Age-specific excess mortality patterns and transmissibility during the 1889–1890 influenza pandemic in Madrid, Spain

Accepted Manuscript Age-specific excess mortality patterns and transmissibility during the 1889-90 influenza pandemic in Madrid, Spain Diego Ramiro, Sara Garcia, Yolanda Casado, Laura Cilek, Gerardo Chowell PII:

S1047-2797(17)30684-1

DOI:

10.1016/j.annepidem.2017.12.009

Reference:

AEP 8338

To appear in:

Annals of Epidemiology

Received Date: 5 July 2017 Revised Date:

15 December 2017

Accepted Date: 19 December 2017

Please cite this article as: Ramiro D, Garcia S, Casado Y, Cilek L, Chowell G, Age-specific excess mortality patterns and transmissibility during the 1889-90 influenza pandemic in Madrid, Spain, Annals of Epidemiology (2018), doi: 10.1016/j.annepidem.2017.12.009. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Age-specific excess mortality patterns and transmissibility during the 1889-90 influenza pandemic in Madrid, Spain

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Diego Ramiro1, Sara Garcia1, Yolanda Casado1, Laura Cilek1, Gerardo Chowell2,3* 1

Institute of Economics, Geography and Demography, Center for Humanities and Social Sciences, CCHS- CSIC, Spanish National Research Council School of Public Health, Georgia State University, Atlanta, Georgia, USA

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2

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Division of International Epidemiology and Population Studies, Fogarty International Center, National Institutes of Health, Bethesda, MD, USA

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*Corresponding author Keywords

1889-90 influenza pandemic, Madrid, Spain, age-specific mortality, reproduction number

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Abstract Background: Although the 1889-1890 influenza pandemic was one of the most important epidemic events of the XIXth century, little is known about the mortality impact of this pandemic based on detailed respiratory mortality datasets. Materials & Methods: We estimated excess mortality rates for the 1889-90 pandemic in Madrid from high-resolution respiratory and all-cause individual-level mortality data retrieved from the Gazeta de Madrid, the Official Bulletin of the Spanish government. We also generated estimates of the reproduction number from the early growth phase of the pandemic. Results: The main pandemic wave in Madrid was evident from respiratory and all-cause mortality rates during the winter of 1889-90. Our estimates of excess mortality for this pandemic were 58.3 per 10,000 for all-cause mortality and 44.5 per 10,000 for respiratory mortality. Agespecific excess mortality rates displayed a J-shape, with school-age children 5-14 year olds (yo) experiencing the lowest respiratory excess death rates (8.8 excess respiratory deaths per 10,000) while older populations >=70 yrs. had the highest rates (367.9 per 10,000). Although seniors experienced the highest absolute excess death rates, the standardized mortality ratio was highest among young adults 15-24 yrs. The early growth phase of the pandemic displayed dynamics consistent with an exponentially growing transmission process. Using the generalized-growth method, we estimated the reproduction number in the range 1.2-1.3 assuming a 3-day mean generation interval and from 1.3-1.5 assuming a 4-day mean generation interval. Discussion: Our study adds to our understanding of the mortality impact and transmissibility of the 1889-90 influenza pandemic using detailed individual-level mortality datasets. More quantitative studies are needed to quantify the variability of the mortality impact of this understudied pandemic at regional and global scales.

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INTRODUCTION

Although the 1889-1890 influenza pandemic was one of the most important epidemic events of the XIXth century, our understanding of the mortality impact of this pandemic across different

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socio-demographic groups has been limited by the lack of high-resolution all-cause and

respiratory mortality datasets. This pandemic is better known as the "Russian Flu" because the rapid global spread of the pandemic virus can be traced back to Saint Petersburg, Rusia in

October 1889 (1). Moreover it was the first to unfold in a world connected by rail and maritime

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transportation (2); it spread across Europe in approximately 6 weeks, with an estimated mean

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speed at 394 km/week (1) and circulated around the world in just 4 months (1, 3).

Increased influenza mortality associated with the 1889-90 pandemic appears to have occurred first in Saint Petersburg, Russia in early December 1889 whereas mortality levels peaked during the last two weeks of January 1890 in several European cities including Berlin, Vienna, Paris, London and Barcelona. In the Americas, peak mortality did not occur until early February 1890. In the US, New York City and Boston were the first cities to report influenza cases during the

epidemic peak (1).

