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.     

Comparison of mortality in Spain and France,following the method of "potential years of life lost"

Mortality trends in Spain from 13 major causes of death are analyzed for the period 1972-1982 and compared with trends for the same period in France. Increases in mortality in Spain are noted for three causes--malignant tumors, cardiac diseases, and suicides and homicides--whereas significant declines in mortality are noted for pneumonia, influenza, chronic bronchitis, and asthma. Excess mortality for males is common to both countries. (SUMMARY IN ENG)     

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.     

Short‐term fluctuations in death by cause,temperature, and income in the United States, 1930–1985

Abstract

Disclosures that this decade has had the five hottest years ever recorded globally raise concern that extreme temperatures might be associated with higher mortality. An analysis of fluctuations in annual cause‐specific deaths, seasonal temperatures, and annual income per capita in Massachusetts, Michigan, Washington, Utah, North Carolina, and Mississippi, 1930 to 1985, suggests that, on the contrary, a temperature increase throughout the year was associated with fewer deaths from all causes combined, including deaths from infectious diseases, heart diseases, cerebrovascular diseases, pneumonia, and influenza. An average temperature increase of one degree Fahrenheit was associated with a more than 2 per cent decline in deaths from pneumonia and influenza. The only category of deaths showing no significant association was death from malignant neoplasms. Compared to spring, summer, and fall temperature fluctuations, unusually cold winter temperatures had the strongest fatal effects, but only in North Carolina and Mississippi. The greatest cumulative temperature effects on mortality were found in the same two states. Controlling for annual fluctuations in income per capita did not influence the relationship between temperature and mortality. There was evidence suggesting that the level of wealth ameliorated the fatal effects of extreme temperatures. In conclusion, unusually warm weather was followed by fewer deaths; unusually cold weather, by more deaths.     

The Impact of Matching Vaccine Strains and Post-SARS Public Health Efforts on Reducing Influenza-Associated Mortality among the Elderly

Public health administrators do not have effective models to predict excess influenza-associated mortality and monitor viral changes associated with it. This study evaluated the effect of matching/mismatching vaccine strains, type/subtype pattern changes in Taiwan''s influenza viruses, and the impact of post-SARS (severe acute respiratory syndrome) public health efforts on excess influenza-associated mortalities among the elderly. A negative binomial model was developed to estimate Taiwan''s monthly influenza-associated mortality among the elderly. We calculated three winter and annual excess influenza-associated mortalities [pneumonia and influenza (P&I), respiratory and circulatory, and all-cause] from the 1999–2000 through the 2006–2007 influenza seasons. Obtaining influenza virus sequences from the months/years in which death from P&I was excessive, we investigated molecular variation in vaccine-mismatched influenza viruses by comparing hemagglutinin 1 (HA1) of the circulating and vaccine strains. We found that the higher the isolation rate of A (H3N2) and vaccine-mismatched influenza viruses, the greater the monthly P&I mortality. However, this significant positive association became negative for higher matching of A (H3N2) and public health efforts with post-SARS effect. Mean excess P&I mortality for winters was significantly higher before 2003 than after that year [mean ± S.D.: 1.44±1.35 vs. 0.35±1.13, p = 0.04]. Further analysis revealed that vaccine-matched circulating influenza A viruses were significantly associated with lower excess P&I mortality during post-SARS winters (i.e., 2005–2007) than during pre-SARS winters [0.03±0.06 vs. 1.57±1.27, p = 0.01]. Stratification of these vaccine-matching and post-SARS effect showed substantial trends toward lower elderly excess P&I mortalities in winters with either mismatching vaccines during the post-SARS period or matching vaccines during the pre-SARS period. Importantly, all three excess mortalities were at their highest in May, 2003, when inter-hospital nosocomial infections were peaking. Furthermore, vaccine-mismatched H3N2 viruses circulating in the years with high excess P&I mortality exhibited both a lower amino acid identity percentage of HA1 between vaccine and circulating strains and a higher numbers of variations at epitope B. Our model can help future decision makers to estimate excess P&I mortality effectively, select and test virus strains for antigenic variation, and evaluate public health strategy effectiveness.     

