The origins of viral infection sleuth.

The events of the past year have underscored the serious and rapid threat that emerging viruses pose to global health. However, much of the rapid progress in understanding and combating SARS-CoV-2 was made possible because of the decades of important groundwork laid from researchers studying other emergent infectious diseases. The 2021 John Dirks Canada Gairdner Global Health award recognizes the contributions of Joseph Sriyal Malik Peiris and Yi Guan toward understanding the origins and options for control of newly emerging infectious disease outbreaks in Asia, notably zoonotic influenza and severe acute respiratory syndrome (SARS). Cell's Nicole Neuman corresponded with Yi Guan about his path to becoming a viral infection sleuth and the challenges of understanding emerging pathogens and their origins. Excerpts of their exchange are included here.

Mortality Rates of the Spanish Flu and Coronavirus Disease 2019 in the Netherlands: A Historical Comparison.

The coronavirus disease 2019 (COVID-19) pandemic has been called the deadliest disease event in history. In this study, we compared the cause-specific mortality rate of the Spanish flu (1918-1920) with that of COVID-19 (2020-2022) in the Netherlands. During the periods of exposure, about 50 000 people died of COVID-19 and 32 000 people of the Spanish flu. In absolute numbers, COVID-19 seems to be deadlier than Spanish flu. However, the crude mortality rates for COVID-19 and Spanish flu were 287 and 486 per 100 000 inhabitants, respectively. Comparing age-standardized mortality rates, there would have been 28 COVID-19- and 194 Spanish flu-related deaths in 1918-1920, or 214 Spanish flu- and 98 COVID-19-related deaths in 2020-2022 per 100 000 inhabitants per year. Thus, taking the population differences into account, the Spanish flu would have been deadlier than COVID-19.

"The Graves Cannot Be Dug Fast Enough": Excess Deaths Among US Amish and Mennonites During the 1918 Flu Pandemic.

Estimating the lethal impact of a pandemic on a religious community with significant barriers to outsiders can be exceedingly difficult. Nevertheless, Stein and colleagues (2021) developed an innovative means of arriving at such an estimate for the lethal impact of COVID-19 on the Amish community in 2020 by counting user-generated death reports in the widely circulated Amish periodical The Budget. By comparing monthly averages of reported deaths before and during the COVID-19 pandemic, Stein and colleagues were able to arrive at a rough estimate of "excess deaths" during the first year of the pandemic. Our research extends the same research method, applying it to the years during and immediately preceding the global influenza pandemic of 1918. Results show similarly robust findings, including three notable "waves" of excess deaths among Amish and conservative Mennonites in the USA in 1918, 1919, and 1920. Such results point to the promise of utilizing religious periodicals like The Budget as a relatively untapped trove of user-generated data on public health outcomes among religious minorities more than a century in the past.

Co-degradation of interferon signaling factor DDX3 by PB1-F2 as a basis for high virulence of 1918 pandemic influenza.

The multifunctional influenza virus protein PB1-F2 plays several roles in deregulation of host innate immune responses and is a known immunopathology enhancer of the 1918 influenza pandemic. Here, we show that the 1918 PB1-F2 protein not only interferes with the mitochondria-dependent pathway of type I interferon (IFN) signaling, but also acquired a novel IFN antagonist function by targeting the DEAD-box helicase DDX3, a key downstream mediator in antiviral interferon signaling, toward proteasome-dependent degradation. Interactome analysis revealed that 1918 PB1-F2, but not PR8 PB1-F2, binds to DDX3 and causes its co-degradation. Consistent with intrinsic protein instability as basis for this gain-of-function, internal structural disorder is associated with the unique cytotoxic sequences of the 1918 PB1-F2 protein. Infusing mice with recombinant DDX3 protein completely rescued them from lethal infection with the 1918 PB1-F2-producing virus. Alongside NS1 protein, 1918 PB1-F2 therefore constitutes a potent IFN antagonist causative for the severe pathogenicity of the 1918 influenza strain. Our identification of molecular determinants of pathogenesis should be useful for the future design of new antiviral strategies against influenza pandemics.

Lost Lessons of the 1918 Influenza: The 1920s Working Hypothesis, the Public Health Paradigm, and the Prevention of Deadly Pandemics.