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first week of January 1890. At the local level, cases occurred on average 5 weeks prior to the

The 1889 pandemic virus likely arrived in Spain via Cataluna in early December 1889, but virus

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introductions originating from the mediterranean via Malaga are also plausible. While the first cases in Barcelona were reported during 8-10 December 1889 (4), the highest incidence levels

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occurred around 20-30 December 1889 (5). In Madrid, the first cases were reported in midDecember 1889, likely importations from Barcelona and/or Paris. Overall, mortality in Madrid was significantly elevated during the months of December 1889 and January 1890.

Little is known about the excess mortality impact and transmissibility associated with the 188990 influenza pandemic (1, 6). In particular, there is a lack of studies that quantify the excess mortality impact associated with this pandemic by relying on pre-pandemic mortality data which is necessary for calibrating baseline mortality models. Hence, here we sought to characterize the age-specific absolute and relative mortality patterns and the reproduction number associated with

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the 1889-90 influenza pandemic in the city of Madrid, Spain by relying on a large mortality dataset comprising 77,169 individual death records covering the period: July 1888 - December 1892.

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MATERIAL AND METHODS

Data sources

From 1888 to 1901, information relating to the burials taking place in the City of Madrid was

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published daily in the Gazeta de Madrid, the Official Bulletin of the Spanish government (Figure 1). A total of 77,169 individual death records covering the period July 1888 - December 1892

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were manually retrieved from the Gazeta de Madrid. For each death, we accessed the age, cause, and date of death. We then analyzed daily and weekly all-cause and respiratory mortality time series stratified into 6 age groups (<5 y, 5-14 y, 15-24 y, 25-49 y, 50-69 y, and >=70 y). We used a broad definition for respiratory deaths, which included deaths due to influenza, pneumonia, lung congestion, bronchopneumonia, or bronchitis, and excluded deaths associated with tuberculosis infection. All records contained cause of death information whereas ~1.3% of

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records lacked age information.

We obtained age-specific population data for Madrid from the 1887 census (total population of 470,283). At the time, Madrid was a fast growing capital city due to rural-urban migration

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reaching 539,835 inhabitants in 1900.

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Statistical analysis

Excess mortality estimates

To quantify the mortality burden associated with the winter 1889-90 pandemic wave, we estimated the cumulative number of deaths occurring in excess of a baseline mortality level defined during the period covering mid October 1888 to March 1889. The absolute mortality burden of the pandemic was estimated as the sum of excess deaths (i.e., above the mortality baseline) during the pandemic period covering mid October 1889 to March 1890.

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Additionally, we calculated the ratio of observed mortality during the pandemic period to the corresponding baseline mortality level, or the standardized mortality ratio (SMR) for pandemic mortality. The standardized mortality ratio is interpreted relative to 1, with values greater than 1

Estimation of the reproduction number

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representing an increased risk of death during the pandemic period (7).

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The basic reproduction number, commonly denoted by R0 , gauges the transmission potential of an infectious disease epidemic in a fully susceptible population during the early transmission

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phase (8). Here, we estimate the effective reproduction number during the early phase of the daily curve of pandemic respiratory deaths using the Generalized-Growth Model (GGM) (9) to characterize and estimate the effective reproduction number Rt (10). The GGM is flexible and can reproduce a range of growth dynamics from constant incidence ( p = 0 ) to exponential growth ( p = 1 ) (9). For instance, application of this generalized-growth model to empirical data has revealed a notably slow spread ( p < 1) of the 2014 Ebola outbreaks at district-level in parts of

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West Africa, intermediate spread profiles for historical plague and smallpox outbreaks ( p = 0.8 ), and near exponential dynamics for the 1918 influenza pandemic in San Francisco ( p ≈ 1 ) (11). Departure from standard epidemic theory may be more common than previously thought as a

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result of multidimensional transmission heterogeneities (9). Specifically, based on the incidence at calendar time ti denoted by I i , and the discretized probability distribution of the generation

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interval denoted by ρ i , the effective reproduction number can be estimated using the renewal equation (12, 13):

Rti =

Ii

i

∑I

i− j

(7)

ρj

j=0

where the denominator represents the total number of cases that contribute (as primary cases) to generating the number of new cases I i (as secondary cases) at calendar time ti (12).

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RESULTS

Pandemic wave and excess mortality estimates

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Our examination of weekly mortality rates from July 1888 to December 1892 revealed a substantial elevation in respiratory and all-cause mortality rates during the winter of 1889-90 in Madrid (Figures 2). This relative increase in winter mortality is also evident across all age

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groups for both respiratory and all-cause mortality (Figure 3). Our estimates of excess mortality derived for this pandemic were 58.3 per 10,000 from all-cause mortality and 44.5 per 10,000

Pandemic age mortality patterns

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from respiratory mortality.