The impact of weather on influenza and pneumonia mortality in New York City, 1975-2002: a retrospective study

The substantial winter influenza peak in temperate climates has lead to the hypothesis that cold and/or dry air is a causal factor in influenza variability. We examined the relationship between cold and/or dry air and daily influenza and pneumonia mortality in the cold season in the New York metropolitan area from 1975–2002. We conducted a retrospective study relating daily pneumonia and influenza mortality for New York City and surroundings from 1975–2002 to daily air temperature, dew point temperature (a measure of atmospheric humidity), and daily air mass type. We identified high mortality days and periods and employed temporal smoothers and lags to account for the latency period and the time between infection and death. Unpaired t-tests were used to compare high mortality events to non-events and nonparametric bootstrapped regression analysis was used to examine the characteristics of longer mortality episodes. We found a statistically significant (p = 0.003) association between periods of low dew point temperature and above normal pneumonia and influenza mortality 17 days later. The duration (r = −0.61) and severity (r = −0.56) of high mortality episodes was inversely correlated with morning dew point temperature prior to and during the episodes. Weeks in which moist polar air masses were common (air masses characterized by low dew point temperatures) were likewise followed by above normal mortality 17 days later (p = 0.019). This research supports the contention that cold, dry air may be related to influenza mortality and suggests that warning systems could provide enough lead time to be effective in mitigating the effects.     

Serial histopathological examination of the lungs of mice infected with influenza A virus PR8 strain

Avian influenza H5N1 and pandemic (H1N1) 2009 viruses are known to induce viral pneumonia and subsequent acute respiratory distress syndrome (ARDS) with diffuse alveolar damage (DAD). The mortality rate of ARDS/DAD is extremely high, at approximately 60%, and no effective treatment for ARDS/DAD has been established. We examined serial pathological changes in the lungs of mice infected with influenza virus to determine the progress from viral pneumonia to ARDS/DAD. Mice were intranasally infected with influenza A/Puerto Rico/8/34 (PR8) virus, and their lungs were examined both macro- and micro-pathologically every 2 days. We also evaluated general condition, survival rate, body weight, viral loads in lung, and surfactant proteins in serum. As a result, all infected mice died within 9 days postinfection. At 2 days postinfection, inflammation in alveolar septa, i.e., interstitial pneumonia, was observed around bronchioles. From 4 to 6 days postinfection, interstitial pneumonia with alveolar collapse expanded throughout the lungs. From 6 to 9 days postinfection, DAD with severe alveolar collapse was observed in the lungs of all of dying and dead mice. In contrast, DAD was not observed in the live infected-mice from 2 to 6 days postinfection, despite their poor general condition. In addition, histopathological analysis was performed in mice infected with a dose of PR8 virus which was 50% of the lethal dose for mice in the 20-day observation period. DAD with alveolar collapse was observed in all dead mice. However, in the surviving mice, instead of DAD, glandular metaplasia was broadly observed in their lungs. The present study indicates that DAD with severe alveolar collapse is associated with death in this mouse infection model of influenza virus. Inhibition of the development of DAD with alveolar collapse may decrease the mortality rate in severe viral pneumonia caused by influenza virus infection.     

Deletions in the neuraminidase stalk region of H2N2 and H9N2 avian influenza virus subtypes do not affect postinfluenza secondary bacterial pneumonia

We investigated the synergism between influenza virus and Streptococcus pneumoniae, particularly the role of deletions in the stalk region of the neuraminidase (NA) of H2N2 and H9N2 avian influenza viruses. Deletions in the NA stalk (ΔNA) had no effect on NA activity or on the adherence of S. pneumoniae to virus-infected human alveolar epithelial (A549) and mouse lung adenoma (LA-4) cells, although it delayed virus elution from turkey red blood cells. Sequential S. pneumoniae infection of mice previously inoculated with isogenic recombinant H2N2 and H9N2 influenza viruses displayed severe pneumonia, elevated levels of intrapulmonary proinflammatory responses, and death. No differences between the WT and ΔNA mutant viruses were detected with respect to effects on postinfluenza pneumococcal pneumonia as measured by bacterial growth, lung inflammation, morbidity, mortality, and cytokine/chemokine concentrations. Differences were observed, however, in influenza virus-infected mice that were treated with oseltamivir prior to a challenge with S. pneumoniae. Under these circumstances, mice infected with ΔNA viruses were associated with a better prognosis following a secondary bacterial challenge. These data suggest that the H2N2 and H9N2 subtypes of avian influenza A viruses can contribute to secondary bacterial pneumonia and deletions in the NA stalk may modulate its outcome in the context of antiviral therapy.     