In standard historical accounts, the hyperlethal 1918 flu pandemic was inevitable once a novel influenza virus appeared. However, in the years following the pandemic, it was obvious to distinguished flu experts from around the world that social and environmental conditions interacted with infectious agents and could enhance the virulence of flu germs. On the basis of the timing and geographic pattern of the pandemic, they hypothesized that an "essential cause" of the pandemic's extraordinary lethality was the extreme, prolonged, and industrial-scale overcrowding of US soldiers in World War I, particularly on troopships. This literature synthesis considers research from history, public health, military medicine, veterinary science, molecular genetics, virology, immunology, and epidemiology. Arguments against the hypothesis do not provide disconfirming evidence. Overall, the findings are consistent with an immunologically similar virus varying in virulence in response to war-related conditions. The enhancement-of-virulence hypothesis deserves to be included in the history of the pandemic and the war. These lost lessons of 1918 point to possibilities for blocking the transformation of innocuous infections into deadly disasters and are relevant beyond influenza for diseases like COVID-19. (Am J Public Health. 2022;112(10):1454-1464. https://doi.org/10.2105/AJPH.2022.306976).

Public Health Interventions, Epidemic Growth, and Regional Variation of the 1918 Influenza Pandemic Outbreak in a Swiss Canton and Its Greater Regions.

Public health interventions implemented during the coronavirus disease 2019 (COVID-19) pandemic are based on experience gained from past pandemics. The 1918 influenza pandemic is the most extensively researched historical influenza outbreak. All 9335 reports available in the State Archives on 121 152 cases of influenza-like illness from the canton of Bern from 473 of 497 municipalities (95.2%) were collected; the cases were registered between 30 June 1918 and 30 June 1919. The overall incidence rates of newly registered cases per week for the 9 greater regions of Bern for both the first and second waves of the pandemic were calculated. Relative incidence rate ratios (RIRRs) were calculated to estimate the change in the slope of incidence curves associated with public health interventions. During the first wave, school closures (RIRR, 0.16 [95% CI, 0.15 to 0.17]) and restrictions of mass gatherings (RIRR, 0.57 [CI, 0.54 to 0.61]) were associated with a deceleration of epidemic growth. During the second wave, in autumn 1918, cantonal authorities initially reacted hesitantly and delegated the responsibility to enact interventions to municipal authorities, which was associated with a lack of containment of the second wave. A premature relaxation of restrictions on mass gatherings was associated with a resurgence of the epidemic (RIRR, 1.18 [CI, 1.12 to 1.25]). Strikingly similar patterns were found in the management of the COVID-19 outbreak in Switzerland, with a considerably higher amplitude and prolonged duration of the second wave and much higher associated rates of hospitalization and mortality.

For the flaring up of the flu: The nurses of the Maggiore Hospital in Milan hit by the Spanish fever.

In the last year of the Great War, Italy was also hit by the Spanish flu. The Civic Hospitals faced a deadly disaster with insufficient resources. All the heavy workload fell on the female nursing staff, who were the only ones able ensure the continuity of the hospital services. This study aimed to explore the impact of the influenza on the health of the nurses at the Maggiore Hospital in Milan during the second and third epidemic waves. Historical research was conducted between February and May 2020. Primary sources were retrieved from the historical archives of the Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico and the daily newspaper Corriere della Sera. In the autumn of 1918, the Maggiore Hospital in Milan changed its organization to hospitalise patients affected by the influenza pandemic. Although the hospital managers wanted to protect their healthcare staff from the risks of contagion by means of prophylaxis rules, 388 lay nurses and 80 religious sister nurses were affected by this insidious disease. The second and third waves of the pandemic claimed 25 victims of duty. Remembered for their altruism and spirit of abnegation, the hospital community honoured their sacrifice, and the citizens expressed their gratitude.

Open Secrets: Silence, Suppression, and Memory in the History of Canada's 1918-20 Influenza Pandemic.

