Data

We obtained monthly pneumonia and influenza (P&I) and all-cause numbers of deaths for 1950 to 1999 from Health Canada (6), by 5-year age groups (details on the International Classification of Diseases codes used are given in Table 1). Canada was the only country with detailed age-specific mortality data for the 1950s readily available in electronic format.

Figure 2

Figure 2. Time series of monthly mortality from pneumonia and influenza (P&I, represented as death rate/100,000) from 1950 to 1972 in A) Canada and B) England and Wales. Black line: observed deaths, Red...

For England and Wales (referred to as "England" for simplicity), we compiled P&I and all-cause deaths by month for 1950 to 1999 from the Registrar General (1950–1958 [7], ), and National Statistics (1959–1999 [8], ). In both countries, monthly deaths were normalized by population size to obtain comparable death rates over time and these were standardized to 30.5-day months (Figure 2). Population data were obtained from the same agencies (6,8).

As US monthly vital statistics were not available electronically since 1950, we compiled excess death estimates from various historical publications (9–12). These estimates were based on National Vital Statistics and death records from P&I and all causes in major American cities compiled by the Centers for Disease Control and Prevention and derived from excess mortality models similar to ours (see below).

We also conducted a literature search to compile reports describing the local patterns and geographic spread of the 1951 influenza epidemic in the 3 countries (5,9,13,14). Moreover, we obtained mortality data specifically for Liverpool, where the 1951 epidemic had the highest impact and death records have been previously described (5,13,15,16) (Figure 1).

Seasonal Excess Death Rate Estimates, Canada and England

Our primary goal in this study was to compare the death rate of the 1951 epidemic with that of the 1957 and 1968 pandemics. For this purpose, we fit a seasonal model to P&I and all-cause deaths for 1950 to 1971, capturing all 3 influenza seasons of interest, as described below. We present monthly time series and seasonal estimates for this period (20 seasons, see Figure 2 for P&I). A secondary goal was to compare the age mortality pattern of the 1951 epidemic with that of other influenza seasons. To have more statistical power and analyze several influenza seasons with substantial death rates, we also used an extended study period, 1950–1999.

For Canada and England, we applied a modified version of Serfling's classical seasonal regression model to monthly data on death rates for each country (17), as described elsewhere (3,18). We obtained a baseline for deaths in the absence of influenza, separately for each outcome (P&I and all-cause) and available age group (see Figure 2 for P&I). Seasonal excess deaths were then estimated as the number of deaths in excess of the baseline during months of increased influenza activity.

Standardization of Seasonal Excess Death Rates

Since our goal was to compare influenza deaths across multiple seasons and countries, we had to control for baseline differences in demography, healthcare, and socioeconomic status that may affect influenza-related deaths. To this end, we calculated age-adjusted seasonal excess death estimates in a manner previously described (3,18). Further, to control for residual differences in baseline death rates related to health and socioeconomic status, we adjusted the seasonal estimates for temporal changes in mortality in the summer months, when influenza is absent (18). We used year 1960, midpoint of the main study period 1950–1971, as an index.

Age-Specific Patterns of Seasonal Excess Death Rates, Canada

We examined whether the 1951 epidemic had an epidemic or pandemic mortality age pattern, as indicated by a shift in the age distribution of deaths towards younger age groups (1). In Canada, the 1950–51 season was the first season in our mortality records with complete age details. Hence, we could not evaluate a potential age shift between earlier seasons and the 1950–51 season, as described elsewhere (1).

We therefore developed an alternative method to identify a pandemic signature, in which we compared the gradual increase of influenza-related deaths with age between epidemic and pandemic seasons. We first used all moderate-to-severe influenza seasons in the interpandemic periods to obtain a null distribution of mortality age patterns during epidemics (we chose the 17 seasons above the median). Second, we checked that we could actually detect a pandemic age pattern by comparing the null epidemic pattern with those of the 1957 and 1968 pandemics. Then, we compared the null pattern with that of the 1951 epidemic. To model the gradual increase of influenza-related deaths with age in adults, we fitted an exponential to unadjusted P&I excess death rates by 5-year age groups for persons >55 years of age. The test then relied on comparing between seasons the values of the age and intercept coefficients of the exponential models. Bootstrap resampling of influenza seasons in the interpandemic periods yielded a p value for the test.

Geographic and Temporal Spread

Influenza activity started to increase in Liverpool, England, in late December 1950 (5,13). The weekly death rate reached a peak in mid-January 1951 that was ≈40% higher than the peak of the 1918–19 pandemic, reflecting a rapid and unprecedented increase in deaths, which lasted for ≈5 weeks [5] and Figure 1). Since the early 20th century, the geographic spread of influenza could be followed across England from the weekly influenza mortality statistics in the country's largest cities, which represented half of the British population (13). During January 1951, the epidemic spread within 2 to 3 weeks from Liverpool throughout the rest of the country.

