Brief communication: Rethinking the impact of the 1918 influenza pandemic on sex differentials in mortality

This study will assess the general impact of the 1918 influenza on overall mortality and its impact on mortality attributable to pulmonary tuberculosis in a small‐scale population. Using life table and decomposition methodologies, changes in mortality in Gibraltar used a scheme that identified a pre‐epidemic period (1904–1917), the epidemic year (1918), and the post‐epidemic period (1919–1927). Overall health in both sexes fell significantly in 1918 with a drop in life expectancy at birth, however, health quickly rebounded in the post‐epidemic period. In the case of women, there was a significant increase in life expectancy at birth after the epidemic. The impact of influenza on the magnitude of sex differentials in the life expectancy at birth fell during epidemic year but returned to a level comparable to that of the pre‐epidemic period. With respect to respiratory tuberculosis deaths, the immediate impact of influenza was restricted to only a significant increase in the rate among women (aged 15–54). In the post‐epidemic period, tuberculosis mortality rates returned to the pre‐epidemic state in both sexes. The findings from Gibraltar stand in contrast opposition to results reported for experience in the United States during the 1918 flu. Am J Phys Anthropol, 2009. © 2009 Wiley‐Liss, Inc.     

Influenza and pneumonia mortality in 66 large cities in the United States in years surrounding the 1918 pandemic

The 1918 influenza pandemic was a major epidemiological event of the twentieth century resulting in at least twenty million deaths worldwide; however, despite its historical, epidemiological, and biological relevance, it remains poorly understood. Here we examine the relationship between annual pneumonia and influenza death rates in the pre-pandemic (1910–17) and pandemic (1918–20) periods and the scaling of mortality with latitude, longitude and population size, using data from 66 large cities of the United States. The mean pre-pandemic pneumonia death rates were highly associated with pneumonia death rates during the pandemic period (Spearman ρ = 0.64–0.72; P<0.001). By contrast, there was a weak correlation between pre-pandemic and pandemic influenza mortality rates. Pneumonia mortality rates partially explained influenza mortality rates in 1918 (ρ = 0.34, P = 0.005) but not during any other year. Pneumonia death counts followed a linear relationship with population size in all study years, suggesting that pneumonia death rates were homogeneous across the range of population sizes studied. By contrast, influenza death counts followed a power law relationship with a scaling exponent of ∼0.81 (95%CI: 0.71, 0.91) in 1918, suggesting that smaller cities experienced worst outcomes during the pandemic. A linear relationship was observed for all other years. Our study suggests that mortality associated with the 1918–20 influenza pandemic was in part predetermined by pre-pandemic pneumonia death rates in 66 large US cities, perhaps through the impact of the physical and social structure of each city. Smaller cities suffered a disproportionately high per capita influenza mortality burden than larger ones in 1918, while city size did not affect pneumonia mortality rates in the pre-pandemic and pandemic periods.     

Can photoperiod predict mortality in the 1918-1920 influenza pandemic?

Amplitude of the seasonal change in day length increases with distance from the equator, and changes in day length markedly alter immune function in diverse nonhuman animal models of infection. Historical records of mortality data, ambient temperature, population density, geography, and economic indicators from 42 countries during 1918-1920 were analyzed to determine relative contributions toward human mortality during the "Spanish" influenza pandemic of 1918-1920. The data identify a strong negative relation between distance from the equator and mortality during the 1918-1920 influenza pandemic, which, in a multiple regression model, manifested independent of major economic, demographic, and temperature variables. Enhanced survival was evident in populations that experienced a winter nadir day length ≤10 h light/day, relative to those that experienced lower amplitude changes in photoperiod. Numerous reports indicate that exposure to short day lengths, typical of those occurring outside the tropics during winter, yields robust and enduring reductions in the magnitude of cytokine, febrile, and behavioral responses to infection. The present results are preliminary but prompt the conjecture that, if similar mechanisms are operant in humans, then they would be predicted to mitigate symptoms of infection in proportion to an individual's distance from the equator. Although limitations and uncertainties accompany regression-based analyses of historical epidemiological data, latitude, per se, may be an underrecognized factor in mortality during the 1918-1920 influenza pandemic. The author proposes that some proportion of the global variance in morbidity and mortality from infectious diseases may be explained by effects of day length on the innate immune response to infection.     