Based on weekly mortality time series in Madrid, the brunt of pandemic mortality occurred in October 1889 - February 1890 (Figure 4). Age-specific excess mortality rates displayed a J-

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shape (Table 1, Figure 5). That is, school-age children 5-14 year olds (yo) experienced the lowest respiratory excess death rates (8.8 excess respiratory deaths per 10,000) while older populations

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>=70 yrs. had the highest rates (367.9 per 10,000). Age mortality patterns were qualitatively

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similar when using all-cause excess mortality rates (Table 1, Figure 5).

The standardized mortality ratio (SMR) quantifying the mortality elevation relative to the baseline mortality level varied from 1.5 to 9.9% during the pandemic period based on respiratory mortality and varied from 1.3 to 2.3 based on all-cause mortality (Figure 5). Although seniors experienced the highest absolute excess death rates (Table 1), the standardized mortality ratio was highest among young adults 15-24 yrs. during the pandemic period.

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Pandemic growth profile and the reproduction number Using the early growth phase in the number of new respiratory deaths, we estimated the deceleration of growth parameter at 0.8 (95%CI: 0.9, 1.0), an epidemic growth profile with

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uncertainty bounds that includes exponential growth dynamics (i.e., p=1) during the early growth trajectory of the pandemic in Madrid. Based on the generalized-growth method, we estimated the reproduction number in the range 1.2-1.3 assuming a 3-day mean generation interval and from

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1.3-1.5 assuming a 4-day mean generation interval while the variance of the generation interval

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was estimated at 1.0 (Table 2; Figure 6).

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DISCUSSION

Our analysis of individual-level mortality datasets revealed a high excess mortality rate for the

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1889-90 influenza pandemic in Madrid, estimated at 58.3 per 10,000 from all-cause mortality and 44.5 per 10,000 from respiratory mortality. Overall the J-shaped age patterns of mortality described here is in line with prior studies based on annual mortality statistics (6). Nevertheless,

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we found that the mortality elevation over the baseline was highest for young adults aged 15-24 yrs. (standardized mortality ratio of 9.9 based on respiratory deaths). Whereas the “Russian flu”

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pandemic hit Madrid during one major pandemic wave in winter 1889-90, three “Spanish flu” pandemic waves affected Madrid during 1918-1920 (14). Madrid experienced the highest excess respiratory death rate during the spring-summer 1918, estimated at 10.3 per 10,000 or a 1.68-fold increase over baseline respiratory mortality rate during this period (15). During the entire 1918-

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1920 pandemic period, the excess respiratory mortality rate has been estimated at ~45-50 per 10,000 in Madrid using multiple sources of mortality data (15, 16).

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It is worth noting that the high excess mortality rates among seniors are indicative of lack of mortality protection in this age group, suggesting a lack of exposure to antigenically-related

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viruses. For comparison with other influenza pandemics, it is generally accepted that senior sparing did not play a major role in the 1957 pandemic, which contrasts the experience of the US (17, 18) and Europe (19, 20) (21, 22) with the 1918 and the 2009 pandemics.

Based on the curve of weekly respiratory deaths for this pandemic in Madrid, we obtained a moderate estimate of the reproduction number in the range 1.2-1.5, with an estimated epidemic

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growth profile whose uncertainty includes the possibility of exponential growth (Table 2). Our R estimates lie in the lower range of R estimates for this pandemic derived for 96 cities using allcause excess mortality data and an SEIR transmission model (1). Moreover, our estimates fall

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within the range of estimates reported for other influenza pandemics. Specifically, R estimates have been reported in the range 1.5-5.4 for community-based settings (23, 24) and from 2.1-7.5 in confined settings (23) for the 1918 influenza pandemic. For the 1957 influenza pandemic,

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estimates lie in the range 1.5-1.8 in England and Wales (25, 26) and in the range 1.4-2.5 in two large cities of Chile (27). For the 1968 influenza pandemic, R estimates lie in the range 1.1-3.6

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(28) whereas estimates lie in the range 1.2-3.1 for the 2009 A/H1N1 influenza pandemic (29).

Our study has several limitations. Due to lack of laboratory confirmation, our excess mortality approach cannot distinguish the elevation in mortality rates associated with other respiratory

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viruses coinciding with the pandemic period. Moreover, our excess mortality calculation approach, which was relatively simple, due to lack of contemporaneous virological surveillance and calibrated a mortality baseline using a single year of mortality data (winter of 1888-89).

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Moreover, the excess methodology employed in our study does not guarantee that excess

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mortality estimates are additive by age group (30).

