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From America’s vantage in 1889, the Russian influenza posed little cause for concern. So what if it had struck with a vengeance in the Russian capital of St. Petersburg that fall, infecting as much as half the population? Or that it had raged swiftly westward across Europe, into the British Isles? Or that some of the continent’s most prominent leaders—the czar of Russia, the king of Belgium, the emperor of Germany—had fallen ill with the virus?
To Americans, it was safely over there, a vast ocean away.
But within a few months, the pandemic spread to virtually every part of the earth. Tracing its path, scientists would observe that it tended to follow the major roads, rivers and, most notably, railway lines—many of which hadn’t existed during last major pandemic in the 1840s.
That finding gave credence to the theory that the disease was spread by human contact, not by the wind or other means—and that as long as people could move with ease from city to city and country to country, stopping its spread would be all but impossible. Today, the Russian influenza is often cited as the first modern flu pandemic.
READ MORE: Pandemics That Changed History: A Timeline
Coming to America
Most Americans first learned of the pandemic in early December of 1889. The nation’s newspapers covered its growing toll in Berlin, Brussels, Lisbon, London, Paris, Prague, Vienna and other cities. When top European leaders fell ill, Americans were updated on their condition on a near-daily basis.
Even so, the news seemed to cause no particular stir in the U.S. and certainly nothing resembling a panic. But just as railroad transportation had allowed the influenza to cross Europe in a matter of weeks, the larger, faster steamships of the day increased the odds that infected travelers would soon be arriving from across the Atlantic.
Indeed, New York and other East Coast port cities became the earliest U.S. locales to report suspected cases, and seven members of one Manhattan family, ranging in age from 14 to 50, were among the first confirmed patients. Their household’s outbreak had begun with sudden chills and headaches, reports said, followed by sore throat, laryngitis and bronchitis. Overall, “the patients were about as sick as persons with a bad cold,” according to one newspaper account.
Initially, public health officials played down the dangers, arguing that the Russian influenza represented a particularly mild strain. Some officials denied that it had arrived at all and insisted that patients merely had the common cold or a more typical, seasonal flu.
The newspapers, too, treated the influenza as nothing to get worked up about. “It is not deadly, not even necessarily dangerous,” The Evening World in New York announced, “but it will afford a grand opportunity for the dealers to work off their surplus of bandanas.”
READ MORE: Why the Second Wave of the Spanish Flu Was So Deadly
A first death—then many more
On December 28, newspapers reported the first death in the U.S., 25-year-old Thomas Smith of Canton, Massachusetts. He was said to have “ventured out too soon after his illness, caught a fresh cold and died of pneumonia.” Soon after, a prominent Boston banker also succumbed.
As the death toll rose, Americans began to take the threat more seriously. For the first week of January 1890, New York reported a wintertime death record of 1,202 people. While only 19 of those cases were attributed to influenza alone, the numbers revealed a startling spike in deaths from related diseases.
“Persons with weak lungs and those suffering from heart disease or kidney troubles are most seriously affected, and in many cases the influenza leads quickly to pneumonia,” the New-York Tribune reported.
READ MORE: How the 1957 Flu Pandemic Was Stopped Early in Its Path
The disease spreads west
Meanwhile, the disease spread inland, helped, as in Europe, by America’s vast network of railroads. Reports came in from Chicago, Detroit, Denver, Kansas City, Los Angeles, San Francisco, and other U.S. cities.
One Los Angeles victim gave a particular vivid description of the experience. “I felt as if I had been beaten with clubs for about an hour and then plunged into a bath of ice,” he told a reporter. “My teeth chattered like castanets, and I consider myself lucky now to have gotten off with a whole tongue.”
People coped as best they could. “On a Sixth Avenue Elevated train this morning fully one-half of the passengers were coughing, sneezing, and applying handkerchiefs to noses and eyes, and many of them had their heads bundled up in scarves and mufflers,” The Evening World reported. “They were a dejected and forlorn appearing crowd.”
Druggists throughout the country noted an unusually high demand for quinine, which some health authorities had suggested as a possible remedy—though medical journals warned against the dangers of self-medicating and urged people to simply let the disease run its course.
READ MORE: How Five of History's Worst Pandemics Finally Ended
An end, for the moment
By early February 1890, according to contemporary accounts, the influenza had largely disappeared in the U.S. Difficult as the pandemic had been, the country had gotten off lucky compared with much of Europe. New York City recorded the highest number of deaths, with 2,503, although Boston, with a smaller population, was harder hit on a per-capita basis. The total U.S. death toll was just under 13,000, according to the U.S. Census Office, out of about 1 million worldwide.
The Russian influenza wasn’t entirely finished, however. It returned several times in subsequent years. Fortunately, a large portion of the U.S. population was immune by then, having been exposed to it during its first visit.
Today, the Russian influenza is largely forgotten, overshadowed by the far more devastating Spanish influenza of 1918. But it did give Americans a preview of life—and death—in an increasingly interconnected world.
The Russian Flu of 1889: The Deadly Pandemic Few Americans Took Seriously - HISTORY
"While the so-called Spanish influenza of 1918–19 is frequently invoked as an analogue for COVID-19, the Russian influenza might be a better cultural parallel." Mark Honigsbaum
The English medical historian and journalist Mark Honigsbaum offers an interesting anecdote on the impact of the 1889–90 Russian flu in a recent article on the COVID-19 pandemic published in the Lancet. The Russian flu pandemic of 1889–1890 had killed around one million worldwide. Several waves of the epidemic recurred over the intervening years from 1891 to 1895.
The English feminist and campaigner for women's suffrage, Josephine Butler, wrote in January of 1892 to her son, "I don't think I ever remember being so weak, not even after the malaria fever at Genoa. I am so weak that if I read or write for half an hour, I become so tired and faint that I have to lie down.” (Honigsbaum & Krishnan, 2020)
During the Christmas season of 1891, she was stricken with the Russian influenza and left weak with conjunctivitis and pneumonia for several days. Though her fevers had subsided, she recounted that there had been little improvement in her overall condition three months later.
A post-epidemic analysis conducted in 1957 using blood obtained from people still alive from the period noted that they had antibodies to H2N2, which may have originated from the Russian flu. Four decades later, a seroarcheological study then asserted the strain was most likely an H3N8 subtype instead. However, more recent studies led by Belgian biologist Leen Vijgen indicated that the contagion could have been a coronavirus, specifically the HCoV-OC43.
The “Asiatic” or “Russian” flu originated in central Asia, where it smoldered regionally throughout Siberia and northern India for a period of six months from May to October of 1889. Once it landed in St. Petersburg in November 1889, the pandemic accelerated westward, spreading, in a matter of weeks, into Europe, followed by the United States, and, then, the rest of the Americas, Australia, and coastal Africa, completing its circumnavigation of the globe by the fall of 1890.
The Russian Influenza has been characterized as the prototype of the modern era of a pandemic for the rapidity of its spread within an increasingly interconnected world.
In a scientific report published in PNAS in 2010 on the 1889 influenza pandemic, the authors wrote, “At that time, the 19 largest European countries, including Russia, had 202,887 kilometers of railroads, which is more than now. Transatlantic travel by boat took less than six days at that time, instead of less than one day now (which is not a substantial difference, given the time scale of the global spread of the pandemic.)”
In their support of the Russian flu pandemic's coronavirus theory, Vijgen and his team explained that in the second half of the 19th century, cattle herds were being affected by a deadly contagious respiratory disease. They hypothesized that the bovine coronavirus might have been the inciting agent in the sickened animals that underwent a zoonotic transfer into humans from 1870 to 1890 when industrialized nations were engaged in massive culling operations to stem the infections in the livestock industry when handlers could have quickly become infected.
The authors determined through a molecular clock technique, which uses the mutation rate of biomolecules to deduce the time in prehistory when two or more life forms diverged, that a common ancestor of the current Bovine coronavirus and HCoV-OC43 dated back to 1890, circa the Russian flu pandemic.
Additionally, they noted that the pronounced neurological symptoms that distinguished the Russian influenza from other influenza outbreaks speaks to coronavirus as a likely candidate.
Other findings indicated that men and the elderly appeared to be more susceptible to the virus. The reproduction number (R0) was 2.1, with a case fatality rate between 0.1 to 0.28 percent.
Infection symptoms included high fevers, crippling fatigue, and central nervous system disorders.
A Dublin physician named John Moore provided an account from a patient who fell ill on December 20, 1889. The female patient wrote, “Then my face and head got very hot and uncomfortable, and pains began in my arms, shoulders, and legs. All night the pains were very bad, sometimes so sharp across the back of my chest that I could have cried out.”
A report authored by Mark Honigsbaum, titled “The ‘Russian’ influenza in the UK: lessons learned, opportunities missed,” explains that after the first case was identified in December 1889, the virus began to kill thousands of people over several weeks. “The disease had already sickened the British Prime Minister, Lord Salisbury, and sparked mass absenteeism in the General Post Office’s Telegraphic Department, the center of communications of the British Empire.”
Perhaps the most famous case was the death of Queen Victoria’s grandson, Prince Albert Victor, which changed the line of succession. Russia’s czar, the king of Belgium, and Germany’s emperor had taken ill but survived their infection.
Honigsbaum notes that the excess deaths from respiratory failure and the pattern of deaths impacting the middle age ranges “should have aided the public health response, but British health authorities preferred to advocate cautious preventive measures that did little to alleviate the pandemic’s impact.” The medical community was consumed by a now obsolete miasmatic theory that held the disease was caused by a noxious form of bad air.
The pandemic returned a year later, killing twice as many people. From 1890 until 1892, it has been estimated that 110,000 died from the infection in England.
In a study mapping the deaths from influenza in Paris in 1889 and 1890, the authors highlighted excerpts from a French newspaper La Lanterne that reported a single-day high of 450 burials on December 31, 1890 as comparable to the present situation in France in its second COVID-19 surge. The high daily deaths in Paris persisted throughout January 1891. (Kimmerly, Mehfoud, & Marin, 2014)
In the context of the present pandemic, specifically considering the post-COVID-19 viral syndrome known better as Long-COVID, Ms. Butler’s words quoted at the beginning strike a dreadful chord.
An untold number of people who have recovered from their infection continue their struggles facing chronic ailments with no end in sight and no help from an incredulous health community that has often attributed their complaints to “being in their heads.” (Yerramilli, 2020) The post-viral syndrome associated with COVID-19 has only recently been gaining coverage in the media.
In a study that is still to be peer-reviewed, out of 4,182 cases of COVID, 558 (13.3 percent) patients noted symptoms beyond four weeks, 189 (4.5 percent) beyond eight weeks, and 95 (2.3 percent) beyond 12 weeks. These symptoms include extreme fatigue, persistent headaches, shortness of breath, and the loss of smell, affecting disproportionately females, older people, and those of higher weight.