Death,demography and the denominator: Age-adjusted Influenza-18 mortality in Ireland

Using the Irish experience of the 1918–1919 Spanish flu pandemic (“Influenza-18”), we demonstrate how pandemic mortality statistics can be sensitive to the demographic composition of a country. We build a new spatially disaggregated population database for Ireland’s 32 counties for 1911–1920 with vital statistics on births, ageing, migration and deaths. Our principal contribution is to show why, and how, age-at-death data should be used to construct the age-standardised statistics necessary to make meaningful comparisons of mortality rates across time and space. We conclude that studies of the economic consequences of pandemics must better control for demographic factors if they are to yield useful policy-relevant insights. For example, while Northern Ireland had a higher crude death rate during the first wave of the Covid-19 pandemic, it also has an older population; age-adjusted mortality paints a very different picture.     

The 1918-1919 influenza pandemic in England and Wales: spatial patterns in transmissibility and mortality impact

Spatial variations in disease patterns of the 1918-1919 influenza pandemic remain poorly studied. We explored the association between influenza death rates, transmissibility and several geographical and demographic indicators for the autumn and winter waves of the 1918-1919 pandemic in cities, towns and rural areas of England and Wales. Average measures of transmissibility, estimated by the reproduction number, ranged between 1.3 and 1.9, depending on model assumptions and pandemic wave and showed little spatial variation. Death rates varied markedly with urbanization, with 30-40% higher rates in cities and towns compared with rural areas. In addition, death rates varied with population size across rural settings, where low population areas fared worse. By contrast, we found no association between transmissibility, death rates and indicators of population density and residential crowding. Further studies of the geographical mortality patterns associated with the 1918-1919 influenza pandemic may be useful for pandemic planning.     

Qualitative analysis of the level of cross-protection between epidemic waves of the 1918-1919 influenza pandemic

The 1918-1919 influenza pandemic was composed of multiple waves within a period of nine months in several regions of the world. Increasing our understanding of the mechanisms responsible for this multi-wave profile has important public health implications. We model the transmission dynamics of two strains of influenza interacting via cross-immunity to simulate two temporal waves of influenza and explore the impact of the basic reproduction number, as a measure of transmissibility associated to each influenza strain, cross-immunity and the timing of the onset of the second influenza epidemic on the pandemic profile. We use time series of case notifications during the 1918 influenza pandemic in Geneva, Switzerland, for illustration. We calibrate our mathematical model to the initial wave of infection to estimate the basic reproduction number of the first wave and the corresponding timing of onset of the second influenza variant. We use this information to explore the impact of cross-immunity levels on the dynamics of the second wave of influenza. Our results for the 1918 pandemic in Geneva, Switzerland, indicate that a second wave can occur whenever R₀₁<1.5 or when cross-immunity levels are less than 0.58 for our estimated R₀₂ of 2.4. We also explore qualitatively profiles of two-wave pandemics and compare them with real temporal profiles of the 1918 influenza pandemic in other regions of the world including several Scandinavian cities, New York City, England and Wales, and Sydney, Australia. Pandemic profiles are classified into three broad categories namely “right-handed”, “left-handed”, and “M-shape”. Our results indicate that avoiding a second influenza epidemic is plausible given sufficient levels of cross-protection are attained via natural infection during an early (herald) wave of infection or vaccination campaigns prior to a second wave. Furthermore, interventions aimed at mitigating the first pandemic wave may be counterproductive by increasing the chances of a second wave of infection that could potentially be more virulent than the first.     

Regional variations and trends in mortality from cardiovascular diseases in population aged 0-64 in Dalmatia and Slavonia, 1998-2009

The aim of this paper was to analyse the regional variations and trends in mortality from cardiovascular diseases in the population aged 0-64 years in Dalmatia and Slavonia, over the period 1998 to 2009. Mortality data were derived from Central Bureau of Statistics. The results show that age-standardized mortality rates from total cardiovascular diseases, ischaemic heart diseases and cerebrovascular diseases were lower in Dalmatia than rates for Slavonia, for both genders. All mortality rates, except rates for ischaemic heart diseases mortality for men in both regions, showed the trend of decline. Dalmatia has a more protective factors in pattern of Mediterranean diet. The improvement of cardiovascular health and reduction of premature mortality from cardiovascular diseases requires a system and comprehensive intervention approach at all levels of health care and multisectorial coordination.     