Influenza A: From highly pathogenic H5N1 to pandemic 2009 H1N1. Epidemiology and clinical features

The last decade has seen the emergence of two new influenza A subtypes and they have become a cause of concern for the global community. These are the highly pathogenic H5N1 influenza A virus (H5N1) and the Pandemic 2009 influenza H1N1 virus. Since 2003 the H5N1 virus has caused widespread disease and death in poultry, mainly in south East Asia and Africa. In humans the number of cases infected with this virus is few but the mortality has been about 60%. Most patients have presented with severe pneumonia and acute respiratory distress syndrome. The second influenza virus, the pandemic H1N1 2009, emerged in Mexico in March this year. This virus acquired the ability for sustained human to human spread and within a few months spread throughout the world and infected over 4 lakh individuals. The symptoms of infection with this virus are similar to seasonal influenza but it currently affecting younger individuals more often. Fortunately the mortality has been low. Both these new influenza viruses are currently circulating and have different clinical and epidemiological characteristics.     

Effect of influenza vaccination on excess deaths occurring during periods of high circulation of influenza: cohort study in elderly people

Objective To estimate the protection against death provided by vaccination against influenza.Design Prospective cohort follow up supplemented by weekly national counts of influenza confirmed in the community.Setting Primary care.Participants 24 535 patients aged over 75 years from 73 general practices in Great Britain.Main outcome measure Death.Results In unvaccinated members of the cohort daily all cause mortality was strongly associated with an index of influenza circulating in the population (mortality ratio 1.16, 95% confidence interval 1.04 to 1.29 at 90th centile of circulating influenza). The association was strongest for respiratory deaths but was also present for cardiovascular deaths. In contrast, in vaccinated people mortality from any cause was not associated with circulating influenza. The difference in patterns between vaccinated and unvaccinated people could not easily be due to chance (P = 0.02, all causes).Conclusions This study, using a novel and robust approach to control for confounding, provides robust evidence of a protective effect on mortality of vaccination against influenza.     

Contribution of vaccines to our understanding of pneumococcal disease

Pneumonia is the leading cause of mortality in children in developing countries and is also the leading infectious cause of death in adults. The most important cause of pneumonia is the Gram-positive bacterial pathogen, Streptococcus pneumoniae, also known as the pneumococcus. It has thus become the leading vaccine-preventable cause of death and is a successful and diverse human pathogen. The development of conjugate pneumococcal vaccines has made possible the prevention of pneumococcal disease in infants, but has also elucidated aspects of pneumococcal biology in a number of ways. Use of the vaccine as a probe has increased our understanding of the burden of pneumococcal disease in children globally. Vaccination has also elucidated the clinical spectrum of vaccine-preventable pneumococcal infections; the identification of a biological niche for multiple pneumococcal serotypes in carriage and the differential invasiveness of pneumococcal serotypes; the impact of pneumococcal transmission among children on disease burden in adults; the role of carriage as a precursor to pneumonia; the plasticity of a naturally transformable pathogen to respond to selective pressure through capsular switching and the accumulation of antibiotic-resistance determinants; and the role of pneumococcal infections in hospitalization and mortality associated with respiratory viral infections, including both seasonal and pandemic influenza. Finally, there has been a recent demonstration that pneumococcal pneumonia in children may be an important cause of hospitalization for those with underlying tuberculosis.     

Augmented Lung Inflammation Protects against Influenza A Pneumonia

Background

Influenza pneumonia causes high mortality every year, and pandemic episodes kill millions of people. Influenza-related mortality has been variously ascribed to an ineffective host response that fails to limit viral replication, an excessive host inflammatory response that results in lung injury and impairment of gas exchange, or to bacterial superinfection. We sought to determine whether lung inflammation promoted or impaired host survival in influenza pneumonia.