In an online survey of self-reported symptoms from patients from Renown Health System in Reno, Nevada, out of 233 COVID-19 positive cases, 43.4 percent had symptoms lasting more than 30 days, and 24.1 percent had at least one symptom 90 days out from their positive results. These symptoms include chest pain, heart palpitations and tachycardia, poor concentration, shortness of breath, memory loss, confusion, headaches, and dizziness. Those with shortness of breath are at higher risk of developing chronic symptoms.
A European study from the Netherlands found that one-third of 1,837 non-hospitalized patients were dependent on caregivers.
Though these patients do not require intensive medical care, those who have joined social media support groups recount how debilitated their condition has made them, complaining of “rolling waves of symptoms” and “brain fog.” As one New Jersey-based administrator for the COVID-19 Slack group poignantly stated, “We’re not dead, but we’re not living.”
One of the most insidious aspects of the chronic effect of COVID-19 infection is the incapacitating exhaustion and ill-feeling. Thousands of those affected report struggling with just getting out of bed, let alone working for more than a few minutes at one time. A small study from Italy of 143 people discharged from a Rome hospital indicated that 53 percent had fatigue, and 43 percent had shortness of breath two months later. (Carfi, Bernabei, & Landi, 2020)
As with the Russian influenza, post-viral syndromes have been frequently reported with viral illnesses. Even with the Spanish flu of 1918, which was caused by the H1N1 influenza virus and killed an estimated 24.7 million to 50 million people, journals kept by treating physicians noted that many of those who survived never fully recovered.
After the Severe Acute Respiratory Syndrome (SARS) pandemic of 2003 that infected over 8,000 individuals and killed close to 800, many of those who survived were followed to assess their health outcomes. In a study of survivors one year out from their infection, 18 percent continued to have decreased walking tolerance while 17 percent had still not returned to work. More than 60 percent had persistent fatigue. Forty-three percent were being evaluated for mental health disorders. Sleep disturbances were common. Caregivers of many of those severely impacted noted a considerable decline in their patients' cognitive capacities. (Tansey & Herridge, 2007)
In a pooled analysis of 28 studies in patients with documented SARS and Middle East Respiratory Syndrome (MERS) infections, six months after discharge, 27 percent had impaired lung functions and reduced exercise tolerance. More than one-third of these patients suffered from post-traumatic stress disorder and depression compounded by anxiety.
During the early phase of the pandemic, in a letter penned in June to the editors of the journal Medical Hypotheses, the lead author Dr. Raymond Perrin, a neuroscientist and specialist in Chronic Fatigue Syndrome from the School of Medicine and Manchester Academic Health Sciences, warned about the potential for a post-viral syndrome that could manifest in patients recovering from a COVID-19 infection, similar to that in SARS patients.
“After the acute SARS episode some patients, many of whom were healthcare workers, went on to develop a Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME)-like illness which nearly 20 months on prevented them returning to work. We propose that once an acute COVID-19 infection has been overcome, a subgroup of remitted patients are likely to experience a long-term adverse effect resembling CFS/ME symptomology such as persistent fatigue, diffuse myalgia, depressive symptoms, and non-restorative sleep.”
CFS/ME is a complex, fatiguing, long-term medical condition distinguished by lengthy exacerbations after mental or physical activity, significantly diminished capacity to accomplish tasks that had been routine previous to their illness, and unrefreshing sleep or insomnia. The proposed mechanism is a byproduct of the immune response to the infection that traverses the blood-brain barrier via the olfactory pathway into the hypothalamus.
The “pro-inflammatory cytokines” that pass through the blood-brain barriers cause inflammation in the central nervous system leading to “autonomic dysfunction,” which manifest “acutely in high fevers and in the long term to dysregulation of the sleep/wake cycle, cognitive dysfunction and profound unremitting anergia (lack of energy).”
There have been over 50 million cases of COVID-19, and by all accounts, the present surge is a massive tsunami of cases that have placed every health system in the Northern Hemisphere on notice. Millions are expected to die. However, millions more, especially within the working class who have lost their jobs, will face an uncertain future of disabling conditions and chronic unemployment unless immediate efforts are made to bring the pandemic under control. Early intervention and supportive care will be necessary to mitigate the long-term consequences for millions. Medical bills and the cost of treatments must be waived.
According to a Wall Street Journal report, Tricia Sales, a 41-year-old who fell ill with COVID-19 in March and is experiencing unremitting symptoms of nausea, dizziness, and numbness in her hands and feet, owes more than $100,000 in medical expenses. Many people are forgoing treatment due to concerns over high deductibles, attempting to live on their savings as they are still too ill to return to work.
The City University of New York Public School of Health estimated that if 20 percent of the US population contracts COVID-19, one-year post-hospitalization costs would be more than $50 billion, without considering the long-term care post-acute recovery. According to the Kaiser Family Foundation, many insurance companies are raising 2021 premiums to account for expected COVID-19 costs.
Though a paramount concern, death is not the only indicator of importance concerning the health crisis caused by the SARS-CoV-2 virus. Experience with post-viral syndromes has a long history in medical journals. The literature on SARS and MERS should have informed public health policies and provided guidance early during the pandemic in the post-treatment management and care of these patients.
It will be critical to developing rehabilitation programs in this context to address the multidimensional aspect of this disease. It has been predicted that 45 percent of discharged patients will require health and social care, while another 4 percent may need continued inpatient treatment. The health impact on all national health systems will be considerable.
Carfi, A., Bernabei, R., & Landi, F. (2020). Persistent symptoms in patients after acute COVID-19. JAMA, 603–605.
Honigsbaum, M., & Krishnan, L. (2020). Taking pandemic sequelae seriously: from the Russian influenza to COVID-19 long-haulers. The Lancet, 1389–1391.
Kimmerly, V., Mehfoud, N., & Marin, S. (2014). Mapping the 1889–1890 Russian Flu. Circulating Now.
Tansey, C. M., & Herridge, M. S. (2007). One-year outcomes and health care utilization in survivors of severe acute respiratory syndrome. Archives of Internal medicine, 1312–1320.
Yerramilli, P. (2020). "I have all the symptoms of a COVID-19 long-hauler - but I'm hesitant to identify myself as one," STAT News.
Influenza viruses belong to the Orthomyxoviridae family. Influenza viruses are enveloped, negative-sense, single-stranded RNA viruses (Wright and Webster, 2001). Their genome consists of 7 or 8 RNA segments encoding at least 10 structural and non-structural proteins. Structural proteins include a hemagglutinin (HA), a neuraminidase (NA), two matrix proteins and a nucleoprotein. Influenza viruses can be distinguished in types A, B, C, and D. Influenza A and B are responsible for outbreaks in tropical regions and seasonal epidemics in temperate regions whereas influenza A viruses are the only ones with a pandemic potential (Lofgren et al., 2007). Indeed, influenza A virus is endemic in a number of species including humans, birds and pigs (Webster et al., 1992). Gene reassortments can thus occur between human and animal influenza A viruses and lead to a new virus subtype which can be pathogenic to humans (Webster et al., 1995).
In a typical seasonal epidemics, influenza virus causes 3 to 5 million cases of severe illness and approximately 500,000 deaths worldwide (Iuliano et al., 2018). Most typical seasonal influenza infections are asymptomatic or cause only mild or classical influenza illness characterized by 4 or 5 days of fever, cough, chills, headache, muscle pain, weakness and sometimes upper respiratory tract symptoms (Zambon, 2001). Severe complications can occur especially in infants, elderly and individuals with chronic conditions such as diabetes mellitus and cardiac/pulmonary diseases. Among the most severe complications is pneumonia which can be associated with secondary bacterial infection.
Annual influenza epidemics are sustained in the human population through mutations occurring especially in the HA and NA viral surface glycoproteins, the major targets for neutralizing antibodies. Seasonal influenza virus results from frequent antigenic drifts every 2𠄵 years in response to selection pressure to evade human immunity (Kim et al., 2018). Its genome contains segmented genes which may undergo reassortments in cells co-infected with two or more influenza viruses. Each influenza A virus has a gene encoding for 1 of 16 possible HAs and another gene encoding for 1 of 9 possible NAs that are involved in viral attachment and release, respectively (Dugan et al., 2008). Of the 144 total combinatorial possibilities, only 3 HAs and 3 NAs in only 4 combinations (A/H1N1, A/H2N2, A/H3N2 and possibly A/H3N8) were found to be truly adapted to humans. Rarely, antigenic shift which results from reassortment between human and animal viruses leads to the emergence of a new virus subtype (Webster et al., 1995 Ma et al., 2009). This antigenically distinct virus may have the ability to infect humans and achieve sustained human-to-human transmission and may cause a pandemic if the immunity in the human population is partial or lacking (Webster et al., 1992).
The time in which influenza virus began to infect humans or cause a pandemic cannot be determined with accuracy but many historians agree that the first influenza pandemic could have likely occurred in 1510 (Morens et al., 2010). The Russian flu that occurred between 1889 and 1893 was the first well-described pandemic (Taubenberger et al., 2007). This pandemic was possibly caused by an A/H3N8 virus based on serologic and epidemiologic data (Worobey et al., 2014). The virus spread rapidly as it took only 4 months to circumvent the planet (Valleron et al., 2010). The pandemic virus reappeared every year for 3 years and caused an estimated 1 million deaths worldwide ( Table 1 ). The median Ro was estimated at 2.1 (interquartile range 1.9𠄲.4) (Valleron et al., 2010). The case fatality rates ranged from 0.10 to 0.28% so the mortality burden of this pandemic was considered as low (Valleron et al., 2010). The median clinical attack rate was 60% (interquartile range 45%) (Valleron et al., 2010). Attack rates were highest in individuals aged 1 years and lower in infants and seniors (Valtat et al., 2011). In contrast, mortality rate showed a J-shape curve with highest rates in infants and people over 20 years of age (Valtat et al., 2011).