Age-Specific Mortality During the 1918 Influenza Pandemic: Unravelling the Mystery of High Young Adult Mortality

The worldwide spread of a novel influenza A (H1N1) virus in 2009 showed that influenza remains a significant health threat, even for individuals in the prime of life. This paper focuses on the unusually high young adult mortality observed during the Spanish flu pandemic of 1918. Using historical records from Canada and the U.S., we report a peak of mortality at the exact age of 28 during the pandemic and argue that this increased mortality resulted from an early life exposure to influenza during the previous Russian flu pandemic of 1889–90. We posit that in specific instances, development of immunological memory to an influenza virus strain in early life may lead to a dysregulated immune response to antigenically novel strains encountered in later life, thereby increasing the risk of death. Exposure during critical periods of development could also create holes in the T cell repertoire and impair fetal maturation in general, thereby increasing mortality from infectious diseases later in life. Knowledge of the age-pattern of susceptibility to mortality from influenza could improve crisis management during future influenza pandemics.

“The war is over – and I must go” Egon Schiele, 1890–1918.

     

Were Equatorial Regions Less Affected by the 2009 Influenza Pandemic? The Brazilian Experience

Although it is in the Tropics where nearly half of the world population lives and infectious disease burden is highest, little is known about the impact of influenza pandemics in this area. We investigated the mortality impact of the 2009 influenza pandemic relative to mortality rates from various outcomes in pre-pandemic years throughout a wide range of latitudes encompassing the entire tropical, and part of the subtropical, zone of the Southern Hemisphere (+5(°)N to -35(°)S) by focusing on a country with relatively uniform health care, disease surveillance, immunization and mitigation policies: Brazil. To this end, we analyzed laboratory-confirmed deaths and vital statistics mortality beyond pre-pandemic levels for each Brazilian state. Pneumonia, influenza and respiratory mortality were significantly higher during the pandemic, affecting predominantly adults aged 25 to 65 years. Overall, there were 2,273 and 2,787 additional P&I- and respiratory deaths during the pandemic, corresponding to a 5.2% and 2.7% increase, respectively, over average pre-pandemic annual mortality. However, there was a marked spatial structure in mortality that was independent of socio-demographic indicators and inversely related with income: mortality was progressively lower towards equatorial regions, where low or no difference from pre-pandemic mortality levels was identified. Additionally, the onset of pandemic-associated mortality was progressively delayed in equatorial states. Unexpectedly, there was no additional mortality from circulatory causes. Comparing disease burden reliably across regions is critical in those areas marked by competing health priorities and limited resources. Our results suggest, however, that tropical regions of the Southern Hemisphere may have been disproportionally less affected by the pandemic, and that climate may have played a key role in this regard. These findings have a direct bearing on global estimates of pandemic burden and the assessment of the role of immunological, socioeconomic and environmental drivers of the transmissibility and severity of this pandemic.     

Persistent Pandemics

We ask whether mortality from historical pandemics has any predictive content for mortality in the Covid-19 pandemic. We find strong persistence in public health performance. Places that performed worse in terms of mortality in the 1918 influenza pandemic also have higher Covid-19 mortality today. This is true across countries as well as across a sample of large US cities. Experience with SARS in 2003 is associated with slightly lower mortality today. We discuss some socio-political factors that may account for persistence including distrust of expert advice, lack of cooperation, over-confidence, and health care supply shortages. Multi-generational effects of past pandemics may also matter.     