For several decades, the 1918-20 global influenza outbreak has been called "the forgotten pandemic." Although recent scholarly and public interest in the pandemic has complicated the narrative of forgetting, the label has stuck. Highlighting historical evidence of influenza's long-term impact upon survivors, family, and community in Canada, the flu stories presented here, diverse in form and content, verify that a key question in pandemic influenza history is not whether the pandemic was forgotten or remembered, but by whom, and in what ways, it has been suppressed - or foregrounded. By moving beyond the classic epidemic plot line, with beginning, middle, and end, historians can find new methodologies and evidence with which to more fully understand the influenza pandemic's unfolding intersection with colonialism, war, social inequality, and labour struggles in the 20th century.

A Centenary Tale of Two Pandemics: The 1918 Influenza Pandemic and COVID-19, Part I.

Separated by a century, the influenza pandemic of 1918 and the COVID-19 pandemic of 2019-2021 are among the most disastrous infectious disease emergences of modern times. Although caused by unrelated viruses, the two pandemics are nevertheless similar in their clinical, pathological, and epidemiological features, and in the civic, public health, and medical responses to combat them. Comparing and contrasting the two pandemics, we consider what lessons we have learned over the span of a century and how we are applying those lessons to the challenges of COVID-19.

A Centenary Tale of Two Pandemics: The 1918 Influenza Pandemic and COVID-19, Part II.

Both the 1918 influenza pandemic and the 2019‒2021 COVID-19 pandemic are among the most disastrous infectious disease emergences of modern times. In addition to similarities in their clinical, pathological, and epidemiological features, the two pandemics, separated by more than a century, were each met with essentially the same, or very similar, public health responses, and elicited research efforts to control them with vaccines, therapeutics, and other medical approaches. Both pandemics had lasting, if at times invisible, psychosocial effects related to loss and hardship. In considering these two deadly pandemics, we ask: what lessons have we learned over the span of a century, and how are we applying those lessons to the challenges of COVID-19?

Historical Insights on Coronavirus Disease 2019 (COVID-19), the 1918 Influenza Pandemic, and Racial Disparities: Illuminating a Path Forward.

The coronavirus disease 2019 (COVID-19) pandemic is exacting a disproportionate toll on ethnic minority communities and magnifying existing disparities in health care access and treatment. To understand this crisis, physicians and public health researchers have searched history for insights, especially from a great outbreak approximately a century ago: the 1918 influenza pandemic. However, of the accounts examining the 1918 influenza pandemic and COVID-19, only a notable few discuss race. Yet, a rich, broader scholarship on race and epidemic disease as a "sampling device for social analysis" exists. This commentary examines the historical arc of the 1918 influenza pandemic, focusing on black Americans and showing the complex and sometimes surprising ways it operated, triggering particular responses both within a minority community and in wider racial, sociopolitical, and public health structures. This analysis reveals that critical structural inequities and health care gaps have historically contributed to and continue to compound disparate health outcomes among communities of color. Shifting from this context to the present, this article frames a discussion of racial health disparities through a resilience approach rather than a deficit approach and offers a blueprint for approaching the COVID-19 crisis and its afterlives through the lens of health equity.

The "saddest repudiation" redux: Structural racism and the unlearned lesson of 1918.

The COVID-19 pandemic reveals how the systems and structures of racism devastate the health and well-being of people of color. The debate is an old one and the lesson we have yet to learn was tragically apparent a century ago during the 1918-1919 influenza pandemic. Any history of structural racism in America must begin with the chronicles of African Americans, Native Alaskans, and Indigenous North Americans as they were the originally enslaved and displaced people, subjected to overt and covert policies of oppression ever since. The experiences of Native Alaskans of Bristol Bay Alaska in 1918-1919 present a parallel, illuminating a wrenching example of structural racism that cost lives and impoverished society, then as now. Proven policy solutions exist to remove the structures that produce inequitable health outcomes, but implementing them will require public health officials and policymakers to take multidisciplinary policy actions, to find policy opportunities for change to be made, and, likely, a change in the political environment. The first exists now, the second is afforded because of the current pandemic and the urgent need for policy solutions, and the third is likely coming soon.

Imagination and remembrance: what role should historical epidemiology play in a world bewitched by mathematical modelling of COVID-19 and other epidemics?

