 1919),
and 4 (January-April 1920).
2,3
We found
no statistically significant association of
the EDR across the 43 cities when com-
paring successive waves. Specifically, the
severity or occurrence of wave 1 is not
associated, either positively or nega-
tively, with the severity of wave 2; the
severity of wave 2 is not associated with
the severity of wave 3; and the severity
of wave 3 is not associated with the sever-
ity of wave 4 (figures appear in the online
supplement at http://www.cdc.gov
/ncidod/dq/index.htm).
28,29
Publishedvirological evidencefor strain
variation during wave 2 is limited to a
single genotypic variant withoutevidence
for significant phenotypic change in
virulence.
30-33
While plausible, novirologi-
Table 2. Nonpharmaceutical Interventions Implemented in 43 US Cities Between September
8, 1918, and February 22, 1919
Type of Nonpharmaceutical Intervention
No. (%) of Cities
Implementing
Nonpharmaceutical
Intervention
for #1 wk (N = 43)
a
Median (Range)
Duration of
Nonpharmaceutical
Intervention, wk
Isolation or quarantine only 15 (35) 1 (1-10)
School closure only 22 (51) 1 (1-7)
Public gathering ban only 6 (14) 1.5 (1-5)
Isolation and quarantine and school closure 2 (5) 5.5 (4-7)
Isolation and quarantine and public gathering ban 4 (9) 4 (2-5)
School closure and public gathering ban 34 (79) 4 (1-10)
Isolation and quarantine, school closure,
and public gathering ban
15 (35) 4 (2-6)
a
Cities often implemented more than 1 nonpharmaceutical intervention combination during the outbreak period, so
the total adds to more than 100%. The number of categories of nonpharmaceutical interventions implemented dur-
ing some part of the outbreak was 1 in 1 city, 2 in 23 cities, and 3 in 19 cities. The total number of weeks that at least
1 nonpharmaceutical intervention was implemented was 4 in 6 cities, 5 in 6 cities, 6 in 8 cities, 7 in 3 cities, 8 in 6
cities, 10 in 5 cities, 11 in 4 cities, 13 in 1 city, 14 in 2 cities, 15 in 1 city, and 16 in 1 city. No cities had at least 1
nonpharmaceutical intervention implemented for durations of 9 and 12 weeks.
INTERVENTIONS DURING 1918-1919 INFLUENZA PANDEMIC
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cal evidence yet exists to explain the per-
plexing mortality difference between the
spring 1918 wave, which was reportedly
milder, and the subsequent fall and win-
ter waves. Additional studies may clarify
the understanding of the 1918 pandem-
ic’s wave phenomena.
Similarly, scatterplots comparing the
cumulative EDR to thecity-specific popu-
lation size and density; sex distribution;
and proportion of ages of younger than
1monthto5years,15to40years,and
older than 65 years, which corresponded
to high reported specific mortality rates
in 1918 demonstrated no association.
Among the 43 cities we investigated, nei-
ther the city’s populationsize, density, sex
distribution, nor age distribution ac-
counted for the differences in mortality
(figures appear in supplement at http:
//www.cdc.gov/ncidod/dq/index.htm).