Twenty five years later, the Spanish flu was caused by an A/H1N1 virus ( Table 1 ) that apparently arose by genetic adaptation of an existing avian influenza virus to a new human host (Reid et al., 2004). Before its identification, the virus spread silently around the world and its region of origin could not be determined. Analysis of formalin-fixed and paraffin-embedded samples as well as permafrost-frozen corpses from that time confirmed that the strain was an A/H1N1 influenza virus (Reid et al., 1999). Typical attack rates were 25% and the Ro was estimated at 2𠄳 (Mills et al., 2004). The 1918 pandemic spread in at least 3 distinct waves within a 9 month interval. The first wave occurred during spring-summer 1918 and caused high morbidity and low mortality. Both the second and third waves in summer-fall 1918 and winter 1918 caused high mortality. The 1918 influenza pandemic resulted in approximately 500 million infections and 50 million deaths worldwide (Johnson and Mueller, 2002). Fatality of epidemic influenza usually follows a characteristic U-shape curve with high mortality rates in the very young (< 5 years) and the elderly (> 65 years). However, the 1918 pandemic showed a W-shaped mortality curve with high case fatality rates in the very young and the elderly as well as in healthy young adults aged 20 years (Morens and Taubenberger, 2018). This uncommon age distribution suggests that the severity of the 1918 influenza pandemic was not primarily due to a hyper-virulent strain but was more likely related to host factors that prevent individuals to control the infection. It is suggested that an A/H3N8 virus was circulating between 1890 and 1900 and that individuals born at this time may have lacked immunity against the antigenically distinct 1918 A/H1N1 virus (Worobey et al., 2014). The most common clinical manifestation was an acute aggressive bronchopneumonia presenting with epithelial necrosis, microvasculitis/vascular necrosis, hemorrhages, edema and severe tissue damage to the lungs (Morens and Fauci, 2007) often followed by secondary bacteria invasion with Streptococcus pneumonia, Streptococcus pyogenes, Staphylococcus aureus and Haemophilus influenzae (Morens et al., 2008). It is suggested that the 1918 influenza virus had an enhanced capacity to spread to and damage bronchial and bronchiolar epithelial cells that could allow bacteria to breach the mucociliary barrier leading to fatal bacterial pneumonia (Morens and Fauci, 2007). The second common clinical manifestation was an acute respiratory distress syndrome (ARDS) associated with severe facial cyanosis that was observed in 10% of cases (Shanks, 2015). The H1 hemagglutinin of the 1918 pandemic virus was identified as a key virulence factor for mammalian and was associated with increased respiratory epithelial pathogenicity and elicitation of a strong pro-inflammatory response (Qi et al., 2014). Most deaths occurred from several days to weeks (median 7 days) after the onset of symptoms (Shanks and Brundage, 2012). In large cities of Western world, health authorities implemented a series of containment strategies to prevent the spread of the disease including the closure of schools, churches and theaters and the suspension of public gatherings. Physicians encouraged the practice of individual measures such as respiratory hygiene and social distancing. However, these measures were implemented too late and in an uncoordinated manner due to World War I. Travel restrictions and border controls were impossible to put in place. The movement of military troops and the poor living conditions of soldiers in the trench warfare in Europe facilitated the spread of the disease.
Over the past century, descendants of the 1918 pandemic virus were the cause of almost all seasonal influenza A epidemics worldwide. All influenza A viruses responsible for the 1957, 1968 and 2009 pandemics ( Table 1 ) also derived from the founding 1918 virus by gene reassortments between human, avian and swine influenza viruses (Morens et al., 2009) as shown in Figure 1 .
Timeline of influenza pandemics caused by the 1918 H1N1 virus and its descendants produced by reassortment of circulating strains with avian influenza viruses (AIV) and swine H1N1 viruses. The reassortment of genes is shown in parenthesis. The re-emergence of H1N1 virus in 1977 is also shown as it co-circulated with the H3N2 virus before being replaced by the H1N1pdm09. HA, hemagglutinin NA, neuraminidase NP, nucleoprotein M, matrix proteins, PB1 polymerase PB2 polymerase PA polymerase NS, non-structural proteins.
The new subtype A/H2N2 that caused the 1957 pandemic (Asian flu) derived from the 1918 virus by acquisition of 3 new avian gene segments (HA, NA and PB1 polymerase) by reassortment (Kawaoka et al., 1989) whereas the circulating A/H1N1 was totally replaced. Sustained transmission of the 1957 pandemic virus started on December 1957 with recurrent waves occurring over several years (Housworth and Langmuir, 1974). The morbidity was highest in children and the mortality was highest at the extremes of age. The case fatality rate was approximately 0.13% (Mc, 1958). The global mortality of the 1957 influenza pandemic was estimated at 1𠄲 millions based on excess death due to respiratory diseases (Viboud et al., 2016). The Ro was estimated at 1.65 (interquartile range 1.53𠄱.70) (Biggerstaff et al., 2014). The highest attack rates were in school-age children through young adults up to 35 or 40 years of age (Serfling et al., 1967). Older adults, including those over the age of 60, had significantly lower attack rates. This unusual distribution was attributed to the absence of protective antibody among children and middle-aged adults. Histopathological studies from autopsies were characterized by a rapid development of bronchial epithelial necrosis, preservation of the basal layer, limited inflammatory response and evidence of prompt repair (Walsh et al., 1961). Secondary bacterial pneumonia was a relatively minor cause of fatalities possibly as a result of the widespread use of antibiotics (Robertson et al., 1958 Oseasohn et al., 1959). The proportion of strains resistant to antibiotics was relatively high in fatal cases compared to those isolated from cases who recovered. Furthermore, mechanical ventilators were available in the intensive care units (ICU) to support cases presenting hypoxemia. At that time, the pathogenic agent had been identified (Smith and Andrewes, 1933) and knowledge on the pathogenesis of the disease had advanced. In 1952, the WHO had implemented a global influenza surveillance network that provided information on the emergence and spread of the novel influenza virus. Containment measures (such as closure of schools and nursery, bans on public gatherings) varied from country to country but delayed the onset of the disease for a few weeks only. Influenza vaccination (vaccine efficacy of 53%) failed to have a significant impact on the pandemic due to inadequate coverage (Henderson et al., 2009).
The 1968 pandemic virus emerged when 2 gene segments encoding for HA and PB1 polymerase moved from an avian virus in the A/H2N2 virus through genetic reassortment whereas the NA remained unchanged (Kawaoka et al., 1989). The new A/H3N2 reassortant replaced the A/H2N2 virus that circulated in the human population since 1957. The global mortality rate of the 1968 pandemic (Hong Kong flu) was estimated to be 0.5𠄲 millions (Saunders-Hastings and Krewski, 2016). The Ro was estimated at 1.80 (interquartile range 1.56𠄱.85) (Biggerstaff et al., 2014). The mean age at death was 62 years. The first pandemic season was more severe than the second one in North America whereas the opposite was seen in Europe and Asia (Viboud et al., 2005). The 1968 influenza pandemic was mild in all countries and comparable to severe seasonal epidemics. The mildness of this pandemic is expected considering pre-existing immunity to the NA antigen in all age groups and to the HA in the elderly. No specific containment measures were implemented during this pandemic. In 1977, a descendant of the 1918 A/H1N1 re-emerged suspiciously in Russia and co-circulated with the reassortant A/H3N2 virus thereafter (Gregg et al., 1978).
The 2009 A/H1N1 pandemic was a triple reassortant made of influenza genes originating from human A/H3N2 (PB1 polymerase gene segment), avian (PB2 polymerase and PA polymerase gene segments) and North American (H1, nucleoprotein and Non-structural proteins gene segments) and Eurasian (N1 and matrix proteins gene segments) swine that was transmitted from pigs to humans (Easterbrook et al., 2011). The 2009 H1 protein had minimal antigenic drift compared to its 1918 counterpart. Due to its pathogenicity in humans, it is suggested that the maintenance of H1 immunity in the population may be important to prevent future pandemics (Morens and Taubenberger, 2018). The 2009 influenza virus emerged in Mexico and almost simultaneous outbreaks began in Mexico and in Southern United States (Neumann and Kawaoka, 2011). The virus then spread globally over the next 6 weeks. The A/H1N1pdm09 virus was associated with a lower attack rate in older individuals possibly because of previous exposition to older A/H1N1 viruses. Clinical symptoms associated to the A/H1N1pdm09 range from mild respiratory irritations to severe pneumonia associated to ARDS when infection progressed (Chowell et al., 2009). Asymptomatic infections accounted for approximately 10% of cases (Papenburg et al., 2010). Severe disease developed in a small proportion of healthy adults, many of whom had no underlying conditions (Viboud et al., 2010). The Ro was estimated at 1.46 (interquartile 1.30𠄱.70) (Biggerstaff et al., 2014). The WHO reported 18,631 laboratory-confirmed deaths. However, the mortality burden was estimated to be between 148,000 and 249,000 based on excess death due to respiratory diseases in several countries (Simonsen et al., 2013). The case fatality rate based on confirmed cases was 0.5% (Nishiura, 2010). Later studies estimated the symptomatic case fatality rate at 0.05% of all medically attended symptomatic cases. Mortality rates in younger populations affecting children, young adults and pregnant women were higher than in a typical influenza season. The average age of people who died with laboratory-confirmed influenza was 37 years (Vaillant et al., 2009). Non-pharmaceutical interventions that were implemented included hand washing, use of face masks and cough etiquette (Cantey et al., 2013). The 2009 pandemic was the first one to combine vaccines and antiviral use. Symptomatic individuals and their contacts were isolated and received antiviral treatment as prophylaxis. Although the vaccine was approved only during the second wave, the immunization program in Canada covered 33 to 50% of its population compared to 13 to 39% in United States (Gilmour and Hofmann, 2010). The new pandemic virus completely replaced the prior circulating seasonal A/H1N1 whereas the influenza A/H3N2 continued to circulate.
Overall, the impacts of an influenza pandemic depend on the transmissibility and virulence of the strain and on the susceptibility of the population, which may vary according to age and past exposure to influenza viruses. The impacts of influenza are not always higher during pandemics than during seasonal epidemic periods. However, a shift in the age distribution of mortality toward younger age groups distinguishes the impacts of a pandemic from those of seasonal epidemics (Simonsen et al., 1998).