Acknowledgements

We thank the staff of the Instituto de Economia, Geografia y Demografia del CSIC for conducting the arduous task of digitizing the mortality records employed in our study.

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Tables Table 1. Total and age-specific estimates of pandemic excess mortality rates per 10,000 population and the standardized mortality ratio (SMR) for respiratory and all-cause mortality

Respiratory mortality Pandemic

<5 yrs

5-14 yrs

15-24 yrs

25-49 yrs

>=70 yrs

All ages

79.0

8.8

13.2

36.1

112.5

367.9

44.5

1.5

1.9

9.9

4.9

3.4

3.3

2.2

25-49 yrs

50-69 yrs

>=70 yrs

All ages

26.3

53.0

162.9

675.2

58.3

2.3

2.3

1.9

1.9

1.6

period

excess

Standardized mortality risk (SMR)

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mortality rate

50-69 yrs

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Absolute

per 10,000

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during the 1889-90 influenza pandemic, Madrid, Spain.

All-cause mortality

period Absolute excess mortality rate 64.1

per 10,000

5-14 yrs

15-24 yrs

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<5 yrs

19.2

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Standardized

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Pandemic

mortality risk (SMR)

1.3

1.3

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Table 2. Mean estimates and the corresponding 95% confidence intervals for the effective reproduction number during the early growth phase of the 1889-90 influenza pandemic in Madrid, Spain. We assumed a generation interval that follows a gamma distribution with a mean of 3 or 4 days and variance of 1. 4-day generation interval

1.3 (1.2, 1.3)

1.4 (1.3, 1.5)

Reproduction number

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3-day generation interval

0.22 (0.12, 0.39)

Growth rate, r Deceleration of growth

0.90 (0.80, 1.0)

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parameter, p

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Figures

Figure 1. This illustration shows the list of deaths in Madrid that were reported on 8-December1889 according to the Gazeta de Madrid. For our study, we accessed the age, cause, and date of

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death from this source. From 1888 until 1901, the information concerning all the burials taking place in the City of Madrid was published on a daily basis in the Gazeta de Madrid, the Official

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Bulletin of the government of Spain.

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Figure 2. Weekly time series of all-cause and respiratory mortality per 10,000 people in Madrid,

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July 1888 to December 1892.

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Figure 3. Age-stratified weekly all-cause and respiratory mortality rates per 10,000 in the city of

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Madrid, 1889-90.

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Figure 4. Age-stratified weekly baseline mortality level (winter of 1888-89) and respiratory mortality rates during the main pandemic period in the city of Madrid during the winter of 1889-

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90.

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Figure 5. Age-specific excess respiratory and all-cause mortality rates per 10,000 and the corresponding standardized mortality ratio (SMR) during the main pandemic period in Madrid,

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Spain, winter of 1889-90.

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Figure 6. Weekly all-age respiratory death counts in Madrid, Spain during the early growth phase of the main pandemic period, 1889-90. Circles correspond to the data, the solid red line corresponds to the generalized-growth model (GGM) best fit while blue lines correspond to the uncertainty. Estimates of the reproduction number are shown in Table 2. We estimated the

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deceleration of growth parameter at 0.8 (95%CI: 0.9, 1.0), an epidemic growth profile with

uncertainty bounds that includes exponential growth dynamics (i.e., p=1) during the early growth

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trajectory of the pandemic in Madrid.

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Fuente: Gaceta de Madrid. Inhumaciones verificadas en los cementerios de la capital el 8 de diciembre de 1889.

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Death rate per 10,000

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30

25

20

15

10

5

0 10-Jul-88 31-Jul-88 21-Aug-88 11-Sep-88 02-Oct-88 23-Oct-88 13-Nov-88 04-Dec-88 25-Dec-88 15-Jan-89 05-Feb-89 26-Feb-89 19-Mar-89 09-Apr-89 30-Apr-89 21-May-89 11-Jun-89 02-Jul-89 23-Jul-89 13-Aug-89 03-Sep-89 24-Sep-89 15-Oct-89 05-Nov-89 26-Nov-89 17-Dec-89 07-Jan-90 28-Jan-90 18-Feb-90 11-Mar-90 01-Apr-90 22-Apr-90 13-May-90 03-Jun-90 24-Jun-90 15-Jul-90 05-Aug-90 26-Aug-90

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All cause Respiratory deaths

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600 500

200

EP

300

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400

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Excess Respiratory Deaths per 10,000 people

700

100

0 <5

5-14

15-24

25-49

50-69

>

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