HW Assignment 3

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ORIGINAL CONTRIBUTION

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

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 were obtained from the US Cen- sus Bureau’s Weekly Health Index17 for 1918-1919, a series of reports listing total 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 had incomplete archival and 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 in US urban areas during the 1918-1919 pandemic.

In addition, we captured all of the available public health documents on nonpharmaceutical interventions imple- mented by these 43 cities during the 1918- 1919 pandemic, including municipal public health department annual and monthly reports and weekly bulletins; every state and federal report on the 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 additional hold- ings housed in 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,

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, and the status (on/off) of every com- bination of nonpharmaceutical interven- tions as the independent variables. In the ANOVA model, each possible combina- tion of nonpharmaceutical interventions was treated as an independent variable to test for layering effects. Any factor with a P value of less than .10 was included in the model. Because there is ambigu- ity over the rigor with which 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. TABLE 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.

TABLE 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 1 of the 3 major categories of nonphar- 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

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 r2 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.

source of the variation in the weekly EDRs within and between the cities. The ANOVA results are shown in TABLE 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 a strategy of nonpharmaceutical inter- 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 FIGURE 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 m o r t a l i t y ( S p e a r m a n r = − 0 . 7 4 , 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; TABLE 4).

Figures 1C and 1D show the associa- tion between early, 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). In summary, the 21 cities that had earlier PHRT (ie, less than the median)

and the most sustained and most days of nonpharmaceutical interventions had a statistically significant reduction in excess pneumonia and influenza mortality rates compared with the 21 cities that had later PHRT and fewer days of nonpharmaceu- tical interventions (Table 4).

FIGURE 2 shows the aggregate city mortality curves by region (East, Mid- west and South, and West). FIGURE 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-May 1918), 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

Publishedvirologicalevidenceforstrain variation during wave 2 is limited to a single genotypic variant without evidence for significant phenotypic change in virulence.30-33 While plausible, no virologi-

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.

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 the city-specific popu- lation size and density; sex distribution; and proportion of ages of younger than 1 month to 5 years, 15 to 40 years, 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 population size, 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

Figure 1. Scatterplot of Public Health Response Time for 43 US Cities From September 8, 1918, Through February 22, 1919

New York City, NY

0 –15 –10 –5 0 5 10 15 20 25 30 35

Public Health Response Time, d

T im

e to

F irs

t P

ea k

E xc

es s

D ea

th R

at e,

Time to first mortality peak by public health response time

Pittsburgh, PA

St Louis, MO

Denver, CO

St Paul, MNGrand Rapids, MI

250

200

150

New York City, NY

0 –15 –10 –5 0 5 10 15 20 25 30 35

Public Health Response Time, d

E xc

es s

D ea

th s/

1 0 0

0 0 0 P

o p

u la

tio n

Magnitude of first mortality peak by public health response time

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

E xc

es s

D ea

th s/

1 0 0

0 0 0 P

o p

u la

tio n

Total excess pneumonia and influenza mortality by public health response time

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

E xc

es s

D ea

th s/

1 0 0

0 0 0 P

o p

u la

tio n

Total excess pneumonia and influenza mortality by total No. of days of nonpharmaceutical interventions

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 cities 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

Figure 2. Aggregate Weekly Excess Death Rates for 43 US Cities by Region From September 8, 1918, Through February 22, 1919

120

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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 Midwest and South region; and 529 for the West region.

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

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u la

tio n

Denver, COC Total excess death rate: 807/100 000 population Public health response time: +7 d Total No. of days of nonpharmaceutical interventions: 53

Pittsburgh, PAD

Total excess death rate: 358/100 000 population Public health response time: +1 d Total No. of days of nonpharmaceutical interventions: 143

100

120

110

130

140

St Louis, MOA 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, NYB

School closure

Public gathering ban

Isolation, quarantine

School closure

Public gathering ban

Otherd

Otherc

Isolation, quarantine

Otherb

Weekly excess death rate

2 × baseline mortality First pneumonia and influenza case

Oct 6

Sep 8,

1918

Nov 3

Dec 1

Jan 5,

1919

23Feb 2

Oct 6

Sep 8,

1918

Nov 3

Dec 1

Jan 5,

1919

23Feb 2

Oct 6

Sep 8,

1918

Nov 3

Dec 1

Jan 5,

1919

23Feb 2

Oct 6

Sep 8,

1918

Nov 3

Dec 1

Jan 5,

1919

23Feb 2

School closure

Public gathering ban

Othera

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.

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