Table 3. Multivariate Model Showing Effect of Combinations of Nonpharmaceutical Interventions on Weekly Excess Death Rates for 43 US
Cities Between September 8, 1918, and February 22, 1919
a
Source of Variation df
Sum of
Squares
Mean
Square F Score P Value
Type of confounders
Week 29 75 677.0 2609.6 16.24 !.001
City 42 65 557.9 1560.9 9.72 !.001
1 Nonpharmaceutical intervention
School closure 1 1288.7 1288.7 8.02 .005
" Week 8 4551.8 569.0 3.54 !.001
Banning public gatherings 1 1342.0 1342.0 8.35 .004
Isolation and quarantine 1 911.1 911.1 5.67 .02
" City 10 3976.5 397.7 2.48 .006
Ancillary nonpharmaceutical interventions 1 897.3 897.3 5.59 .02
" Week 13 6122.4 471.0 2.93 !.001
" City 12 10 257.6 854.8 5.32 !.001
2 Nonpharmaceutical interventions
School closure and banning public gatherings 1 681.3 681.3 4.24 .04
" Week 9 6497.0 721.9 4.49 !.001
" City 13 6229.9 479.2 2.98 !.001
School closure and isolation and quarantine 1 2335.3 2335.3 14.54 !.001
" Week 4 2434.2 608.6 3.79 .005
Banning public gatherings and isolation and quarantine 1 292.3 292.3 1.82 .18
" Week 1 563.9 563.9 3.51 .06
Banning public gatherings and ancillary nonpharmaceutical interventions 1 272.6 272.6 1.70 .19
" Week 4 7444.6 1861.1 11.59 !.001
" City 4 5547.6 1386.9 8.63 !.001
Isolation and quarantine and ancillary nonpharmaceutical interventions 1 48.1 48.1 0.30 .58
" Week 2 1507.6 753.8 4.69 .009
" City 2 824.7 412.4 2.57 .08
3 Nonpharmaceutical interventions
School closure, banning public gatherings, and isolation and quarantine 1 762.4 762.4 4.75 .03
" Week 2 2239.3 1119.7 6.97 .001
School closure, banning public gatherings, and ancillary
nonpharmaceutical interventions
1 691.6 691.6 4.41 .04
" Week 10 12 260.5 1226.0 7.63 !.001
" City 26 51 423.8 1977.8 12.31 !.001
School closure, isolation and quarantine, and ancillary
nonpharmaceutical interventions
1 3451.1 3451.1 21.48 !.001
" Week 4 2493.5 623.4 3.88 .004
Banning public gatherings, isolation and quarantine, and ancillary
nonpharmaceutical interventions
1 51.9 51.9 0.32 .57
" Week 8 4535.2 566.9 3.53 !.001
4 Nonpharmaceutical interventions
School closure, banning public gatherings, isolation and quarantine,
and ancillary nonpharmaceutical interventions
1 503.7 503.7 3.14 .08
" Week 9 6068.3 674.3 4.20 !.001
" City 13 23 509.7 1808.4 11.26 !.001
Error 770 123 691.2 160.6
a
r
2
= 86.7%
INTERVENTIONS DURING 1918-1919 INFLUENZA PANDEMIC
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COMMENT
During the 1918-1919 influenza pan-
demic, all 43 cities eventually imple-
mented nonpharmaceutical interventions
but the time of activation, duration, and
choice or combination of these nonphar-
maceutical interventions appear to have
been keyfactors in their success orfailure.
In 1918, decisions to activate nonphar-
maceutical interventions were typically
triggered by excess morbidity, mortality,
or both, as well as situational awareness
ofother communitiesnearand far.Because
discerning precisely the first arrival of
pandemic virus in a community was dif-
ficult, we chose to measure public health
response time in reference to excess
pneumonia and influenza mortality (ie,
when weekly EDR first crossed the thresh-
old of 2" the baseline and the mortality
rates entered an acceleration phase).
Figure 1. Scatterplot of Public Health Response Time for 43 US Cities From September 8, 1918, Through February 22, 1919
35
15
30
25
20
New York City, NY
10
5
0
–15 –10 –5 0 5 10 15 20 25 30 35
Public Health Response Time, d
Time to First Peak
Excess Death Rate, d
Time to first mortality peak by public
health response time
A
Pittsburgh, PA
St Louis, MO
Denver, CO
St Paul, MN
Grand Rapids, MI
250
200
150
50
New York City, NY
0
–15 –10 –5 0 5 10 15 20 25 30 35
Public Health Response Time, d
Excess Deaths/100
000 Population
Magnitude of first mortality peak by public
health response time
B
Pittsburgh, PA
St Louis, MO
Denver, CO
St Paul, MN
Grand Rapids, MI
New York
City, NY
500
600
700
800
400
300
200
500
600
700
800
400
300
200
–15 –10 –5 0 5 10 15 20 25 30 35
Public Health Response Time, d
Excess Deaths/100
000 Population
Total excess pneumonia and influenza mortality
by public health response time
C
Pittsburgh, PA
St Louis, MO
r
=
0.74
P<.001
r
=
0.31
P
=
.02
Denver, CO
St Paul, MN
Grand Rapids, MI
New York City, NY
20 40 16060 80 100 120 140
Total No. of Days of Nonpharmaceutical Interventions
Excess Deaths/100
000 Population
Total excess pneumonia and influenza mortality by
total No. of days of nonpharmaceutical interventions
D
Pittsburgh, PA
St Louis, MO
Denver, CO
St Paul, MN
Grand Rapids, MI
r
=
0.37
P
=
.008
r
=
0.39
P
=
.005
The 4 cities represented by black circles are discussed further in the text. The 2 citie s represented by blue circles are outliers chosen to demonstrate that the associations
shown are not perfect. The Spearman rank correlation coefficient was used.