Avian Influenza and the Risks for a New Pandemic
The constant adaptation and exchange of genes between influenza viruses in different species, including at the animal-human interface, is still a critical challenge for the emergence of pandemic viruses nowadays. In this respect, a series of avian influenza A viruses have caused sporadic cases and outbreaks of severe diseases and deaths in humans (Li et al., 2019). These viruses are divided into two groups, low pathogenic avian influenza (LPAI) and highly pathogenic avian influenza (HPAI) viruses, based on their virulence in chicken. The first human outbreak due to a HPAI was caused by an A/H5N1 virus in 1997 in Hong Kong where 18 positive cases associated with 6 deaths were reported (Chan, 2002). This A/H5N1 HPAI virus continues to spread in poultry and in a large number of wild bird species on several continents. This virus caused severe and fatal spillover infections in humans and rarely resulted in human-to-human transmission (Ungchusak et al., 2005). This virus was eventually detected in 17 countries and led to 861 human cases with a case fatality rate of 53% as of October 23, 2020 (World Health Organization [WHO], 2020b). The A/H5N1 virus has thus a potential for high morbidity and mortality in humans but it seems unlikely that it could become adapted with efficient human-to-human transmission (Morens and Taubenberger, 2015). A LPAI A/H7N9 virus emerged in China in 2013 (Gao et al., 2013). This virus was then shown to evolve to highly pathogenic strains in late 2016 (Kile et al., 2017). Infection with A/H7N9 has been reported in 1,567 human cases with a fatality rate of 39% as of September 5, 2018 (World Health Organization [WHO], 2018b). To date, sporadic familial clusters of A/H7N9 have been reported but there is still no evidence of sustained human-to-human transmission of the virus (Wu et al., 2020). Sporadic cases of human infections with avian influenza viruses also occurred with A/H5N6, A/H6N1, A/H7N2, A/H7N3, A/H7N4, A/H7N7, A/H9N2, A/H10N7 and A/H10N8 strains (Widdowson et al., 2017). Surveillance programs for monitoring animal influenza viruses with zoonotic potential facilitate the rapid detection of human threats. However, obvious clinical manifestations of influenza infections may be lacking in avian species thereby complicating early detection and efficient control of potential outbreaks (Li et al., 2019). Furthermore, the conditions required for cross-species transmission from avian species to humans are not yet elucidated and surveillance programs would most likely require longitudinal surveillance in multiple hosts. Non-pharmaceutical measures aim to reduce the number of live-bird markets and to decrease contacts between humans and birds in breeding facilities have been implemented to prevent and control zoonotic influenza virus infections. Animal facilities must be periodically disinfected and employees exposed to birds must wear protective personal equipment and be isolated in case of suspected contamination. Pharmaceutical measures include the use of vaccines (including poultry vaccination) and antiviral agents such as the neuraminidase inhibitors (oseltamivir, zanamivir and peramivir) and polymerase inhibitors (baloxavir marboxil and favipiravir) (Beigel and Hayden, 2020). The WHO together with reference laboratories determine viral antigenicity of strains circulating in avian species that could be used in the development of candidate vaccines for pandemic preparedness. To date, candidate vaccines are available for H5, H7 and H9 influenza viruses (World Health Organization [WHO], 2020a). The development of a universal vaccine to prevent any subtype of influenza virus is a priority (Yamayoshi and Kawaoka, 2019). Finally, it is not excluded that the circulating human A/H3N2 virus could acquire an avian H2 gene by reassortment. As the majority of the population has no protective immunity against the H2 subtype that circulated between 1957 and 1968, the emergence of a H2N2 reassortant could be a potential risk for a future pandemic (Taubenberger and Morens, 2010).
1957 flu pandemic
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1957 flu pandemic, also called Asian flu pandemic of 1957 or Asian flu of 1957, outbreak of influenza that was first identified in February 1957 in East Asia and that subsequently spread to countries worldwide. The 1957 flu pandemic was the second major influenza pandemic to occur in the 20th century it followed the influenza pandemic of 1918–19 and preceded the 1968 flu pandemic. The 1957 flu outbreak caused an estimated one million to two million deaths worldwide and is generally considered to have been the least severe of the three influenza pandemics of the 20th century.
Where did the 1957 flu pandemic originate?
The 1957 outbreak of influenza was first detected in Singapore in February that year. In the months that followed, the outbreak spread to Hong Kong and surrounding regions. By the summer of 1957, it had reached coastal areas of the United States.
How many deaths were caused by the 1957 flu pandemic?
The 1957 flu pandemic caused an estimated one million to two million deaths worldwide and is generally considered to have been the least severe of the three influenza pandemics of the 20th century.
How did the 1957 flu pandemic impact flu vaccine development?
The 1957 flu pandemic was caused by influenza H2N2 virus, to which few people had previous exposure. A vaccine was rapidly developed against H2N2, though later assessment showed that more vaccine than usual was needed to produce immunity. H2N2 no longer circulates in humans but is carried by animals. Because of the pandemic potential of H2 viruses, researchers are developing putative H2 vaccines as part of pre-pandemic vaccine planning.
Why did the 1957 flu cause some people to become more ill than others?
The 1957 flu outbreak was associated with variation in susceptibility and course of influenza illness. Some infected individuals experienced only minor symptoms, whereas others experienced life-threatening complications such as pneumonia. Persons who were unaffected or only mildly affected likely possessed protective antibodies to other, closely related strains of influenza.
The 1957 outbreak was caused by a virus known as influenza A subtype H2N2. Research has indicated that this virus was a reassortant (mixed species) strain, originating from strains of avian influenza and human influenza viruses. In the 1960s the human H2N2 strain underwent a series of minor genetic modifications, a process known as antigenic drift. These slight modifications produced periodic epidemics. After 10 years of evolution, the 1957 flu virus disappeared, having been replaced through antigenic shift by a new influenza A subtype, H3N2, which gave rise to the 1968 flu pandemic.
In the first months of the 1957 flu pandemic, the virus spread throughout China and surrounding regions. By midsummer it had reached the United States, where it appears to have initially infected relatively few people. Several months later, however, numerous cases of infection were reported, especially in young children, the elderly, and pregnant women. This upsurge in cases was the result of a second pandemic wave of illness that struck the Northern Hemisphere in November 1957. At that time the pandemic was also already widespread in the United Kingdom. By December a total of some 3,550 deaths had been reported in England and Wales. The second wave was particularly devastating, and by March 1958 an estimated 69,800 deaths had occurred in the United States.
Similar to the 1968 flu pandemic, the 1957 outbreak was associated with variation in susceptibility and course of illness. Whereas some infected individuals experienced only minor symptoms, such as cough and mild fever, others experienced life-threatening complications such as pneumonia. Those persons who were unaffected by the virus were believed to have possessed protective antibodies to other, closely related strains of influenza. The rapid development of a vaccine against the H2N2 virus and the availability of antibiotics to treat secondary infections limited the spread and mortality of the pandemic.
Vaccination programmes begin in the US and Europe, but many healthcare workers are reluctant to have the vaccine, even though it is virtually identical to the seasonal vaccines used in previous years, which have a good safety record.
Production delays also continue to plague the deployment of vaccine. By 22 October, the US has only 27 million doses available, compared with the expected 45 million. Researchers show that this much vaccine will reduce the number of cases in the second wave by less than 6 per cent – but that is still enough to save 2000 lives.
Six months after swine flu first shot to world attention, US President Barack Obama declares the virus a national emergency.
In mid-October 1918, Washington, D.C., ran out of coffins. The city was in the throes of the "Spanish influenza" pandemic, and between 70 and 100 people were dying each day. Gravediggers also were in short supply William Fowler, the city's health officer, said that anyone who volunteered for the job would be well paid, but fear of contracting the virus kept potential workers home. With bodies piling up in morgues and cemetery vaults, Fowler commandeered a trainload of caskets bound for Pittsburgh (which was facing its own shortage) and ordered inmates from Occoquan Prison to start digging graves.
No mourners were present at the burials: Public funerals had been banned in an attempt to stop the spread of the virus. Similar scenes were playing out across the country, as doctors and local officials struggled to halt the pandemic's advance across the United States. In less than a year, the flu would kill an estimated 675,000 Americans, a share of the population equivalent to nearly 2 million people today. Worldwide, the death toll may have been as high as 100 million &mdash an economic and social shock from which scientists and economists are still trying to learn.
The Virus Emerges
The first reported cases of the Spanish flu in the United States occurred at Camp Funston, an Army training camp in Kansas. On March 4, 1918, soldiers preparing for deployment to World War I began arriving at the infirmary complaining of fevers and backaches. Most of the 1,100 men who eventually would be hospitalized had what appeared to be a typical flu virus. But in some cases, the soldiers began having nosebleeds and coughing up blood as it became more difficult for them to breathe, they slowly turned blue. The virus had attacked the men's lungs, filling them with a thin, bloody fluid that led to suffocation. Within a few weeks, between 40 and 50 soldiers had died.
Outbreaks occurred at other camps that spring but did not attract much attention it wasn't uncommon for a contagious disease to sweep through a military installation, and many of the deaths were attributed to pneumonia rather than the flu. The so-called "first wave" of the virus also went relatively unnoticed in the civilian world, in large part because the country's attention was focused on the news from Europe. In addition, flu, unlike tuberculosis or cholera, was not an illness that had to be reported to state or federal health departments, so no one connected an outbreak of unusual flu cases in Detroit with similar cases in South Carolina.
Some scientists and historians believe the virus originated on farms in Haskell County, Kan., and was brought to Camp Funston when county residents reported for duty. From there, traveling soldiers might have carried the flu to other army camps and eventually across the ocean to Europe. Other researchers trace the virus to a British training camp in Étaples, France, or to Chinese laborers conscripted by French and British forces. (The virus was dubbed the "Spanish flu" because Spain was the source of the first major news about the pandemic the country was neutral during World War I, and its press was not obliged to censor news that might damage morale.)
However the flu got to Europe, World War I was a perfect breeding ground. Soldiers, sailors, and laborers from all over the world mingled in hospitals and in trenches and on ships as they sneezed and coughed, the virus quickly mutated and spread. When hundreds of thousands of U.S. military personnel arrived in Europe during the summer of 1918, they met with a flu strain that had become significantly more dangerous than the one encountered at training camps in the spring.
By most accounts, the second wave of the Spanish flu in the United States started in Boston, where a few sailors who had recently returned home became sick in late August. Within days, dozens of sailors at Commonwealth Pier were diagnosed with the flu within weeks, the number of military patients had climbed into the thousands and civilian cases were being reported as well. By the end of September, recalled one nurse, it seemed as if "all the city was dying."
Before officials in Boston fully realized the seriousness of the flu outbreak, servicemen were already returning to other coastal cities and traveling across the United States, coming into contact with other soldiers, sailors, and civilians at ports and on trains and in their hometowns. Soon, the entire country had been visited by the "Spanish Lady."
The Virus Kills
The Spanish flu was not the first flu pandemic the world had encountered &mdash researchers have identified 12 that occurred since the 1700s &mdash but it was the most lethal. (An epidemic reaches pandemic status when it spreads to multiple countries or continents.) During the "Russian pandemic" of 1889 and 1890, for example, about 1 million people died worldwide the case mortality rate, or the share of people infected who die, was roughly 0.15 percent, a rate comparable to more recent pandemics. The Spanish flu killed more than 2.5 percent of people who contracted the virus, on average in some parts of the world, the case mortality rate was two or even three times higher.
