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Influenza - 100 Years

Amy Sherman, MD

Vincent Valentine, MD
University of Alabama Birmingham
Birmingham, AL, USA

Stephanie Pouch, MD

Emory University School of Medicine
Atlanta, GA, USA

1918: Shifts and Drifts in Disease and History
An incomprehensible but important fact about the Spanish flu is it killed over 3% of the world population in less than two years. Nothing; no infection, no war, no famine nor any calamity has killed so many by something so small in so little time. The mortality surpassed the deaths seen in World War I, with an estimated 50-100 million people worldwide and 675,000 in the United States who succumbed to the illness [1]. Deaths were largely due to respiratory complications, such as secondary bacterial pneumonias; however, unlike prior influenza pandemics, the 1918 pandemic presented with more aggressive and fatal complications such as severe bronchopneumonia and progressive cyanosis [2]. Another surprising aspect of this pandemic was the excess mortality in otherwise healthy, young patients between 20-40 years old with a lower than expected mortality among the elderly. It also likely changed the course of history.

Nobody knows precisely where the 1918 influenza pandemic began, but evidence points to Haskell County, Kansas. Local physician, Dr. Loring Miner was seeing many patients stricken by an unusually virulent form of the flu between January and mid-March 1918. It faded away as quickly and as mysteriously as it had appeared. Dr. Miner was so concerned with its intensity that he reported it to the US Public Health Service, who neglected his published cautionary note. There it might have ended, except for one unalterable fact: we were in the midst of "the war to end all wars."

Some 300 miles from Haskell County was Camp Funston, part of the huge Fort Riley military complex. In early March, soldiers began to report to the infirmary with flu-like symptoms. Within days, several thousand were afflicted and 38 deaths - not enough to quarantine a camp in wartime. Nonetheless, troop movement soon distributed the flu to other army camps. Soldiers from Fort Riley were loaded onto troopships by the thousands. Those lucky enough to disembark soon began to disseminate the illness to healthy troops, prisoners of war and civilians who spread the disease throughout Europe which marked the beginning of the 1918 influenza pandemic.

Apparently, the Spanish flu returned to the United States on August 12, 1918 from passengers on the Norwegian ship, the Bergensfjord. The liner entered New York harbor with 200 people sick and four buried at sea. All sick and exposed were so frightened they hurriedly disembarked and scattered into the abyss of the New York population. From sailors and soldiers in coastal cities, influenza spread inland by rivers and rail. As many as 500,000 US citizens became infected, and at least 12,000 died. Across America, the fate of the survivors was problematic. Many families were impoverished, with one or more bread winners sick or dead. Influenza also left behind a world filled with widows and orphans, including 21,000 orphans in New York City alone.

As WWI was coming to an end, not unlike the flu, rumors of the armistice were spreading, but President Woodrow Wilson was determined to fight to the death and concede nothing to the aggressors. He met with Lloyd George and Clemenceau in Paris in early 1919 to work out the terms of surrender as the third wave of the virus was hitting Paris and killing thousands. On Thursday, April 3, 1919, Wilson was struck by a coughing spell so severe he had difficulty breathing. The attack was so sudden that Dr. Cary Grayson, Wilson's White House physician, at first thought that Wilson had been poisoned. He was very ill, with severe diarrhea and a fever over 103 degrees. Although the peacemakers, George and Clemenceau met in Wilson's room to continue the talks, Wilson's health deteriorated. Wilson had changed after his illness, becoming stubborn and unwilling to listen to advice; he became paranoid, insisting that his home was filled with French spies as he grew obsessed with trivial details, like who was using what official vehicle. He had a complete change of face, conceding to Clemenceau on virtually every point he had previously fought so hard to make. Later authorities speculated that Wilson had suffered a mild stroke, which is an idea that persists to this day; however, neurological complications were described during the 1918 pandemic, leading some to wonder whether Wilson's mentation was altered by the influenza virus itself. We may never know whether Wilson's concessions resulted from his struggle with influenza, but his changes in attitude and behavior helped to create the conditions that ultimately led to the next World War.

At the time, the cause of the 1918 pandemic remained elusive. We later learned, however, that the etiology of the 1918 pandemic was an influenza A virus of the H1N1 subtype. Taubenberger et al have demonstrated links to an avian ancestral source by using techniques of sequence analysis [3]. However, unlike prior pandemics whose strains developed by a re-assortment between circulating human virus and avian influenza strains, the 1918 strain is thought to have arisen by genetic adaptation of an avian virus to a new human host [4,5]. Several authors have proposed that the influenza strain itself was not hypervirulent, but the effects it caused, such as virus-induced aberrant immune responses, were responsible for the high mortality. Based on historical records, patients who were exposed to the 1918 influenza strain likely had dysregulated and pathologic cellular immune responses to infections with the influenza A H1N1 strain [6,7]. It is hypothesized that these effects transiently increased susceptibility to secondary bacterial infections; thus potentially explaining the high mortality rate in otherwise young and healthy individuals. The most common bacteria recovered from the sputum, lungs, and blood of patients (alive and dead) included Hemophilus influenza, Streptococcus pneumoniae, S. pyogenes, and Staphylococcus aureus [8]. Taubenberger and Fauci examined 58 slides of lung tissue obtained during autopsy from 58 influenza fatalities in 1918-1919 from various United States military bases. They confirmed that almost all of the histologic evidence showed proof of severe acute bacterial infection; indeed, bacteria were often found in massive amounts in the sections studied. The samples also showed evidence of injury from the influenza virus itself, with features including necrosis and desquamation of the respiratory epithelium admixed with dilation of alveolar ducts [9]. Another pathological finding that Taubenberger found in the autopsies was similar to an ARDS-pattern, although it is thought that this represented a rarer cause of fatality related to influenza infection [10].