Table 4. Implementation Strategy of Nonpharmaceutical Interventions for 21 Cities Between September 8, 1918, and February 22, 1919
Outcome Variable
Public Health Response Time, d
P
Value
Early (!7 d)
Late (#7 d)
25th
Percentile
50th
Percentile
75th
Percentile
25th
Percentile
50th
Percentile
75th
Percentile
Time to peak, d 13 18 22 9 11 13 !.001
Magnitude of first peak (weekly EDR) 54.7 67.6 84.8 101.5 125.8 145.4 .001
Excess pneumonia and influenza
mortality rate (total EDR)
359.1 451.2 505.2 529.5 580.3 654.7 !.001
Total Days of Nonpharmaceutical Interventions
Most (#65 d) Least (!65 d)
Excess pneumonia and influenza
mortality rate (total EDR)
358.0 451.2 505.2 529.5 559.3 610.4 !.001
Abbreviation: EDR, excess death rate.
INTERVENTIONS DURING 1918-1919 INFLUENZA PANDEMIC
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Hence, the difference in time between the
first nonpharmaceutical interventionsand
this excess mortality threshold may be a
positive or negative value. For example,
in Philadelphia,Pennsylvania, which was
affected early and was unprepared to re-
spond, the PHRT was 8 and the EDR was
approximately 37/100 000 population at
the point of implementing nonpharma-
ceutical interventions; in contrast, New
York City’s PHRT was 11 days and the
EDR was 0/100 000 population at the
point of implementing nonpharmaceu-
tical interventions. New York City re-
sponded toits first influenza cases and the
perceived severity of the epidemic in
nearby cities without waiting for excess
deaths to accumulate.
The US Centersfor DiseaseControl and
Prevention’s newlyreleased interim com-
munity mitigation guidance recommends
activating nonpharmaceutical interven-
tions when outbreaks due to a pandemic
virus strain first are confirmed in a state
or metropolitan service region.
16
Several
theoretical models suggest that the effect
of targeted, layered strategies for nonphar-
maceutical interventions may be opti-
mized when community influenza attack
rates are 1% or lower.
11-15
Given the ex-
ponential growth of an unmitigated in-
fluenza pandemic, it is reasonable to ex-
pect that the timing of interventions will
be among the most critical factors. Such
expectations and biological realities are
consistent with our observations of the
1918 pandemic, when rapidpublic health
response time was a critical factor in the
successful applicationof nonpharmaceu-
tical interventions.
Late interventions, regardless of their
duration or permutation of use, al-
most always were associated with worse
outcomes. However, timing alone was
not consistently associated with suc-
cess. The combination and choice of
nonpharmaceutical interventions also
appeared to be critical as confirmed by
the multivariate model.
For example, New York City reacted
earliest to the gathering influenza crisis,
primarily with the sustained (%10weeks
beginning September 19, 1918) and rig-
idly enforced application of compulsory
isolationand quarantineprocedures,along
with anenforced staggered business hour
ordinance from October 5 through No-
vember 3, 1918.
34
During this era, New
York City’s health department was re-
nowned internationally for its innovative
policies of mandatory case reporting and
rigidly enforced isolation and quarantine
procedures.
35
Typically, individualsdiag-
nosed with influenza wereisolated in hos-
pitals or makeshift facilities, while those
suspected to have contact with an ill per-
son (but who were not yet ill themselves)
were quarantined in their homes with an
official placard declaring that location to
be under quarantine. New York City
mounted an early and sustained response
to the epidemic and experienced thelow-
est death rate on the Eastern seaboard but
it did not layer its response. New York
City’s cumulative mortality burden, 452/
100 000, ranked 15 out of the 43 cities
studied.
In contrast, Pittsburgh, under orders
from the Pennsylvania health depart-
ment, executed a public gathering ban
on October 4, 1918, but city officials de-
layed until October 24 before imple-
menting school closure. A week later, on
November 2, the state rescinded public
gathering bans. The city applied its non-
pharmaceutical interventions late and in-
dividually rather than combined. Pitts-
burgh’s cumulative excess mortality
burden (EDR=807/100 000) ranked 43
out of 43 cities during the study period.
However, the benefits of theseinterven-
tions were not equally distributed. Those
cities acting in a timely and comprehen-
sive manner appearto havebenefited most
in terms of reductions in total EDR. For
example, St Louis, which implemented
arelativelyearly,layeredstrategy(school
closure and cancellation of public gath-
erings), and sustained these nonpharma-
ceutical interventions for about 10 weeks
each, did not experience nearly as delete-
rious an outbreak as 36 other communi-
ties in the study (cumulative EDR=358/
100 000 population).