In 1927, the American bacteriologist Edwin Oakes Jordan calculated that the Spanish flu had killed roughly 21.5 million people worldwide. His estimate was based on the best available data at the time, but today, that number is considered much too low. The most recent reputable estimate is nearly 50 million dead, from a 2002 paper by Niall Johnson of the Australian Commission on Safety and Quality in Health Care and Juergen Mueller, a historian and geographer based in Hannover, Germany. But given large inconsistencies in how flu deaths were recorded and reported, Johnson and Mueller concluded the toll could actually have been as high as 100 million.
It's also uncertain exactly how many people died in the United States. At the time, only about 80 percent of the population lived in the "registration area," or the cities or states for which the Census Bureau had accurate and complete mortality statistics. And even within the registration area, many flu deaths probably went unreported or were attributed to another illness. Thus, the estimate of 675,000 American deaths is likely to be conservative. Roughly 550,000 of those deaths were "excess deaths" beyond what would likely have occurred during a typical flu season. Overall, U.S. life expectancy fell almost 12 years from 1917 to 1918. (See chart below.)
Of the nearly 117,000 American military personnel who died in World War I, about 43,000 were killed by the Spanish flu, compared with 53,402 combat deaths. (The remainder died of other causes.) More Americans, civilian and military, died during the pandemic than died in combat in World War I, World War II, Korea, and Vietnam combined.
In absolute terms, the Spanish flu pandemic ranks among the deadliest pandemics in world history. As many as 100 million people died during the Plague of Justinian, which began around 540 A.D the Black Death killed an estimated 25 million Europeans &mdash one-quarter of the continent's population &mdash in the mid-14th century.
The flu that struck the world in 1918 differed in several ways from other flu strains. First, the Spanish flu virus afflicted the lungs and respiratory systems, leading many of its victims to develop bacterial pneumonia, which is what eventually killed them (and why many cases were initially misdiagnosed). In other cases, victims died within just a few days of showing symptoms, as their lungs filled rapidly with fluid. And most notably, the Spanish flu was unusually deadly for otherwise-healthy younger adults. Typically, flu deaths follow a U-shaped curve, with deaths peaking for the very young and the very old. But the Spanish flu followed a W-shape, with a sharp peak among adults between 20 and 40 years old. The flu death rate for younger adults was more than 20 times the rate in previous years, and almost half of all flu deaths in the United States were in that age group.
Scientists still aren't certain exactly why the Spanish flu killed so many younger people. One reason might be that unlike older generations of the time, they hadn't been exposed to the Russian flu a few decades earlier and thus lacked immunity. Another explanation, based on research with a virus reconstructed from the DNA of a victim found in the Alaskan permafrost, is that the virus turned the body's immune system against itself. Younger adults tend to have more robust immune systems &mdash and in 1918, that was a liability rather than an asset.
The States (Try to) Respond
Flu mortality varied widely across the United States: Among the 25 states in the death registration area as of 1915, the excess mortality rate ranged from 360 per 100,000 people in Wisconsin to 757 per 100,000 people in Pennsylvania, according to historian Alfred Crosby's comprehensive 1976 account of the flu, Epidemic and Peace, 1918. The disparities do not seem to be entirely explained by either geography or demography. In Colorado, for example, the excess death rate was 681 per 100,000 people in neighboring Kansas, the rate was a relatively low 423. In New York, an extra 479 people per 100,000 died, versus 649 in New Jersey. (The states with the highest excess mortality rates were Pennsylvania, Montana, Maryland, and Colorado.)
Population density played some role within states, excess mortality was higher in cities than in rural areas. But there was also significant variation across cities. In Missouri, for example, the rate in St. Louis was 386, versus 624 in Kansas City. Cities also differed in the timing of the pandemic. Some experienced just the second wave of the flu during the fall of 1918, while others were hit by a third wave later that winter or in early 1919.
One factor that might have contributed to different outcomes among cities was the promptness and duration of the public health response. In some cities, officials implemented preventive measures, such as banning public gatherings, requiring people to wear masks, and closing movie theaters and schools, within days of the first flu cases being reported. In other cities, such measures were not put in place until weeks after the flu appeared. Cities also varied in how long they kept the rules in place and in how strictly they were enforced. In a 2007 article in the Proceedings of the National Academy of Sciences, researchers concluded that cities that implemented multiple measures early in the outbreak had lower peak mortality rates. There was not much effect on cumulative mortality, however, since few cities kept the measures in place longer than a few weeks. And cities that did enforce preventive measures for longer faced an unfortunate side effect: They were more likely to experience an additional wave of the pandemic later that winter since fewer people had gained immunity during the fall, further limiting the effect on overall mortality.
The gaps in prevention were many and wide. Churches and dance halls might have been closed, but people still went shopping and crowded onto streetcars, despite warnings to the contrary. The gauze masks distributed by volunteers were actually highly porous and did little to prevent the spread of germs. And exceptions were made for patriotism: On Sept. 28, the Treasury Department kicked off its fourth "Liberty Loan" drive to sell $6 billion in Liberty Bonds. The event was marked with huge parades all across the country, and in many places, rallies and door-to-door solicitations continued throughout October, even when other public gatherings were banned. While it's possible the Spanish flu would have reached similar proportions in the absence of the bond drive, it certainly didn't help. Two days after more than 200,000 Philadelphians gathered to demonstrate their support for the war effort, 635 new cases of flu were reported.
The Virus Reverberates
The United States' medical system was overwhelmed. The country already had a shortage of doctors and nurses since many were serving overseas, and many of those who remained home became sick with the flu themselves. The U.S. Public Health Service (PHS) issued urgent calls for physicians to volunteer to treat flu patients the Red Cross recruited women without any medical training to work as nurses. Medical school exams were expedited and dentists were authorized to practice as doctors. Thousands of people volunteered, but still there were not enough personnel to treat all the sick. And there was nowhere to put them university campuses and state armories were turned into makeshift hospitals, and existing hospitals filled their hallways and porches with patients. Many people endured the flu at home, aided by volunteers &mdash nearly all women &mdash who brought cool washcloths and clean linens and helped feed the children of stricken parents.
Some essential services were limited or suspended. Telephone calls could be made only in emergencies because there weren't enough operators garbage collectors and police officers were too sick to report to work. Retailers reported huge declines in business and revenue, found Thomas Garrett, then with the St. Louis Fed, in a 2007 report. The flu also may have contributed to substantial business failures, according to a 2002 paper by Elizabeth Brainerd of Brandeis University and Mark Siegler of Sacramento State University.
While it's difficult to separate the macroeconomic effects of the pandemic from the effects of World War I, some economists have tried. Brainerd and Siegler concluded that the pandemic may have been a factor in the recession that began in August 1918 and ended in March 1919, as well as in a more severe recession in 1920 and 1921. Research by Robert Barro of Harvard University and Jose Ursua of Dodge and Cox Funds also attributes the 1920-1921 recession at least in part to the flu. Barro and Ursua linked the flu pandemic to declines in GDP and consumer spending in 24 other countries as well, including some that were not involved in the war.
Perhaps counterintuitively, Brainerd and Siegler also found that states with higher flu mortality during the pandemic experienced faster per capita income growth than states with lower mortality during the decade following the pandemic. In part, this could reflect the fact that productivity increases when there are fewer people performing the same amount of work. (Some research suggests that workers' wages in Europe increased significantly following the Black Death.) But it could also be that states with higher flu mortality were further below trend than other states, and their subsequent growth simply represents catching up.
Not all the effects were felt during or immediately after the pandemic. Pregnant women were more likely to become infected than nonpregnant women, and modern research has linked in utero flu exposure to a host of long-term physical effects, including a greater risk of heart attacks, schizophrenia, and other mental and physical ailments. There were also economic effects from fetal exposure: In a 2006 article in the Journal of Political Economy, Douglas Almond of Columbia University found that children who were in utero during the pandemic were less likely to graduate from high school and more likely to be poor, on welfare, or disabled as adults.
Destroyer and Teacher
In a December 1918 article, physician George Price reflected that the Spanish flu had arrived as both "destroyer and teacher." For example, the pandemic exposed major weaknesses in the United States' public health system. At the beginning of the outbreak, the lack of coordination and communication between federal and local health officials meant that the scale of the problem went unrecognized until it was too late. Once the U.S. surgeon general, Rupert Blue, did realize that something more serious than the typical seasonal flu was underway, he had to scramble to create an infrastructure that would enable local authorities to share information with the PHS. Blue believed the pandemic had demonstrated the "imperative need of a permanent organization, within the Public Health Service, available with each emergency." He developed a plan for such a system, but the proposal went nowhere. It wasn't until the 1940s, when the precursor to the Centers for Disease Control and Prevention was established, that anything like Blue's dream became reality.
On a local level, the Spanish flu did prompt some changes. Prior to the pandemic, most states had a state public health board. But efforts to expand to the county level had met with resistance, particularly in the South, where citizens were concerned about the intrusion of a centralized authority. As a result, when the flu struck, local efforts were conducted largely by volunteers who were not prepared for the pandemic. The flu changed people's attitudes and helped spur the development of county health boards, according to historian David Cockrell. After the past few years, one North Carolina doctor wrote in 1920, "the people would no better know how to get along without their health officer than they would know how to dispense with their Sheriff."
In a 1996 article in the North Carolina Historical Review, Cockrell also detailed how the pandemic led to the "hospital age" in North Carolina. The state was severely lacking in hospital capacity, and what hospitals there were didn't have modern equipment. After the pandemic, "the press of patients, the physical demands, almost beyond endurance, on physicians [and] nurses&hellip plus the strain on accommodation" motivated many towns to upgrade their medical facilities. James B. Duke, the tobacco magnate turned philanthropist, established a multimillion-dollar endowment to construct rural hospitals. By the end of the 1920s, the number of hospital beds in the state had doubled.
The pandemic also helped solidify in the public's mind the validity of "germ theory," which had been gaining currency since the turn of the century. Thirty years earlier, people had believed that the Russian flu was caused by a microorganism that floated through the air but died once it entered its host, rendering the illness itself noncontagious. As a result, people took few preventive measures. During the Spanish flu, in addition to trying to limit contact between people, health authorities also emphasized hygiene. They enforced bans on public spitting and ran extensive ad campaigns urging citizens to cover their coughs and sneezes with handkerchiefs. (The Detroit health commissioner suggested that people use a disposable paper napkin, presaging the invention of paper tissues in the 1920s.) The makers of toothpaste, cough drops, and other products used the focus on hygiene to great effect during the 1920s, warning potential buyers that "a cold may be something far more dangerous." The mouthwash Listerine advertised itself as protection against "street car colds," with pictures of men sneezing on public transportation.