Pathogenicity of influenza viruses with genes from the 1918 pandemic virus: functional roles of alveolar macrophages and neutrophils in limiting virus replication and mortality in mice

The Spanish influenza pandemic of 1918 to 1919 swept the globe and resulted in the deaths of at least 20 million people. The basis of the pulmonary damage and high lethality caused by the 1918 H1N1 influenza virus remains largely unknown. Recombinant influenza viruses bearing the 1918 influenza virus hemagglutinin (HA) and neuraminidase (NA) glycoproteins were rescued in the genetic background of the human A/Texas/36/91 (H1N1) (1918 HA/NA:Tx/91) virus. Pathogenesis experiments revealed that the 1918 HA/NA:Tx/91 virus was lethal for BALB/c mice without the prior adaptation that is usually required for human influenza A H1N1 viruses. The increased mortality of 1918 HA/NA:Tx/91-infected mice was accompanied by (i) increased (>200-fold) viral replication, (ii) greater influx of neutrophils into the lung, (iii) increased numbers of alveolar macrophages (AMs), and (iv) increased protein expression of cytokines and chemokines in lung tissues compared with the levels seen for control Tx/91 virus-infected mice. Because pathological changes in AMs and neutrophil migration correlated with lung inflammation, we assessed the role of these cells in the pathogenesis associated with 1918 HA/NA:Tx/91 virus infection. Neutrophil and/or AM depletion initiated 3 or 5 days after infection did not have a significant effect on the disease outcome following a lethal 1918 HA/NA:Tx/91 virus infection. By contrast, depletion of these cells before a sublethal infection with 1918 HA/NA:Tx/91 virus resulted in uncontrolled virus growth and mortality in mice. In addition, neutrophil and/or AM depletion was associated with decreased expression of cytokines and chemokines. These results indicate that a human influenza H1N1 virus possessing the 1918 HA and NA glycoproteins can induce severe lung inflammation consisting of AMs and neutrophils, which play a role in controlling the replication and spread of 1918 HA/NA:Tx/91 virus after intranasal infection of mice.     

The genesis of a pandemic influenza virus

Pandemic influenza viruses pose a significant threat to public health worldwide. In a recent Nature paper, Taubenberger et al. (2005) now report remarkable similarities between the polymerase genes of the influenza virus that caused the 1918 Spanish influenza pandemic and those of avian influenza viruses. Meanwhile, Tumpey et al. (2005) reporting in Science show that the reconstructed 1918 Spanish influenza virus kills mice faster than any other influenza virus so far tested.     

Analysis by Single-Gene Reassortment Demonstrates that the 1918 Influenza Virus Is Functionally Compatible with a Low-Pathogenicity Avian Influenza Virus in Mice

The 1918-1919 "Spanish" influenza pandemic is estimated to have caused 50 million deaths worldwide. Understanding the origin, virulence, and pathogenic properties of past pandemic influenza viruses, including the 1918 virus, is crucial for current public health preparedness and future pandemic planning. The origin of the 1918 pandemic virus has not been resolved, but its coding sequences are very like those of avian influenza virus. The proteins encoded by the 1918 virus differ from typical low-pathogenicity avian influenza viruses at only a small number of amino acids in each open reading frame. In this study, a series of chimeric 1918 influenza viruses were created in which each of the eight 1918 pandemic virus gene segments was replaced individually with the corresponding gene segment of a prototypical low-pathogenicity avian influenza (LPAI) H1N1 virus in order to investigate functional compatibility of the 1918 virus genome with gene segments from an LPAI virus and to identify gene segments and mutations important for mammalian adaptation. This set of eight "7:1" chimeric viruses was compared to the parental 1918 and LPAI H1N1 viruses in intranasally infected mice. Seven of the 1918 LPAI 7:1 chimeric viruses replicated and caused disease equivalent to the fully reconstructed 1918 virus. Only the chimeric 1918 virus containing the avian influenza PB2 gene segment was attenuated in mice. This attenuation could be corrected by the single E627K amino acid change, further confirming the importance of this change in mammalian adaptation and mouse pathogenicity. While the mechanisms of influenza virus host switch, and particularly mammalian host adaptation are still only partly understood, these data suggest that the 1918 virus, whatever its origin, is very similar to avian influenza virus.     