The 1918 experience suggests that sus-
tained nonpharmaceutical interven-
tions are beneficial and need to be “on”
throughout the particular peak of a lo-
cal experience. Many of the 43 cities in
the study, particularly in the Midwest and
South and West, experienced 2 peaks of
excess pneumonia and influenza mor-
tality (eg, Birmingham, Alabama, Cin-
cinnati, Ohio, Columbus, Ohio, Den-
ver, Indianapolis, Indiana, Kansas City,
Figure 2. Aggregate Weekly Excess Death Rates for 43 US Cities by Region From September
8, 1918, Through February 22, 1919
120
60
40
80
100
20
0
Weekly Excess Death Rate, No. of
Deaths per 100
000 Population
Sep
8,
1918
15 22 29 Oct
6
13 20 27 Nov
3
10 17 24 8Dec
1
15 22 29 Jan
5,
1919
12 2619 9 16 23Feb
2
West EastMidwest and South
The total excess death rate is 555 for the East region; 413 for the Midwe st and South region; and 529 for the
West region.
INTERVENTIONS DURING 1918-1919 INFLUENZA PANDEMIC
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Louisville, Kentucky, Milwaukee, Wis-
consin, Minneapolis, Minnesota, Oak-
land, California, Omaha, Nebraska, Port-
land, Oregon, Rochester, New York, St
Louis, San Francisco, California, Se-
attle, Washington, Spokane, Washing-
ton, Toledo, Ohio; see figures in online
supplement at http://www.cdc.gov
/ncidod/dq/index.htm). These second
Figure 3. Weekly Excess Death Rates From September 8, 1918, Through February 22, 1919
Total excess death rate: 631/100
000 population
Public health response time: +9 d
Total No. of days of nonpharmaceutical
interventions: 151
30
20
40
50
10
0
80
70
90
100
60
120
110
130
140
Weekly Excess Death Rate, No. of
Deaths per 100
000 Population
Weekly Excess Death Rate, No. of
Deaths per 100
000 Population
Denver, CO
C
Total excess death rate: 807/100
000 population
Public health response time: +7 d
Total No. of days of nonpharmaceutical
interventions: 53
Pittsburgh, PA
D
Total excess death rate: 358/100
000 population
Public health response time: +1 d
Total No. of days of nonpharmaceutical
interventions: 143
30
20
40
50
10
0
80
70
90
100
60
120
110
130
140
St Louis, MO
A
Total excess death rate: 452/100
000 population
Public health response time: –11 d
Total No. of days of nonpharmaceutical
interventions: 73
New York City, NY
B
School closure
Public gathering ban
Isolation, quarantine
School closure
Public gathering ban
Other
d
Other
c
Isolation, quarantine
Other
b
Weekly excess death rate
2 × baseline mortality
First pneumonia and influenza case
Oct
6
Sep
8,
1918
Nov
3
Dec
1
Jan
5,
1919
23
Feb
2
Oct
6
Sep
8,
1918
Nov
3
Dec
1
Jan
5,
1919
23
Feb
2
Oct
6
Sep
8,
1918
Nov
3
Dec
1
Jan
5,
1919
23
Feb
2
Oct
6
Sep
8,
1918
Nov
3
Dec
1
Jan
5,
1919
23
Feb
2
School closure
Public gathering ban
Other
a
Type and duration of nonpharmaceutical interventions are indicated under each plot. For the specific nonpharmaceutical interventions, black bars indicate activation.
a
Business hours restricted, streetcars’ capacity limited.
b
Staggered business hours, signs with “cover coughs.”
c
Staggered business hours, warning signs posted in theaters.
d
Schoolchildren given information to take home, warned not to gather in groups.
INTERVENTIONS DURING 1918-1919 INFLUENZA PANDEMIC
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peaks frequently followed the sequen-
tial activation, deactivation, and reacti-
vation of nonpharmaceutical interven-
tions, highlighting the transient
protective nature of nonpharmaceuti-
cal interventions and the need for a sus-
tained response. For example, Denver
(cumulative EDR=631/100 000 popu-
lation) responded twice with an exten-
sive menu of nonpharmaceutical inter-
ventions that included public gathering
bans, school closure, isolation and quar-
antine, and several ancillary nonphar-
maceutical interventions and these ac-
tions are reflected temporally in its
2-peak mortality curve.