Although every emerging infectious disease occurs in a unique context, the behaviour of previous pandemics offers an insight into the medium- and long-term outcomes of the current threat. Where an informative historical analogue exists, epidemiologists and policymakers should consider how the insights of the past can inform current forecasts and responses.

Avian Influenza Human Infections at the Human-Animal Interface.

BACKGROUND: Avian influenza A viruses (AIVs) are among the most concerning emerging and re-emerging pathogens because of the potential risk for causing an influenza pandemic with catastrophic impact. The recent increase in domestic animals and poultry worldwide was followed by an increase of human AIV outbreaks reported. METHODS: We reviewed the epidemiology of human infections with AIV from the literature including reports from the World Health Organization, extracting information on virus subtype, time, location, age, sex, outcome, and exposure. RESULTS: We described the characteristics of more than 2500 laboratory-confirmed human infections with AIVs. Human infections with H5N1 and H7N9 were more frequently reported than other subtypes. Risk of death was highest among reported cases infected with H5N1, H5N6, H7N9, and H10N8 infections. Older people and males tended to have a lower risk of infection with most AIV subtypes, except for H7N9. Visiting live poultry markets was mostly reported by H7N9, H5N6, and H10N8 cases, while exposure to sick or dead bird was mostly reported by H5N1, H7N2, H7N3, H7N4, H7N7, and H10N7 cases. CONCLUSIONS: Understanding the profile of human cases of different AIV subtypes would guide control strategies. Continued monitoring of human infections with AIVs is essential for pandemic preparedness.

Covid-19 in Historical Context: Creating a Practical Past.

Decades ago, in his foundational essay on the early days of the AIDS crisis, medical historian Charles Rosenberg wrote, "epidemics start at a moment in time, proceed on a stage limited in space and duration, following a plot line of increasing revelatory tension, move to a crisis of individual and collective character, then drift toward closure." In the course of epidemics, societies grappled with sudden and unexpected mortality and also returned to fundamental questions about core social values. "Epidemics," Rosenberg wrote, "have always provided occasion for retrospective moral judgment" (Rosenberg 1989, pp. 2, 9). Following Rosenberg's observations, this essay places COVID-19 in the context of epidemic history to examine common issues faced during health crises-moral, political, social, and individual. Each disease crisis unfolds in its own time and place. Yet, despite specific contexts, we can see patterns and recurring concerns in the history of pandemics: (1) pandemics and disease crises in the past, along with public health responses to them, have had implications for civil liberties and government authority; (2) disease crises have acted as a sort of stress test on society, revealing, amplifying or widening existing social fissures and health disparities; (3) pandemics have forced people to cope with uncertain knowledge about the origin and nature of disease, the best sources of therapies, and what the future will hold after the crisis. While historians are not prognosticators, understanding past experience offers new perspectives for the present. The essay concludes by identifying aspects of history relevant to the road ahead.

May the analysis of 1918 influenza pandemic give hints to imagine the possible magnitude of Corona Virus Disease-2019 (COVID-19)?

BACKGROUND: In 1918 an unknown infectious agent spread around the world infecting over one-third of the general population and killing almost 50 million people. Many countries were at war, the First World War. Since Spain was a neutral country and Spanish press could report about the infection without censorship, this condition is commonly remembered as "Spanish influenza". This review examines several aspects during the 1918 influenza pandemic to bring out evidences which might be useful to imagine the possible magnitude of the present coronavirus disease 2019 (COVID-19). METHODS: In the first part of this review we will examine the origin of the SARS-Coronavirus-2 and 1918 Spanish Influenza Virus and the role played by host and environment in its diffusion. We will also include in our analysis an evaluation of different approaches utilized to restrain the spread of pandemic and to treat infected patients. In the second part, we will try to imagine the magnitude of the present COVID-19 pandemic and the possible measures able to restrain in the present environment its spread. RESULTS: Several factors characterize the outcome in a viral pandemic infection. They include the complete knowledge of the virus, the complete knowledge of the host and of the environment where the host lives and the pandemic develops. CONCLUSION: By comparing the situation seen in 1918 with the current one, we are now in a more favourable position. The experience of the past teaches us that their success is linked to a rapid, constant and lasting application. Then, rather than coercion, awareness of the need to observe such prevention measures works better.