Coronary heart disease (CHD)--one or several diseases? Changes in the prevalence and features of CHD

In retrospect, mortality from coronary heart disease (CHD) in the 20th century followed an epidemic pattern: mortality rates increased dramatically from 1920 until about 1960, remained roughly constant for almost a decade, and have been decreasing since the late 1960s. CHD has traditionally been conceived of as a single disease with multifactorial causality. We suggest instead that CHD cases may comprise at least two distinct populations: those associated with hypercholesterolemia, and those associated with insulin resistance. The epidemic of CHD was due primarily to changes in the incidence of the hypercholesterolemia subgroup. We propose that young adults who survived the 1918 influenza pandemic were rendered vulnerable to lipid-associated CHD and coronary thrombosis upon reinfection with influenza later in life. This vulnerability may be due to autoimmune disruption of low-density lipoprotein-receptor interactions. Historical events may affect the health of populations by affecting the susceptibility of populations to chronic diseases such as CHD. The life experiences of individuals are known to influence their susceptibility to infectious diseases; we suggest that life experiences may also influence individual susceptibility to chronic diseases.     

Lessons learned from the 1918–1919 influenza pandemic

The 1918 influenza pandemic was one of the most virulent strains of influenza in history. Phylogenic evidence of the novel H1N1 strain of influenza discovered in Mexico last spring (2009) links it to the 1918 influenza strain. With information gained from analyzing viral genetics, public health records and advances in medical science we can confront the 2009 H1N1 influenza on a global scale. The paper analyses the causes and characteristics of a pandemic, and major issues in controlling the spread of the disease. Wide public vaccination and open communication between government and health sciences professionals will be an essential and vital component in managing the 2009 H1N1 pandemic and any future pandemics.     

Excess mortality associated with influenza epidemics in Portugal, 1980 to 2004

Background

Influenza epidemics have a substantial impact on human health, by increasing the mortality from pneumonia and influenza, respiratory and circulatory diseases, and all causes. This paper provides estimates of excess mortality rates associated with influenza virus circulation for 7 causes of death and 8 age groups in Portugal during the period of 1980–2004.

Methodology/Principal Findings

We compiled monthly mortality time series data by age for all-cause mortality, cerebrovascular diseases, ischemic heart diseases, diseases of the respiratory system, chronic respiratory diseases, pneumonia and influenza. We also used a control outcome, deaths from injuries. Age- and cause-specific baseline mortality was modelled by the ARIMA approach; excess deaths attributable to influenza were calculated by subtracting expected deaths from observed deaths during influenza epidemic periods. Influenza was associated with a seasonal average of 24.7 all-cause excess deaths per 100,000 inhabitants, approximately 90% of which were among seniors over 65 yrs. Excess mortality was 3–6 fold higher during seasons dominated by the A(H3N2) subtype than seasons dominated by A(H1N1)/B. High excess mortality impact was also seen in children under the age of four years. Seasonal excess mortality rates from all the studied causes of death were highly correlated with each other (Pearson correlation range, 0.65 to 0.95, P<0.001) and with seasonal rates of influenza-like-illness (ILI) among seniors over 65 years (Pearson correlation rho>0.64, P<0.05). By contrast, there was no correlation with excess mortality from injuries.

Conclusions/Significance

Our excess mortality approach is specific to influenza virus activity and produces influenza-related mortality rates for Portugal that are similar to those published for other countries. Our results indicate that all-cause excess mortality is a robust indicator of influenza burden in Portugal, and could be used to monitor the impact of influenza epidemics in this country. Additional studies are warranted to confirm these findings in other settings.     

Disease and fertility: Evidence from the 1918–19 influenza pandemic in Sweden

What are the consequences of a severe health shock like an influenza pandemic on fertility? Using rich administrative data and a difference-in-differences approach, we evaluate fertility responses to the 1918–19 influenza pandemic in Sweden. We find evidence of a small baby boom following the end of the pandemic, but we show that this effect is second-order compared to a strong long-term negative fertility effect. Within this net fertility decline there are compositional effects: we observe a relative increase in births to married women and to better-off families. Several factors – including disruptions to the marriage market and income effects – contribute to the long-term fertility reduction. The results are consistent with studies that find a positive fertility response following natural disasters, but we show that this effect is short-lived.     