Such dual-peaked cities are of particu-
lar interest because of the specificity and
temporal associations between excess
mortality and the triggers of activation
and deactivation of nonpharmaceutical
interventions and the implications for a
causal relationship. Among the 43 cit-
ies, we found no example of a city that
had a second peak of influenza while the
first set of nonpharmaceutical interven-
tions were still in effect, suggesting that
each city with a bimodal pattern served
as its own control. In dual-peaked cit-
ies, activation of nonpharmaceutical in-
terventions was followed by a diminu-
tion of deaths and, typically, when
nonpharmaceutical interventions were
deactivated, death rates increased.
History is not a predictive science.
There exist numerous well-documented
and vast differences between US society
and public health during the 1918 pan-
demic comparedwith the present. We ac-
knowledge the inherent difficulties of in-
terpreting data recorded nearly 90 years
ago and contending with the gaps, omis-
sions, and errors that may be included in
the extant historical record. The associa-
tions observed are not perfect; for ex-
ample, 2 outlier cities (Grand Rapids and
St Paul) experiencedbetter outcomeswith
less than perfect public health responses.
Future work by our research team will
explore social, political, and ecological
determinants, which may further help to
explain some of this variation.
The United States of 1918 had many
similar features to the present era: rapid
transportation in the form of trains and
automobiles; rapid means of commu-
nication in the form of the telegraph and
telephone; large, heterogeneous popu-
lations with substantial urban concen-
trations (although a much higher per-
centage of the US population lived in
rural areas compared with the pres-
ent); a news system that was able to cir-
culate information widely during the
epidemic, including many daily news-
papers and broadsheets distributed in
communities; and a wide spectrum of
public health agencies at various lev-
els of government.
When examining the 1918 pan-
demic, however, it is important to rec-
ognize the numerous social, cultural, and
scientific differences that do exist be-
tween that period and the present. For
example, the legal understanding of pri-
vacy, civil, and constitutional rights as
they relate to public health and govern-
mentally directed measures (such as mass
vaccination programs) has changed
markedly over the past 9 decades. In ad-
dition, public support of and trust in
these measures, along with trust in the
medical profession as a whole, has shifted
over time. Finally, other features of the
modern era that need to be considered
when applying lessons from history to
the present era include the increased
speed and mode of travel, above all high-
volume commercial aviation; instanta-
neous access to information via the In-
ternet and personal computers; a baseline
understanding among the general popu-
lation that the etiologic agents of infec-
tious diseases are microbial; and ad-
vances in medical technology and
therapeutics that have expanded con-
siderably the options available for deal-
ing with a pandemic.
Historical contextual issues and sta-
tistical limitations aside, the US urban
experience with nonpharmaceutical in-
terventions during the 1918-1919 pan-
demic constitutes one of the largest data
sets of its kind ever assembled in the
modern, postgerm theory era.
Our findings conform to 8 of A. Brad-
ford Hill’s 9 tenets on causal associa-
tions in the consideration of disease and
the environment.
36
Specifically, dur-
ing the 1918-1919 pandemic, the rela-
tion of early, sustained, and layered
nonpharmaceutical interventions to
EDR in 43 US cities demonstrate sat-
isfaction of the criteria of strength (the
magnitude and statistical significance
of our findings, which also argue against
an association by chance alone), con-
sistency (early and combined nonphar-
maceutical interventions were consis-
tently associated with reductions in
mortality, and our analysis is consis-
tent with 2 recent smaller, prelimi-
nary historical epidemiological re-
ports, although these studies look at
only 16 US urban centers, do not in-
clude actual activation and deactiva-
tion time points, duration, or layering
of nonpharmaceutical interventions,
and rely extensively on secondary his-
torical sources.
37,38
Further, our retrospective study is
consistent with the results from recent
theoretical models of the spread of a con-
temporary pandemic, which highlight
the value of early, combined, and sus-
tained nonpharmaceutical interven-
tions to mitigate a pandemic
11-15
), speci-
ficity (best demonstrated in cities with
bimodal mortality peaks when the trig-
gers were activated, deactivated, and re-
activated), temporality (interventions al-
ways preceded the reduction of EDR),
dose response (layering and increased du-
ration of the nonpharmaceutical inter-
ventions were associated with better out-
comes), biological plausibility (these
interventions reduce person-to-person
interactions and biologically would be
expected to reduce the spread of a com-
municable agent such as influenza), co-
herence (our data align with the estab-
lished body of knowledge on the
epidemiology of influenza), and anal-
ogy (isolation and social distancing have
been demonstrated as effective means of
preventing person-to-person spread of
other respiratory tract diseases, such as
rhinovirus, severe acute respiratory syn-
drome, respiratory syncytial virus, vari-
cella, and seasonal influenza).