Methods and Findings

To distinguish among these possible causes of influenza-related death, we induced robust lung inflammation by exposing mice to an aerosolized bacterial lysate prior to challenge with live virus. The treatment induced expression of the inflammatory cytokines IL-6 and TNF in bronchoalveolar lavage fluid 8- and 40-fold greater, respectively, than that caused by lethal influenza infection. Yet, this augmented inflammation was associated with striking resistance to host mortality (0% vs 90% survival, p = 0.0001) and reduced viral titers (p = 0.004). Bacterial superinfection of virus infected lungs was not observed. When mice were repeatedly exposed to the bacterial lysate, as would be clinically desirable during an influenza epidemic, there was no tachyphylaxis of the induced viral resistance. When the bacterial lysate was administered after the viral challenge, there was still some mortality benefit, and when ribavirin was added to the aerosolized bacterial lysate, host survival was synergistically improved (0% vs 93.3% survival, p<0.0001).

Conclusions

Together, these data indicate that innate immune resistance to influenza can be effectively stimulated, and suggest that ineffective rather than excessive inflammation is the major cause of mortality in influenza pneumonia.     

New infections: myths and reality

New contemporary data about new infectious diseases of XXI century are presented. Data on morbidity and mortality from severe acute respiratory syndrome (SARS, atypical pneumonia) and avian influenza are analyzed and compared with World Health Organization data on human influenza. Biologic characteristics of avian influenza virus A/H5N1 are discussed as well as possibility of its human-to-human transmission. Principles of SARS and avian influenza infections transmission as zoonoses are described as well as mechanisms of transmission impeding their ability to infect humans. It has been argued that SARS should be regarded as contagious infection, whereas avian influenza - as non-contagious. Features of all stages of epidemic process of these infections are analyzed.     

Cytokine and chemokine responses in pediatric patients with severe pneumonia associated with pandemic A/H1N1/2009 influenza virus

Severe pneumonia and leukocytosis are characteristic, frequently observed, clinical findings in pediatric patients with pandemic A/H1N1/2009 influenza virus infection. The aim of this study was to elucidate the role of cytokines and chemokines in complicating pneumonia and leukocytosis in patients with pandemic A/H1N1/2009 influenza virus infection. Forty‐seven patients with pandemic A/H1N1/2009 influenza virus infection were enrolled in this study. Expression of interleukin (IL)‐10 (P = 0.027) and IL‐5 (P = 0.014) was significantly greater in patients with pneumonia than in those without pneumonia. Additionally, serum concentrations of interferon‐γ (P = 0.009), tumor necrosis factor‐α (P = 0.01), IL‐4 (P = 0.024), and IL‐2 (P = 0.012) were significantly lower in pneumonia patients with neutrophilic leukocytosis than in those without neutrophilic leukocytosis. Of the five serum chemokine concentrations assessed, only IL‐8 was significantly lower in pneumonia patients with neutrophilic leukocytosis than in those without leukocytosis (P = 0.001). These cytokines and chemokines may play important roles in the pathogenesis of childhood pneumonia associated with A/H1N1/2009 influenza virus infection.     

P1 and P3 proteins of influenza virus are required for complementary RNA synthesis.

Members of two temperature-sensitive (ts) mutant groups of influenza A/WSN virus defective in complementary RNA synthesis were analyzed with respect to the identity of their defective genes. RNA analysis of recombinants having a ts+ phenotype derived from the mutants and HK virus permitted the identification of RNA 1 and RNA 2 as the single defective gene in mutant groups I and III, respectively. Based on knowledge obtained by mapping the WSN virus genome, it then was possible to determine that biologically functional P3 protein (coded for by RNA 1) and P1 protein (RNA 2) are required for complementary RNA synthesis of influenza virus.     