Daily persistent headache after a viral illness during a worldwide pandemic may not be a new occurrence: Lessons from the 1890 Russian/Asiatic flu.

New daily persistent headache was first documented in the medical literature in the 1980s. The leading trigger is a viral illness. As we navigate our way thru the current SARS-CoV-2 pandemic, looking back at past viral epidemics may help guide us for what to expect in the near future in regard to headaches as a persistent manifestation of the SARS-CoV-2 infection. The 1890 viral pandemic known as the "Russian or Asiatic flu", has extensive documentation about the neurologic sequelae that presented months to years after the pandemic ended. One of the complications was daily persistent headache. There are actually many similarities between the viral presentation of the 1890 pandemic and the current SARS-CoV-2 pandemic, which may then suggest that not only will NDPH be part of the neurological sequelae but a possible key consequence of the SARS-CoV-2 infection.

Long-term dynamics of measles in London: Titrating the impact of wars, the 1918 pandemic, and vaccination.

A key question in ecology is the relative impact of internal nonlinear dynamics and external perturbations on the long-term trajectories of natural systems. Measles has been analyzed extensively as a paradigm for consumer-resource dynamics due to the oscillatory nature of the host-pathogen life cycle, the abundance of rich data to test theory, and public health relevance. The dynamics of measles in London, in particular, has acted as a prototypical test bed for such analysis using incidence data from the pre-vaccination era (1944-1967). However, during this timeframe there were few external large-scale perturbations, limiting an assessment of the relative impact of internal and extra demographic perturbations to the host population. Here, we extended the previous London analyses to include nearly a century of data that also contains four major demographic changes: the First and Second World Wars, the 1918 influenza pandemic, and the start of a measles mass vaccination program. By combining mortality and incidence data using particle filtering methods, we show that a simple stochastic epidemic model, with minimal historical specifications, can capture the nearly 100 years of dynamics including changes caused by each of the major perturbations. We show that the majority of dynamic changes are explainable by the internal nonlinear dynamics of the system, tuned by demographic changes. In addition, the 1918 influenza pandemic and World War II acted as extra perturbations to this basic epidemic oscillator. Our analysis underlines that long-term ecological and epidemiological dynamics can follow very simple rules, even in a non-stationary population subject to significant perturbations and major secular changes.

[The "blow", the 1918 pandemic in Mexico]. / El "trancazo",la pandemia de 1918 en México.

After eight years of a civil war which devastated the country, Spanish flu, one of the worst pandemics in the history of humankind, arrived in Mexico in October of 1918. This article discusses its arrival to the port of Veracruz in ships coming from Habana and New York City; its dissemination from the Gulf of Mexico area to the rest of the country, including Mexico City; and the responses of both federal and local health authorities. Two events associated to this pandemic are particularly relevant, in addition to the high number of deaths: the testing of the sanitary dispositions added to the 1917 Mexican Constitution and the extraordinary role played by civil society organizations.

Después de ocho años de una cruenta lucha armada que dejó devastado al país, en octubre de 1918 llegó a México la gripe española, una de las peores pandemias en la histo-ria de la humanidad. En este artículo se narra su llegada a Veracruz en buques procedentes de La Habana y Nueva York, su diseminación del Golfo al resto del país, incluyendo la ciudad de México, y las respuestas que implementaron las autoridades sanitarias federales y estatales. Dos hechos son particularmente destacables de la pandemia de 1918 en México, además del número insólito de decesos: la puesta a prueba de las disposiciones incorporadas a la Constitución de 1917 en materia sanitaria y el extraordinario papel que jugó la sociedad civil.

Looking Sideways: Locating Epidemics and Erasures in South Asia.

While focused on the United States, Rosenberg's work on epidemics offers a nuanced framing that defines the stages and unfolding trajectories of epidemics. His writing is a good starting point to analyze the scope and challenges of epidemic historiography in South Asia. To redress its gaps, I have suggested an approach focused on writing histories of epidemics "sideways" and examined plague and influenza epidemics to situate the fluid politics of lived risks and marginality, moving away from dominant interpretations that have tried to characterize epidemics as finite and episodic.