The ninth tenet, experiment,could
not be demonstrated directly because
of the paucity of influenza pandemics
in the past century, the trend away from
such traditional public health mea-
INTERVENTIONS DURING 1918-1919 INFLUENZA PANDEMIC
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sures for disease control during the past
50 years, and ethical limitations of using
population-wide nonpharmaceutical in-
terventions in the absence of a serious
threat.
These findings contrast with the con-
ventional wisdom that the 1918 pan-
demic rapidly spread through each
community killing everyone in its path.
Although these urban communities had
neither effective vaccines nor antivi-
rals, cities that were able to organize and
execute a suite of classic public health
interventions before the pandemic
swept fully through the city appeared
to have an associated mitigated epi-
demic experience. Our study suggests
that nonpharmaceutical interventions
can play a critical role in mitigating the
consequences of future severe influ-
enza pandemics (category 4 and 5) and
should be considered for inclusion in
contemporary planning efforts as com-
panion measures to developing effec-
tive vaccines and medications for pro-
phylaxis and treatment. The history of
US epidemics also cautions that the
public’s acceptance of these health mea-
sures is enhanced when guided by ethi-
cal and humane principles.
39-41
Author Contributions: Drs Markel and Cetron had full
access to all of the data in the study and take respon-
sibility for the integrity of the data and the accuracy
of the data analysis.
Study concept and design: Markel, Lipman, Navarro,
Stern, Cetron.
Acquisition of data: Markel, Navarro, Sloan, Michalsen,
Stern.
Analysis and interpretation of data: Markel, Lipman,
Navarro, Sloan, Michalsen, Stern, Cetron.
Drafting of the manuscript: Markel, Lipman, Navarro,
Sloan, Michalsen, Stern, Cetron.
Critical revision of the manuscript for important in-
tellectual content: Markel, Lipman, Navarro, Stern,
Cetron.
Statistical analysis: Markel, Lipman, Cetron.
Obtained funding: Markel, Cetron.
Administrative, technical, or material support: Markel,
Navarro, Sloan, Michalsen, Cetron.
Study supervision: Markel, Cetron.
Financial Disclosures: None reported.
Funding/Support: This study was funded by a con-
tract from the US Centers for Disease Control and Pre-
vention (Sol No. 2006-N-08562, Non-Pharmaceuti-
cal Interventions Study/contract 200-2006-16894).
Role of the Sponsor: The US Centers for Disease Con-
trol and Prevention provided funding as part of pan-
demic preparedness research. Drs Cetron and Lip-
man from the Division of Global Migration and
Quarantine at the Centers for Disease Control and Pre-
vention participated as full scientific collaborators in
the investigation.
Acknowledgment: Matthew Cartter, MD, MPH,
Cleto DiGiovanni Jr, Jeffrey Duchin, MD, Bruce Gel-
lin, MD, Richard Goodman, MD, JD, Daniel Jerni-
gan, MD, MPH, Lisa Koonin, MN, MPH, Anthony
Marfin, MD, Martin Meltzer, PhD, William Thomp-
son, PhD, David Shay, MD, and Mary Wilson, MD,
provided constructive review of this manuscript. No
one metioned in this section was compensated for
contributing.
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INTERVENTIONS DURING 1918-1919 INFLUENZA PANDEMIC
654 JAMA, August 8, 2007—Vol 298, No. 6 (Reprinted) ©2007 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a J H Quillen College User on 05/29/2015
Saturated fatty acids increase levels of low-density lipo-
protein cholesterol (LDL-C) and HDL-C,
2
whereas trans-
fatty acids increase LDL-C level but decrease HDL-C level.
2,3
This distinction is important, because trans-fatty acids are
more strongly associated with the risk of cardiovascular dis-
ease than saturated fatty acids due to their undesirable ef-
fects on LDL-C and HDL-C levels, endothelial cell func-
tion, adipocytes, and inflammatory response.
3,4
Dae Hyun Kim, MD, MPH
dae-hyun.kim@mail.tju.edu
Department of Medicine
Jefferson Medical College
Philadelphia, Pennsylvania
Financial Disclosures: None reported.