Descendants of the Spanish flu still circulate today, as the H1N1 and H3N2 viruses in humans, in addition to several strains in pigs. They are much less virulent than the 1918 strain &mdash but the original, deadly virus does exist in closely guarded laboratories. Studying the reconstructed virus has helped scientists understand how flu viruses mutate and spread and has helped guide more recent public health efforts. During the swine flu pandemic in 2009, for example, researchers discovered the virus was closely related to the Spanish flu virus and that elderly persons who had been exposed in 1918 already had some immunity. That enabled them to target vaccines toward younger people, a group that is not typically the focus of flu vaccination efforts. In that case, there was more to be learned than destroyed.
Cockrell, David L. "'A Blessing in Disguise'": The Influenza Pandemic of 1918 and North Carolina's Medical and Public Health Communities." North Carolina Historical Review, July 1996, vol. 73, no. 3, pp. 309-327.(Article available with free JSTOR registration.)
Crosby, Alfred W. Epidemic and Peace, 1918. Westport, Conn.: Greenwood Press, 1976. (Reprinted by Cambridge University Press in 2003 as America's Forgotten Pandemic.)
Garrett, Thomas A. "Economic Effects of the 1918 Influenza Pandemic." Federal Reserve Bank of St. Louis, November 2007.
Taubenberger, Jeffery K., and David M. Morens. "1918 Influenza: the Mother of All Pandemics." Emerging Infectious Diseases, January 2006, vol. 12, no. 1, pp. 15-22.
Tomes, Nancy. "'Destroyer and Teacher': Managing the Masses during the 1918-1919 Influenza Pandemic." Public Health Reports, April 2010, vol. 125, supplement 3, pp. 48-62. (Article available with subscription.)
The Russian Flu of 1889: The Deadly Pandemic Few Americans Took Seriously - HISTORY
The "Spanish" influenza pandemic of 1918–1919, which caused ≈50 million deaths worldwide, remains an ominous warning to public health. Many questions about its origins, its unusual epidemiologic features, and the basis of its pathogenicity remain unanswered. The public health implications of the pandemic therefore remain in doubt even as we now grapple with the feared emergence of a pandemic caused by H5N1 or other virus. However, new information about the 1918 virus is emerging, for example, sequencing of the entire genome from archival autopsy tissues. But, the viral genome alone is unlikely to provide answers to some critical questions. Understanding the 1918 pandemic and its implications for future pandemics requires careful experimentation and in-depth historical analysis.
"Curiouser and curiouser!" cried Alice
Lewis Carroll, Alice's Adventures in Wonderland, 1865
An estimated one third of the world's population (or &asymp500 million persons) were infected and had clinically apparent illnesses (1,2) during the 1918&ndash1919 influenza pandemic. The disease was exceptionally severe. Case-fatality rates were >2.5%, compared to <0.1% in other influenza pandemics (3,4). Total deaths were estimated at &asymp50 million (5&ndash7) and were arguably as high as 100 million (7).
The impact of this pandemic was not limited to 1918&ndash1919. All influenza A pandemics since that time, and indeed almost all cases of influenza A worldwide (excepting human infections from avian viruses such as H5N1 and H7N7), have been caused by descendants of the 1918 virus, including "drifted" H1N1 viruses and reassorted H2N2 and H3N2 viruses. The latter are composed of key genes from the 1918 virus, updated by subsequently incorporated avian influenza genes that code for novel surface proteins, making the 1918 virus indeed the "mother" of all pandemics.
In 1918, the cause of human influenza and its links to avian and swine influenza were unknown. Despite clinical and epidemiologic similarities to influenza pandemics of 1889, 1847, and even earlier, many questioned whether such an explosively fatal disease could be influenza at all. That question did not begin to be resolved until the 1930s, when closely related influenza viruses (now known to be H1N1 viruses) were isolated, first from pigs and shortly thereafter from humans. Seroepidemiologic studies soon linked both of these viruses to the 1918 pandemic (8). Subsequent research indicates that descendants of the 1918 virus still persists enzootically in pigs. They probably also circulated continuously in humans, undergoing gradual antigenic drift and causing annual epidemics, until the 1950s. With the appearance of a new H2N2 pandemic strain in 1957 ("Asian flu"), the direct H1N1 viral descendants of the 1918 pandemic strain disappeared from human circulation entirely, although the related lineage persisted enzootically in pigs. But in 1977, human H1N1 viruses suddenly "reemerged" from a laboratory freezer (9). They continue to circulate endemically and epidemically.
Thus in 2006, 2 major descendant lineages of the 1918 H1N1 virus, as well as 2 additional reassortant lineages, persist naturally: a human epidemic/endemic H1N1 lineage, a porcine enzootic H1N1 lineage (so-called classic swine flu), and the reassorted human H3N2 virus lineage, which like the human H1N1 virus, has led to a porcine H3N2 lineage. None of these viral descendants, however, approaches the pathogenicity of the 1918 parent virus. Apparently, the porcine H1N1 and H3N2 lineages uncommonly infect humans, and the human H1N1 and H3N2 lineages have both been associated with substantially lower rates of illness and death than the virus of 1918. In fact, current H1N1 death rates are even lower than those for H3N2 lineage strains (prevalent from 1968 until the present). H1N1 viruses descended from the 1918 strain, as well as H3N2 viruses, have now been cocirculating worldwide for 29 years and show little evidence of imminent extinction.
Trying To Understand What Happened
By the early 1990s, 75 years of research had failed to answer a most basic question about the 1918 pandemic: why was it so fatal? No virus from 1918 had been isolated, but all of its apparent descendants caused substantially milder human disease. Moreover, examination of mortality data from the 1920s suggests that within a few years after 1918, influenza epidemics had settled into a pattern of annual epidemicity associated with strain drifting and substantially lowered death rates. Did some critical viral genetic event produce a 1918 virus of remarkable pathogenicity and then other critical genetic event occur soon after the 1918 pandemic to produce an attenuated H1N1 virus?
In 1995, a scientific team identified archival influenza autopsy materials collected in the autumn of 1918 and began the slow process of sequencing small viral RNA fragments to determine the genomic structure of the causative influenza virus (10). These efforts have now determined the complete genomic sequence of 1 virus and partial sequences from 4 others. The primary data from the above studies (11&ndash17) and a number of reviews covering different aspects of the 1918 pandemic have recently been published (18&ndash20) and confirm that the 1918 virus is the likely ancestor of all 4 of the human and swine H1N1 and H3N2 lineages, as well as the "extinct" H2N2 lineage. No known mutations correlated with high pathogenicity in other human or animal influenza viruses have been found in the 1918 genome, but ongoing studies to map virulence factors are yielding interesting results. The 1918 sequence data, however, leave unanswered questions about the origin of the virus (19) and about the epidemiology of the pandemic.
When and Where Did the 1918 Influenza Pandemic Arise?
Before and after 1918, most influenza pandemics developed in Asia and spread from there to the rest of the world. Confounding definite assignment of a geographic point of origin, the 1918 pandemic spread more or less simultaneously in 3 distinct waves during an &asymp12-month period in 1918&ndash1919, in Europe, Asia, and North America (the first wave was best described in the United States in March 1918). Historical and epidemiologic data are inadequate to identify the geographic origin of the virus (21), and recent phylogenetic analysis of the 1918 viral genome does not place the virus in any geographic context (19).
Figure 1. Three pandemic waves: weekly combined influenza and pneumonia mortality, United Kingdom, 1918–1919 (21).
Although in 1918 influenza was not a nationally reportable disease and diagnostic criteria for influenza and pneumonia were vague, death rates from influenza and pneumonia in the United States had risen sharply in 1915 and 1916 because of a major respiratory disease epidemic beginning in December 1915 (22). Death rates then dipped slightly in 1917. The first pandemic influenza wave appeared in the spring of 1918, followed in rapid succession by much more fatal second and third waves in the fall and winter of 1918&ndash1919, respectively (Figure 1). Is it possible that a poorly-adapted H1N1 virus was already beginning to spread in 1915, causing some serious illnesses but not yet sufficiently fit to initiate a pandemic? Data consistent with this possibility were reported at the time from European military camps (23), but a counter argument is that if a strain with a new hemagglutinin (HA) was causing enough illness to affect the US national death rates from pneumonia and influenza, it should have caused a pandemic sooner, and when it eventually did, in 1918, many people should have been immune or at least partially immunoprotected. "Herald" events in 1915, 1916, and possibly even in early 1918, if they occurred, would be difficult to identify.
The 1918 influenza pandemic had another unique feature, the simultaneous (or nearly simultaneous) infection of humans and swine. The virus of the 1918 pandemic likely expressed an antigenically novel subtype to which most humans and swine were immunologically naive in 1918 (12,20). Recently published sequence and phylogenetic analyses suggest that the genes encoding the HA and neuraminidase (NA) surface proteins of the 1918 virus were derived from an avianlike influenza virus shortly before the start of the pandemic and that the precursor virus had not circulated widely in humans or swine in the few decades before (12,15,24). More recent analyses of the other gene segments of the virus also support this conclusion. Regression analyses of human and swine influenza sequences obtained from 1930 to the present place the initial circulation of the 1918 precursor virus in humans at approximately 1915&ndash1918 (20). Thus, the precursor was probably not circulating widely in humans until shortly before 1918, nor did it appear to have jumped directly from any species of bird studied to date (19). In summary, its origin remains puzzling.
Were the 3 Waves in 1918&ndash1919 Caused by the Same Virus? If So, How and Why?
Historical records since the 16th century suggest that new influenza pandemics may appear at any time of year, not necessarily in the familiar annual winter patterns of interpandemic years, presumably because newly shifted influenza viruses behave differently when they find a universal or highly susceptible human population. Thereafter, confronted by the selection pressures of population immunity, these pandemic viruses begin to drift genetically and eventually settle into a pattern of annual epidemic recurrences caused by the drifted virus variants.
In the 1918&ndash1919 pandemic, a first or spring wave began in March 1918 and spread unevenly through the United States, Europe, and possibly Asia over the next 6 months (Figure 1). Illness rates were high, but death rates in most locales were not appreciably above normal. A second or fall wave spread globally from September to November 1918 and was highly fatal. In many nations, a third wave occurred in early 1919 (21). Clinical similarities led contemporary observers to conclude initially that they were observing the same disease in the successive waves. The milder forms of illness in all 3 waves were identical and typical of influenza seen in the 1889 pandemic and in prior interpandemic years. In retrospect, even the rapid progressions from uncomplicated influenza infections to fatal pneumonia, a hallmark of the 1918&ndash1919 fall and winter waves, had been noted in the relatively few severe spring wave cases. The differences between the waves thus seemed to be primarily in the much higher frequency of complicated, severe, and fatal cases in the last 2 waves.