Treatment options were limited during the 1918 pandemic, as were public health initiatives. Medical treatment consisted mostly of comforting; however, other therapies included bleeding, saline or glucose injections, enemas, alcohol, camphor oil, heroin, morphine, mustard plasters, castor oil, sulfur smoke, lard mixed with camphor and chloroform as well as lard mixed with turpentine. Such interventions will cure you or kill you. Public health responses included fumigating campaigns against spitting and sneezing, warnings about public gatherings and a general prescription of rest, fresh air and reporting cases to the authorities. However, these efforts and basic knowledge about transmission of the virus were likely also hindered during this pandemic, as World War I entangled physicians and medical personnel overseas. In the United States, analyses of mortality data from large cities have shown that public health interventions such as isolation, quarantine, and banning public gatherings were associated with decreased influenza-related mortality rates [11]. However, these interventions likely reduced spread of secondary infections and pneumonia but did not primarily decrease rates of influenza transmission. During this time, folk cures abounded and included stuffing salt up children's noses, magic charms, wearing goose grease poultices, hanging little bags of garlic and onions round your neck and gargling with disinfectants. Charlatans, mountebanks and snake oil salesmen were everywhere.

Unfortunately, this was an era before the development and widespread use of antibiotics, which could have prevented deaths due to secondary bacterial infections. Vaccinations for pneumococcus and Hemophilus influenza B also did not yet exist. Interestingly, two vaccines were developed in Minnesota during the 1918 pandemic, one by a bacteriologist at the University of Minnesota that was made to prevent pneumonia, and a second created at the Mayo Clinic that was proposed to prevent pneumonia and influenza [12,13]. Unfortunately, neither of these vaccines contained influenza virus or proteins and were not shown to be effective for protection.

2018: The More Things Change, The More They Stay the Same
As compared to the 1918 pandemic, we are much better equipped now to respond to an emerging influenza threat. Public health and knowledge about transmission have improved. Through the Centers for Disease Control and Prevention and the World Health Organization, both national and international influenza surveillance programs are in place. Prevention has also been a main target, with encouraged annual vaccination for influenza. Drug development has also been important. Two classes of antiviral drugs, adamantanes and neuroaminidase inhibitors, are available and have proven effective against most circulating H5N1 viruses. Furthermore, we now have effective antibiotics to treat secondary bacterial complications of influenza that were not available in 1918. Intensive care units that host mechanical ventilation and circulatory support systems are also widespread in the 21st century. Without such modern marvels of medicine in 2018 nearly a quarter of a billion of the world's population might succumb to a similar deadly influenza strain from 100 years ago, and possibly more given the swifter means of dispersion through our modern networks of highways and air travel. Not to mention our means of less self-reliant behaviors, over reliance on more perishable items and fast food restaurants along with our overcrowded behaviors.

Despite these advances, many challenges remain. Seasonal influenza outbreaks continue to cause substantial disease burden, with an estimated 3-5 million cases of severe illness, and 250,000 to 500,000 deaths worldwide each year [14]. While we do have antiviral medications, there is growing concern for adamantane resistance [15]. The seasonal vaccinations that we use are problematic, since they must be developed and manufactured months before the influenza season is upon us, and there is some degree of guesswork and estimation in predicting which strains will be prevalent for the upcoming season. There is an urgent need to develop a more effective vaccine that does not rely on annual updates, provides broad protection and is durable; i.e., a universal influenza vaccine.

Humans have been on the losing and winning sides of the battle with the microbes. We conquered the germ of laziness (Necator americanus, the American hookworm), but we were slaughtered by the 1918 flu. There may be a very good reason why we've managed to survive the evolutionary arms race so far: our highly evolved immune system provides us an arsenal to dispose of our unseen or microscopic rivals - unless, of course, our immune system is suppressed. Does a suppressed immune system dampen the cytokine storm, leading to decreased mortality, but prolonged viral shedding and increased transmissibility? On the 100-year anniversary of the 1918 influenza pandemic, we have much to learn, and an improved understanding of the effect of influenza on transplant patients may be the key. ■

Disclosure Statement: The authors have no conflicts of interest.


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