1. Singh IM, Shishehbor MH, Ansell BJ. High-density lipoprotein as a therapeutic
target: a systematic review. JAMA.2007;298(7):786-798.
2. Kris-Etherton PM, Yu S. Individual fatty acid effects on plasma lipids and lipo-
proteins: human studies. Am J Clin Nutr.1997;65(5)(suppl):1628S-1644S.
3. Mozaffarian D, Katan MB, Ascherio A, Stampfer MJ, Willett WC. Trans fatty
acids and cardiovascular disease. NEnglJMed.2006;354(15):1601-1613.
4. Hu FB, Stampfer MJ, Manson JE, et al. Dietary fat intake and the risk of coro-
nary heart disease in women. NEnglJMed.1997;337(21):1491-1499.
In Reply: Dr Kim distinguishes the effects of saturated fatty
acids and trans-fatty acids on lipoproteins. However, re-
ports of the effect of trans-fatty acids on HDL-C have been
variable, with a large meta-analysis finding a statistically non-
significant effect on HDL-C.
1
In addition to increasing lev-
els of LDL-C, trans-fatty acids promote vascular inflamma-
tion and endothelial dysfunction and reduce paraoxonase
activity.
2
These lipid and biochemical effects act synergis-
tically to increase cardiovascular disease risk.
2
The issue is more complex than indicated by HDL-C. Satu-
rated fat rapidly promotes proinflammatory changes in HDL
without changing HDL-C level.
3
Thus, as mentioned in our
review, dietary intake of both saturated fatty acids and trans-
fatty acids should be avoided and substituted with intake
of monounsaturated and polyunsaturated fatty acids.
Inder M. Singh, MD, MS
Department of Cardiovascular Medicine
Krannert Institute of Cardiology
Indiana University Medical Center
Indianapolis
Mehdi H. Shishehbor, DO, MPH
shishem@gmail.com
Department of Cardiovascular Medicine
Cleveland Clinic
Cleveland, Ohio
Benjamin J. Ansell, MD
Department of Medicine
David Geffen School of Medicine at UCLA
Los Angeles, California
Financial Disclosures: Dr Ansell reported receiving speaking honoraria from As-
traZeneca, Kos Pharmaceuticals, Merck, and Pfizer; receiving research medication
from Merck and Pfizer in the past; and having equity interest in Bruin Pharma. No
other disclosures were reported.
1. Mensink RP, Zock PL, Kester AD, Katan MB. Effects of dietary fatty acids and
carbohydrates on the ratio of serum total to HDL cholesterol and on serum lipids
and apolipoproteins: a meta-analysis of 60 controlled trials. Am J Clin Nutr.2003;
77(5):1146-1155.
2. Mozaffarian D, Katan MB, Ascherio A, Stampfer MJ, Willett WC. Trans fatty
acids and cardiovascular disease. NEnglJMed.2006;354(15):1601-1613.
3. Nicholls SJ, Lundman P, Harmer JA, et al. Consumption of saturated fat im-
pairs the anti-inflammatory properties of high-density lipoproteins and endothe-
lial function. JAmCollCardiol.2006;48(4):715-720.
CORRECTIONS
Data Error: In the Review article entitled “Data Extraction Errors in Meta-analyses
That Use Standardized Mean Differences” published in the July 25, 2007, issue of
JAMA (2007;298:430-437), Figure 4 included incorrect data. The reported point
estimate and its 95% confidence interval for the meta-analysis standardized mean
differences 0.74 (0.98 to 0.49)” for the Edmonds et al article should have
read 0.77 (1.26 to 0.28).” The error was caused by a wrong label in the Coch-
rane Library at the time of the study. A meta-analysis was stated to have been
done with a random-effects model; however, it was done with a fixed-effect model.
The Cochrane Library no longer contains this error.
Typographical Errors in Tables: In the Research Letter entitled “Patterns of Preva-
lent Major Chronic Disease Among Older Adults in the United States” published
in the September 12, 2007, issue of JAMA (2007;298[10]:1160-1162), both tables
contained typographical errors. In both tables, the column headings of “Esti-
mated Frequency (!1000)” and “CVA” were erroneously transposed and the brace
under the column head “Disease Pattern, No. of Diseases” should have extended
to include the CVA column. Online versions of this article on the JAMA Web site
were corrected on October 4, 2007.