But 3 extensive pandemic waves of influenza within 1 year, occurring in rapid succession, with only the briefest of quiescent intervals between them, was unprecedented. The occurrence, and to some extent the severity, of recurrent annual outbreaks, are driven by viral antigenic drift, with an antigenic variant virus emerging to become dominant approximately every 2 to 3 years. Without such drift, circulating human influenza viruses would presumably disappear once herd immunity had reached a critical threshold at which further virus spread was sufficiently limited. The timing and spacing of influenza epidemics in interpandemic years have been subjects of speculation for decades. Factors believed to be responsible include partial herd immunity limiting virus spread in all but the most favorable circumstances, which include lower environmental temperatures and human nasal temperatures (beneficial to thermolabile viruses such as influenza), optimal humidity, increased crowding indoors, and imperfect ventilation due to closed windows and suboptimal airflow.
However, such factors cannot explain the 3 pandemic waves of 1918&ndash1919, which occurred in the spring-summer, summer-fall, and winter (of the Northern Hemisphere), respectively. The first 2 waves occurred at a time of year normally unfavorable to influenza virus spread. The second wave caused simultaneous outbreaks in the Northern and Southern Hemispheres from September to November. Furthermore, the interwave periods were so brief as to be almost undetectable in some locales. Reconciling epidemiologically the steep drop in cases in the first and second waves with the sharp rises in cases of the second and third waves is difficult. Assuming even transient postinfection immunity, how could susceptible persons be too few to sustain transmission at 1 point and yet enough to start a new explosive pandemic wave a few weeks later? Could the virus have mutated profoundly and almost simultaneously around the world, in the short periods between the successive waves? Acquiring viral drift sufficient to produce new influenza strains capable of escaping population immunity is believed to take years of global circulation, not weeks of local circulation. And having occurred, such mutated viruses normally take months to spread around the world.
At the beginning of other "off season" influenza pandemics, successive distinct waves within a year have not been reported. The 1889 pandemic, for example, began in the late spring of 1889 and took several months to spread throughout the world, peaking in northern Europe and the United States late in 1889 or early in 1890. The second recurrence peaked in late spring 1891 (more than a year after the first pandemic appearance) and the third in early 1892 (21). As was true for the 1918 pandemic, the second 1891 recurrence produced of the most deaths. The 3 recurrences in 1889&ndash1892, however, were spread over >3 years, in contrast to 1918&ndash1919, when the sequential waves seen in individual countries were typically compressed into &asymp8&ndash9 months.
What gave the 1918 virus the unprecedented ability to generate rapidly successive pandemic waves is unclear. Because the only 1918 pandemic virus samples we have yet identified are from second-wave patients (16), nothing can yet be said about whether the first (spring) wave, or for that matter, the third wave, represented circulation of the same virus or variants of it. Data from 1918 suggest that persons infected in the second wave may have been protected from influenza in the third wave. But the few data bearing on protection during the second and third waves after infection in the first wave are inconclusive and do little to resolve the question of whether the first wave was caused by the same virus or whether major genetic evolutionary events were occurring even as the pandemic exploded and progressed. Only influenza RNA&ndashpositive human samples from before 1918, and from all 3 waves, can answer this question.
What Was the Animal Host Origin of the Pandemic Virus?
Viral sequence data now suggest that the entire 1918 virus was novel to humans in, or shortly before, 1918, and that it thus was not a reassortant virus produced from old existing strains that acquired 1 or more new genes, such as those causing the 1957 and 1968 pandemics. On the contrary, the 1918 virus appears to be an avianlike influenza virus derived in toto from an unknown source (17,19), as its 8 genome segments are substantially different from contemporary avian influenza genes. Influenza virus gene sequences from a number of fixed specimens of wild birds collected circa 1918 show little difference from avian viruses isolated today, indicating that avian viruses likely undergo little antigenic change in their natural hosts even over long periods (24,25).
For example, the 1918 nucleoprotein (NP) gene sequence is similar to that of viruses found in wild birds at the amino acid level but very divergent at the nucleotide level, which suggests considerable evolutionary distance between the sources of the 1918 NP and of currently sequenced NP genes in wild bird strains (13,19). One way of looking at the evolutionary distance of genes is to compare ratios of synonymous to nonsynonymous nucleotide substitutions. A synonymous substitution represents a silent change, a nucleotide change in a codon that does not result in an amino acid replacement. A nonsynonymous substitution is a nucleotide change in a codon that results in an amino acid replacement. Generally, a viral gene subjected to immunologic drift pressure or adapting to a new host exhibits a greater percentage of nonsynonymous mutations, while a virus under little selective pressure accumulates mainly synonymous changes. Since little or no selection pressure is exerted on synonymous changes, they are thought to reflect evolutionary distance.
Because the 1918 gene segments have more synonymous changes from known sequences of wild bird strains than expected, they are unlikely to have emerged directly from an avian influenza virus similar to those that have been sequenced so far. This is especially apparent when one examines the differences at 4-fold degenerate codons, the subset of synonymous changes in which, at the third codon position, any of the 4 possible nucleotides can be substituted without changing the resulting amino acid. At the same time, the 1918 sequences have too few amino acid differences from those of wild-bird strains to have spent many years adapting only in a human or swine intermediate host. One possible explanation is that these unusual gene segments were acquired from a reservoir of influenza virus that has not yet been identified or sampled. All of these findings beg the question: where did the 1918 virus come from?
In contrast to the genetic makeup of the 1918 pandemic virus, the novel gene segments of the reassorted 1957 and 1968 pandemic viruses all originated in Eurasian avian viruses (26) both human viruses arose by the same mechanism&mdashreassortment of a Eurasian wild waterfowl strain with the previously circulating human H1N1 strain. Proving the hypothesis that the virus responsible for the 1918 pandemic had a markedly different origin requires samples of human influenza strains circulating before 1918 and samples of influenza strains in the wild that more closely resemble the 1918 sequences.
What Was the Biological Basis for 1918 Pandemic Virus Pathogenicity?
Sequence analysis alone does not offer clues to the pathogenicity of the 1918 virus. A series of experiments are under way to model virulence in vitro and in animal models by using viral constructs containing 1918 genes produced by reverse genetics.
Influenza virus infection requires binding of the HA protein to sialic acid receptors on host cell surface. The HA receptor-binding site configuration is different for those influenza viruses adapted to infect birds and those adapted to infect humans. Influenza virus strains adapted to birds preferentially bind sialic acid receptors with &alpha (2&ndash3) linked sugars (27&ndash29). Human-adapted influenza viruses are thought to preferentially bind receptors with &alpha (2&ndash6) linkages. The switch from this avian receptor configuration requires of the virus only 1 amino acid change (30), and the HAs of all 5 sequenced 1918 viruses have this change, which suggests that it could be a critical step in human host adaptation. A second change that greatly augments virus binding to the human receptor may also occur, but only 3 of 5 1918 HA sequences have it (16).
This means that at least 2 H1N1 receptor-binding variants cocirculated in 1918: 1 with high-affinity binding to the human receptor and 1 with mixed-affinity binding to both avian and human receptors. No geographic or chronologic indication exists to suggest that one of these variants was the precursor of the other, nor are there consistent differences between the case histories or histopathologic features of the 5 patients infected with them. Whether the viruses were equally transmissible in 1918, whether they had identical patterns of replication in the respiratory tree, and whether one or both also circulated in the first and third pandemic waves, are unknown.
In a series of in vivo experiments, recombinant influenza viruses containing between 1 and 5 gene segments of the 1918 virus have been produced. Those constructs bearing the 1918 HA and NA are all highly pathogenic in mice (31). Furthermore, expression microarray analysis performed on whole lung tissue of mice infected with the 1918 HA/NA recombinant showed increased upregulation of genes involved in apoptosis, tissue injury, and oxidative damage (32). These findings are unexpected because the viruses with the 1918 genes had not been adapted to mice control experiments in which mice were infected with modern human viruses showed little disease and limited viral replication. The lungs of animals infected with the 1918 HA/NA construct showed bronchial and alveolar epithelial necrosis and a marked inflammatory infiltrate, which suggests that the 1918 HA (and possibly the NA) contain virulence factors for mice. The viral genotypic basis of this pathogenicity is not yet mapped. Whether pathogenicity in mice effectively models pathogenicity in humans is unclear. The potential role of the other 1918 proteins, singularly and in combination, is also unknown. Experiments to map further the genetic basis of virulence of the 1918 virus in various animal models are planned. These experiments may help define the viral component to the unusual pathogenicity of the 1918 virus but cannot address whether specific host factors in 1918 accounted for unique influenza mortality patterns.
Why Did the 1918 Virus Kill So Many Healthy Young Adults?
Figure 2. "U-" and "W-" shaped combined influenza and pneumonia mortality, by age at death, per 100,000 persons in each age group, United States, 1911–1918. Influenza- and pneumonia-specific death rates are plotted for.
The curve of influenza deaths by age at death has historically, for at least 150 years, been U-shaped (Figure 2), exhibiting mortality peaks in the very young and the very old, with a comparatively low frequency of deaths at all ages in between. In contrast, age-specific death rates in the 1918 pandemic exhibited a distinct pattern that has not been documented before or since: a "W-shaped" curve, similar to the familiar U-shaped curve but with the addition of a third (middle) distinct peak of deaths in young adults &asymp20&ndash40 years of age. Influenza and pneumonia death rates for those 15&ndash34 years of age in 1918&ndash1919, for example, were >20 times higher than in previous years (35). Overall, nearly half of the influenza-related deaths in the 1918 pandemic were in young adults 20&ndash40 years of age, a phenomenon unique to that pandemic year. The 1918 pandemic is also unique among influenza pandemics in that absolute risk of influenza death was higher in those <65 years of age than in those >65 persons <65 years of age accounted for >99% of all excess influenza-related deaths in 1918&ndash1919. In comparison, the <65-year age group accounted for 36% of all excess influenza-related deaths in the 1957 H2N2 pandemic and 48% in the 1968 H3N2 pandemic (33).
Figure 3. Influenza plus pneumonia (P&I) (combined) age-specific incidence rates per 1,000 persons per age group (panel A), death rates per 1,000 persons, ill and well combined (panel B), and case-fatality rates (panel.