Differential effect of prior influenza infection on alveolar macrophage phagocytosis of Staphylococcus aureus and Escherichia coli: involvement of interferon-gamma production

The influenza A virus is one of the main causes of respiratory infection. Although influenza virus infection alone can result in pneumonia, secondary bacterial infection combined with the virus is the major cause of morbidity and mortality. Interestingly, while influenza infection increases susceptibility to some bacteria, including Streptococcus pneumoniae, Staphylococcus aureus (S. aureus), and Haemophilus influenzae, other bacteria such as Escherichia coli (E. coli) and Klebsiella pneumoniae are not associated with influenza infection. The reason for this discrepancy is not known. In this study, it was found that prior influenza virus infection inhibits murine alveolar macrophage phagocytosis of S. aureus but not of E. coli. Here, the mechanism for this inhibition is elucidated: prior influenza virus infection strongly increases interferon gamma (IFN-γ) production. Furthermore, it was shown that IFN-γ differentially affects alveolar macrophage phagocytosis of S. aureus and E. coli. The findings of the present study explain how influenza virus infection increases susceptibility to some bacteria, such as S. aureus, but not others, and provides evidence that IFN-γ might be a promising target for protecting the human population from secondary bacterial infection by influenza.     

Situating mortality: Quantifying crisis points and periods of stability

A wide range of stressors can cause a dramatic and sudden rise in the death rate in populations, typically resulting in what is referred to as crisis mortality. Here we present a method to standardize the assessment of identifying moments of crises. A modification of the mortality Z‐score methodology which is combined with time series analysis was used to investigate mortality events over the course of nearly two centuries for two populations: Gibraltar and Malta. A benefit of this method is that it situates the yearly death rate within the prevailing mortality pattern, and by doing so allows the researcher to assess the relative impact of that event against the norm for the period under investigation. A series of threshold values were established to develop levels of mortality to distinguish moments of lower mortality than expected, background mortality, a crisis, and a catastrophe. Our findings suggested that within defined periods, a limited number of events constituted moments of excessive mortality in the range of a crisis or higher. These included epidemics (yellow fever and influenza in Gibraltar only, and cholera) and casualties associated with World War II. Episodes of lower than expected mortality were only detected (although not significant) in the 20th century in Malta, and at the micro level, the harvesting effect appears to have occurred following cholera epidemics in both locations and influenza in Gibraltar. The analysis demonstrates clearly that the impact of epidemics can be highly variable across time and populations. Am J Phys Anthropol 152:459–470, 2013. © 2013 Wiley Periodicals, Inc.     

妊娠合并肺炎及甲型H1N1 流感的处理及预防探讨

目的:探讨妊娠合并肺炎及甲型H1N1流感的处理及预防措施。方法:我院2009年3月至2010年5月收治的12例妊娠合并肺炎及7例妊娠合并甲型H1N1流感的情况,包括对年龄、孕周、病情、其他合并症、辅助检查、治疗情况及转归进行回顾性分析。结果:19例经治疗后治愈14例,死亡5例,均为晚期妊娠,其中4例合并重症肺炎,1例合并重度子痫前期。12例妊娠合并肺炎者,死亡3例,治愈9例;7例妊娠合并甲型H1N1流感者,死亡2例,治愈5例。结论:妊娠合并肺炎及甲型H1N1流感者,病情控制越及时,母儿结局越好,若病情不见好转,应尽早终止妊娠。     

Vaccinal prophylaxis of infarction, insult and lethality in the epidemic rise of influenza

The data of literature on the evaluation of the medical consequences of influenza and the role of vaccinal prophylaxis are presented and analyzed. The causes of differences in the characteristics of delayed lethality in influenza are noted. The fact was substantiated that delayed death in influenza may be essentially decreased if patients belonging to the group of risk (mainly persons over 65 years) were vaccinated before the beginning of the seasonal rise of infection. Vaccination against influenza was shown to decrease the frequency of hospitalization for pneumonia and influenza by 20-40%. In the group of vaccines the number of lethal outcomes due to infarctions and insults decreased by 48-50%, the risk of hospitalization for cardiovascular diseases decreased by 19% and that for disturbances of cerebral circulation, by 16%. The conclusion was made that the modern strategy of vaccination against influenza was aimed at the protection of the groups of risk and the prevention of complications appearing in the course of development of this infection (the exacerbation of chronic pathology, hospitalization, delayed death).