Unreported Financial Disclosures: In the Original Contribution entitled “Non-
pharmaceutical Interventions Implemented by US Cities During the 1918-1919
Influenza Pandemic” published in the August 8, 2007, issue of JAMA (2007;
298[6]:644-654), financial disclosures were inadvertently not reported. On page
654, under “Financial Disclosures,” the following should appear: “Dr Markel re-
ported having received honoraria for delivering lectures on the social and cultural
history of the 1918-1919 influenza pandemic at academic conferences or collo-
quia presented by Yale University, the US Department of Defense, the RAND Cor-
poration, Columbia University, the US Department of Health and Human Ser-
vices, the Michigan Society for Infection Control and Prevention, University of
Michigan, and Emory University. None of the other authors reported financial dis-
closures.”
Incorrect Affiliation: In the Research Letter entitled “Cardiovascular Response to
aModernRollerCoasterRide”publishedintheAugust15,2007,issueofJAMA
(2007;298[7]:739-741), the affiliations were reversed for 2 authors and 1 au-
thor’s name was listed out of order. Joachim Brade, MSc, is affiliated with the De-
partment of Medical Statistics and Dariusch Haghi, MD, is affiliated with the 1st
Department of Medicine-Cardiology, University Hospital of Mannheim, Mannheim,
Germany. The name for Christian Wolpert, MD, should have been placed last among
the list of author names.
LETTERS
2264 JAMA, November 21, 2007—Vol 298, No. 19 (Reprinted) ©2007 American Medical Association. All rights reserved.
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Discussion

The black plague killed more people, and was estimated to have killed 30% to 60% of Europe's population, but occurred in many waves over many years: https://en.wikipedia.org/wiki/Black_Death There were three big waves of the 1918-1919 pandemic. ![Imgur](https://imgur.com/SH7qohb.jpeg) Source: https://www.cdc.gov/flu/pandemic-resources/1918-commemoration/three-waves.htm ![Imgur](https://imgur.com/XT2mTSD.jpg) Source: https://en.wikipedia.org/wiki/Pandemic_severity_index#cite_note-HHS-1 In 1918, NYC was considered a world leader in public health, and their rapid response was exemplary. 100 years later, NYC acted too slowly. Positive correlation and the graph shows that longer response times were associated with worse outcomes for cities. "In dual-peaked cities, activation of nonpharmaceutical interventions was followed by a diminution of deaths and, typically, when nonpharmaceutical interventions were deactivated, death rates increased." This is the risk that cities/states will face if they reopen society, lifting quarantine restrictions too soon. Source: "Pandemics Depress the Economy, Public Health Interventions Do Not: Evidence from the 1918 Flu" The major reason to reopen prematurely is to reactivate the economy and get people back to work. However, a recent economic study analyzing the 1918 pandemic found that cities that kept their restrictions in place longer, experienced greater economic growth following the pandemic. ![Imgur](https://imgur.com/8ieRzXL.jpeg) “History is not a predictive science. There exist numerous well-documented and vast differences between US society and public health during the 1918 pandemic compared with the present. We acknowledge the inherent difficulties of interpreting data recorded nearly 90 years ago and contending with the gaps, omissions, and errors that may be included in the extant historical record.” Important limitation is that 1918 was a long time ago and history doesn’t always repeat itself. "One compelling question emerges: can lessons from the 1918-1919 pandemic be applied to contemporary pandemic planning efforts to maximize public health benefit while minimizing the disruptive social consequences of the pandemic as well as those accompanying public health response measures?" Yes. And we are seeing that firsthand with the NPI measures taken for COVID. "These findings contrast with the conventional wisdom that the 1918 pandemic rapidly spread through each community killing everyone in its path. Although these urban communities had neither effective vaccines nor antivirals, cities that were able to organize and execute a suite of classic public health interventions before the pandemic swept fully through the city appeared to have an associate mitigated epidemic experience." This is the hope with the mitigation strategies now being employed throughout the world for COVID. "Our study suggests that nonpharmaceutical interventions can play a critical role in mitigating the consequences of future severe influenza pandemics (category 4 and 5) and should be considered for inclusion in contemporary planning efforts as companion measures to developing effective vaccines and medications for prophylaxis and treatment. The history of US epidemics also cautions that the public’s acceptance of these health measures is enhanced when guided by ethical and humane principles." This study, and all of the interventions discussed, are directly applicable to our current situation. Even though at the time of the 1918-1919 pandemic, viruses had not been discovered yet, vaccines did not exist, and the common treatments were enemas, bloodletting and leeches, we are in a very similar boat in 2020 until we have a vaccine and effective antiviral treatments. NPIs are the way we deal with this during the mitigation phase.