A sharper perspective emerges when 1918 age-specific influenza morbidity rates (21) are used to adjust the W-shaped mortality curve (Figure 3, panels, A, B, and C [35,37]). Persons <35 years of age in 1918 had a disproportionately high influenza incidence (Figure 3, panel A). But even after adjusting age-specific deaths by age-specific clinical attack rates (Figure 3, panel B), a W-shaped curve with a case-fatality peak in young adults remains and is significantly different from U-shaped age-specific case-fatality curves typically seen in other influenza years, e.g., 1928&ndash1929 (Figure 3, panel C). Also, in 1918 those 5 to 14 years of age accounted for a disproportionate number of influenza cases, but had a much lower death rate from influenza and pneumonia than other age groups. To explain this pattern, we must look beyond properties of the virus to host and environmental factors, possibly including immunopathology (e.g., antibody-dependent infection enhancement associated with prior virus exposures ) and exposure to risk cofactors such as coinfecting agents, medications, and environmental agents.
One theory that may partially explain these findings is that the 1918 virus had an intrinsically high virulence, tempered only in those patients who had been born before 1889, e.g., because of exposure to a then-circulating virus capable of providing partial immunoprotection against the 1918 virus strain only in persons old enough (>35 years) to have been infected during that prior era (35). But this theory would present an additional paradox: an obscure precursor virus that left no detectable trace today would have had to have appeared and disappeared before 1889 and then reappeared more than 3 decades later.
Epidemiologic data on rates of clinical influenza by age, collected between 1900 and 1918, provide good evidence for the emergence of an antigenically novel influenza virus in 1918 (21). Jordan showed that from 1900 to 1917, the 5- to 15-year age group accounted for 11% of total influenza cases, while the >65-year age group accounted for 6% of influenza cases. But in 1918, cases in the 5- to 15-year-old group jumped to 25% of influenza cases (compatible with exposure to an antigenically novel virus strain), while the >65 age group only accounted for 0.6% of the influenza cases, findings consistent with previously acquired protective immunity caused by an identical or closely related viral protein to which older persons had once been exposed. Mortality data are in accord. In 1918, persons >75 years had lower influenza and pneumonia case-fatality rates than they had during the prepandemic period of 1911&ndash1917. At the other end of the age spectrum (Figure 2), a high proportion of deaths in infancy and early childhood in 1918 mimics the age pattern, if not the mortality rate, of other influenza pandemics.
Could a 1918-like Pandemic Appear Again? If So, What Could We Do About It?
In its disease course and pathologic features, the 1918 pandemic was different in degree, but not in kind, from previous and subsequent pandemics. Despite the extraordinary number of global deaths, most influenza cases in 1918 (>95% in most locales in industrialized nations) were mild and essentially indistinguishable from influenza cases today. Furthermore, laboratory experiments with recombinant influenza viruses containing genes from the 1918 virus suggest that the 1918 and 1918-like viruses would be as sensitive as other typical virus strains to the Food and Drug Administration&ndashapproved antiinfluenza drugs rimantadine and oseltamivir.
However, some characteristics of the 1918 pandemic appear unique: most notably, death rates were 5&ndash20 times higher than expected. Clinically and pathologically, these high death rates appear to be the result of several factors, including a higher proportion of severe and complicated infections of the respiratory tract, rather than involvement of organ systems outside the normal range of the influenza virus. Also, the deaths were concentrated in an unusually young age group. Finally, in 1918, 3 separate recurrences of influenza followed each other with unusual rapidity, resulting in 3 explosive pandemic waves within a year's time (Figure 1). Each of these unique characteristics may reflect genetic features of the 1918 virus, but understanding them will also require examination of host and environmental factors.
Until we can ascertain which of these factors gave rise to the mortality patterns observed and learn more about the formation of the pandemic, predictions are only educated guesses. We can only conclude that since it happened once, analogous conditions could lead to an equally devastating pandemic.
Like the 1918 virus, H5N1 is an avian virus (39), though a distantly related one. The evolutionary path that led to pandemic emergence in 1918 is entirely unknown, but it appears to be different in many respects from the current situation with H5N1. There are no historical data, either in 1918 or in any other pandemic, for establishing that a pandemic "precursor" virus caused a highly pathogenic outbreak in domestic poultry, and no highly pathogenic avian influenza (HPAI) virus, including H5N1 and a number of others, has ever been known to cause a major human epidemic, let alone a pandemic. While data bearing on influenza virus human cell adaptation (e.g., receptor binding) are beginning to be understood at the molecular level, the basis for viral adaptation to efficient human-to-human spread, the chief prerequisite for pandemic emergence, is unknown for any influenza virus. The 1918 virus acquired this trait, but we do not know how, and we currently have no way of knowing whether H5N1 viruses are now in a parallel process of acquiring human-to-human transmissibility. Despite an explosion of data on the 1918 virus during the past decade, we are not much closer to understanding pandemic emergence in 2006 than we were in understanding the risk of H1N1 "swine flu" emergence in 1976.
Even with modern antiviral and antibacterial drugs, vaccines, and prevention knowledge, the return of a pandemic virus equivalent in pathogenicity to the virus of 1918 would likely kill >100 million people worldwide. A pandemic virus with the (alleged) pathogenic potential of some recent H5N1 outbreaks could cause substantially more deaths.
Whether because of viral, host or environmental factors, the 1918 virus causing the first or &lsquospring' wave was not associated with the exceptional pathogenicity of the second (fall) and third (winter) waves. Identification of an influenza RNA-positive case from the first wave could point to a genetic basis for virulence by allowing differences in viral sequences to be highlighted. Identification of pre-1918 human influenza RNA samples would help us understand the timing of emergence of the 1918 virus. Surveillance and genomic sequencing of large numbers of animal influenza viruses will help us understand the genetic basis of host adaptation and the extent of the natural reservoir of influenza viruses. Understanding influenza pandemics in general requires understanding the 1918 pandemic in all its historical, epidemiologic, and biologic aspects.
Dr Taubenberger is chair of the Department of Molecular Pathology at the Armed Forces Institute of Pathology, Rockville, Maryland. His research interests include the molecular pathophysiology and evolution of influenza viruses.
Dr Morens is an epidemiologist with a long-standing interest in emerging infectious diseases, virology, tropical medicine, and medical history. Since 1999, he has worked at the National Institute of Allergy and Infectious Diseases.
These Are the Deadliest Years for the Flu in History
Think this year's flu is the worst one yet? Think again.
The recent flu outbreak has been undeniably devastating, but the good news is that flu season has peaked for this year. The bad news? A secondary strain of the virus has popped up and could start making the rounds. The 2017-2018 flu season has been one of the worst in recent history, with the CDC estimating that it will cause at least 56,000 deaths in the United States alone before it's over. While that number is nothing to sneeze at, it pales in comparison to the worst flu outbreaks in history, some of which killed millions of people.
The single worst flu pandemic in recent history, however, was the 2009 "swine flu" outbreak that spread across the world and caused widespread panic. You might remember China quarantined a group of students and three of their teachers in a hotel out of fear that one of them might have been exposed to the flu via a passenger on their plane. And their fears weren't unjustified. It is now estimated that the flu pandemic of 2009-2010 killed an estimated 284,500 people.
The next deadliest flu outbreak was the Hong Kong flu pandemic of 1968-1969, which started in Hong Kong and spread across Asia. Soldiers returning from Vietnam brought it back to the United States, and it soon spread to Japan, Africa, and South America. This widespread strain of the flu had a fairly low death rate, all things considered, but terrifyingly still killed an estimated one million people.
Deadlier yet, however, was the Asian flu pandemic, which started in China in 1956 and ended in 1958. During that time, it killed two million people, although some estimates claim the death toll was twice as high. The virus that caused this particular outbreak later combined with another strain of flu and mutated into the flu virus that caused the Hong Kong flu pandemic in 1968.
However, it's the Russian flu pandemic of 1889-1890 that earned the dubious honor of being the first flu pandemic in the modern world. It started in Saint Petersburg and took only four months to spread across the northern hemisphere, thanks to railroads and transatlantic travel. It killed around one million people.
But the single deadliest year for the flu in history was 1918. That's the year the Spanish flu swept the globe. During the pandemic, life expectancy in the United States dropped by 12 years because so many people were dying. The flu killed more people than World War I, which was being fought in Europe at the time. Half a billion people were infected with the virus, and it killed somewhere in the order of 50 to 100 million people, three to five percent of the world's total population at the time.
However, thanks to improved sanitation, vaccines, and increasing awareness of how illness is spread, it's unlikely we'll ever see a flu outbreak of this magnitude ever again. But just in case, arming yourself with the 20 Habits That Slash Your Flu Risk will help keep you and your loved ones safe.
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The Spread of the Pandemic in North America
In the United States, in December 1889 the developing pandemic had become apparent as it spread across Europe. Newspapers at the time reported it and it was apparent to many public health officials the pandemic would reach the United States. However, the United States was relatively relaxed when the pandemic struck, with major port cities including New York first hit despite having time to prepare. The flu quickly spread in port cities and spread to other cities via rail lines. The flu was notable in affecting different ages young and old. Symptoms included headaches sore throat, laryngitis and bronchitis, although some reported symptoms more comparable to a common cold. Initially, political leaders and public health officials played down the spreading infections in the United States, but soon the increasing number of cases made officials acknowledge there was a problem. Newspapers were particularly calm and the local media did not think much of the pandemic, with one newspaper stating: "It is not deadly, not even necessarily dangerous.” However, by January 1890, it was clear far more people were dying than normal. The flu particularly struck those with underlying health conditions, with people with heart disease or kidney troubles most seriously affected. Soon, many people throughout the United States began to wear scarves or handkerchiefs to cover their noses and mouths. The peak of the outbreak in the United States seems to have occurred in February 1890. By the time the pandemic began to diminish, over 13,000 in the United States died, with New York leading in deaths and having 2,503 deaths. This was considered a low number considering the total deaths worldwide were about a 1 million or more. To a large extent, the United States was lucky despite being unprepared. There were second and more waves in the winter of 1890 and later in the 1890s. However, these were relatively mild, as many people had developed natural immunity by then. 
2. No Prevention and No Treatment for the 1918 Pandemic Virus
In 1918, as scientists had not yet discovered flu viruses, there were no laboratory tests to detect, or characterize these viruses. There were no vaccines to help prevent flu infection, no antiviral drugs to treat flu illness, and no antibiotics to treat secondary bacterial infections that can be associated with flu infections. Available tools to control the spread of flu were largely limited to non-pharmaceutical interventions (NPI’s) such as isolation, quarantine, good personal hygiene, use of disinfectants, and limits on public gatherings, which were used in many cities. The science behind these was very young, and applied inconsistently. City residents were advised to avoid crowds, and instructed to pay particular attention to personal hygiene. In some cities, dance halls were closed. Some streetcar conductors were ordered to keep the windows of their cars open in all but rainy weather. Some municipalities moved court cases outside. Many physicians and nurses were instructed to wear gauze masks when with flu patients.