Elevated 17β-estradiol protects females from influenza A virus pathogenesis by suppressing inflammatory responses

Studies of the 1918 H1N1 influenza pandemic, the H5N1 avian influenza outbreak, and the 2009 H1N1 pandemic illustrate that sex and pregnancy contribute to severe outcome from infection, suggesting a role for sex steroids. To test the hypothesis that the sexes respond differently to influenza, the pathogenesis of influenza A virus infection was investigated in adult male and female C57BL/6 mice. Influenza infection reduced reproductive function in females and resulted in greater body mass loss, hypothermia, and mortality in females than males. Whereas lung virus titers were similar between the sexes, females had higher induction of proinflammatory cytokines and chemokines, including TNF-α, IFN-γ, IL-6, and CCL2, in their lungs than males. Removal of the gonads in both sexes eliminated the sex difference in influenza pathogenesis. Manipulation of testosterone or dihydrotestosterone concentrations in males did not significantly impact virus pathogenesis. Conversely, females administered high doses of estradiol had a ≥10-fold lower induction of TNF-α and CCL2 in the lungs and increased rates of survival as compared with females that had either low or no estradiol. The protective effects of estradiol on proinflammatory cytokines and chemokines, morbidity, and mortality were primarily mediated by signaling through estrogen receptor α (ERα). In summary, females suffer a worse outcome from influenza A virus infection than males, which can be reversed by administration of high doses of estradiol to females and reflects differences in the induction of proinflammatory responses and not in virus load.     

The anticipated severity of a "1918-like" influenza pandemic in contemporary populations: the contribution of antibacterial interventions

Recent studies have shown that most of deaths in the 1918 influenza pandemic were caused by secondary bacterial infections, primarily pneumococcal pneumonia. Given the availability of antibiotics and pneumococcal vaccination, how will contemporary populations fare when they are next confronted with pandemic influenza due to a virus with the transmissibility and virulence of that of 1918? To address this question we use a mathematical model and computer simulations. Our model considers the epidemiology of both the influenza virus and pneumonia-causing bacteria and allows for co-infection by these two agents as well as antibiotic treatment, prophylaxis and pneumococcal vaccination. For our simulations we use influenza transmission and virulence parameters estimated from 1918 pandemic data. We explore the anticipated rates of secondary pneumococcal pneumonia and death in populations with different prevalence of pneumococcal carriage and contributions of antibiotic prophylaxis, treatment, and vaccination to these rates. Our analysis predicts that in countries with lower prevalence of pneumococcal carriage and access to antibiotics and pneumococcal conjugate vaccines, there would substantially fewer deaths due to pneumonia in contemporary populations confronted with a 1918-like virus than that observed in the 1918. Our results also predict that if the pneumococcal carriage prevalence is less than 40%, the positive effects of antibiotic prophylaxis and treatment would be manifest primarily at of level of individuals. These antibiotic interventions would have little effect on the incidence of pneumonia in the population at large. We conclude with the recommendation that pandemic preparedness plans should consider co-infection with and the prevalence of carriage of pneumococci and other bacteria responsible for pneumonia. While antibiotics and vaccines will certainly reduce the rate of individual mortality, the factor contributing most to the relatively lower anticipated lethality of a pandemic with a 1918-like influenza virus in contemporary population is the lower prevalence of pneumococcal carriage.     

Coinfection can trigger multiple pandemic waves

Sequences of epidemic waves have been observed in past influenza pandemics, such as the Spanish influenza. Possible explanations may be sought either in mechanisms altering the structure of the network of contacts, such as those induced by changes in the rates of movement of people or by public health measures, or in the genetic drift of the influenza virus, since the appearance of new strains can reduce or eliminate herd immunity. The pandemic outbreaks may also be influenced by coinfection with other acute respiratory infections (ARI) that increase transmissibility of influenza virus (by coughing, sneezing, running nose). In fact, some viruses (e.g., Rhinovirus and Adenovirus) have been found to induce “clouds” of bacteria and increase the transmissibility of Staphylococcus aureus. Moreover, Rhinovirus and Adenovirus were detected in patients during past pandemics, and their presence is linked to superspreading events. In this paper, by assuming increased transmissibility in coinfected individuals, we propose and study a model where multiple pandemic waves are triggered by coinfection with ARI. The model agrees well with mortality excess data during the 1918 pandemic influenza, thereby providing indications for potential pandemic mitigation.