For Canada, the first report of influenza illness came the third week of January from Grand Falls, Newfoundland (19). Within a week, the epidemic had reached the eastern provinces, and influenza subsequently spread rapidly westward (19).

For the United States, substantial increases in influenza illness and excess deaths were reported in New England from February to April 1951, at a level unprecedented since the severe 1943-44 influenza season. Much milder epidemics occurred later in the spring elsewhere in the country (9).

Local disparities were found in all 3 countries, with a consistent pattern of higher numbers of deaths in locations affected earlier (9,13,14). In England, influenza-related death rates were ≈3-fold higher in Liverpool than in the rest of the country (13). In Canada, death rates were ≈2.4-fold higher in the eastern seaboard provinces than in the rest of the country (13,14). Similarly, in the United States, rates were ≈2.3-fold higher in New England than in the rest of the country (9).

Patterns of Seasonal Excess Death Rates, All Ages, 3 Countries

Figure 3

Figure 3. Seasonal pneumonia and influenza (P&I) excess death rates, all ages, 1950–51 to 1970–71. Crude death rates (blue bars), death rates adjusted for summer trends in mortality unrelated to influenza (pink bars)...

Crude and adjusted seasonal excess death estimates in the 3 countries are presented for the period 1950–1971 in Figure 3 (P&I). A specific comparison of the 1951 epidemic and 1957 pandemic is provided in Table 2 (P&I and all-cause).

For Canada, the 1951 epidemic was the most severe influenza season in the period 1950–1999, as indicated by crude seasonal excess death rates from P&I and all causes (data not shown). On the basis of both outcomes, the 1951 epidemic caused a 1.5-fold higher death rate than the 1957 pandemic; the rate was 3- to 4-fold higher than that seen in the 1968 pandemic. Adjusting for factors unrelated to influenza, such as demographics, health, and socioeconomic status only marginally modified our estimates (by <11%).

In England, the 1951 epidemic had similar death patterns. It was responsible for the largest increase in winter deaths from P&I and all causes in the period 1950–1999 (data not shown), with 1.3- to 1.4-fold higher crude excess death rates than those seen in the 1957 and 1968 pandemics. In contrast to Canada, adjusting for trends in demographics and health care substantially changed our excess death estimates, exacerbating the impact of the 1951 epidemic. Baseline P&I summer death rates doubled from 1950 to 1970 (Figure 2), probably because of rapid aging of the British population. During these 2 decades, the proportion of persons >65 years of age increased by 2.3% in England, which explains the trend in British death rates; in comparison, it increased by only 0.3% in Canada (6,8).

In the United States, by contrast, the 1951 epidemic was not particularly severe, except possibly in the New England region, adjacent to Canada. In the United States, this epidemic ranked with low-to-moderate influenza seasons, with only half the impact of the 1957 pandemic for P&I deaths and even less for all-cause deaths.

Estimation of crude and adjusted excess deaths suggests that the 1951 epidemic was unusually severe in England and Canada but not in the United States. The absolute rates of excess deaths were very different between countries, with systematically higher rates in England (by 3- to 5-fold, Table 2). The difference remained even after adjusting for international differences in demographics and healthcare and was also found for deaths from all causes, which controls for potential differences in the coding of death certificates (Table 2). Such international discrepancies in influenza-related death rates have been highlighted on several occasions in the past, although not elucidated (18,20–22). Because of these unresolved differences, this analysis focused on the relative impact of the 1951 epidemic as compared with surrounding influenza seasons.

Age-specific Patterns of Seasonal Excess Death Rates, Canada

Given the unusual death rate of the 1951 influenza epidemic in England and Canada, we hypothesized that an emerging virus subtype may have circulated there, perhaps with pandemic potential. We investigated the age-specific mortality pattern of the 1951 epidemic in Canada in relation to other seasons to address this aspect.

Figure 4

Figure 4. Age-specific pneumonia and influenza (P&I) excess death rates in the 1951 influenza epidemic, 1957, and 1968 pandemics, Canada. A) Observed. B) Exponential models using 5-year age groups starting at age 55...

Inspection of P&I excess death rates by age shows that the 1951 epidemic had the typical pattern of death rates found in other epidemics, steeply increasing with age after infancy (Figure 4). Statistical analysis showed that the age pattern in 1951 was well within the range of the null distribution of reference epidemic seasons in influenza interpandemic periods (Table 3). Conversely, we found lower age coefficients for the 1957 and 1968 pandemics as compared with reference epidemic seasons, illustrating that deaths increased less with age in pandemics than in epidemics and that our statistical approach could detect a pandemic signature (p<0.001) (1).