Called "La grippe," "three-day fever" and the "Spanish flu," the influenza pandemic of 1918-1919 ravaged communities worldwide, claiming the lives of an estimated 25 million to 50 million people. In the United States, more than 25 percent of the population was affected by the extremely virulent influenza A H1N1 virus, forcing schools, theaters and public places to close. Americans were ordered to wear masks to try to slow the spread of the disease, which often progressed rapidly -- sometimes in as little as two days -- to a lethal form of pneumonia. Nearly 100 years later, the threat of another influenza pandemic looms large as the scientific and global health communities find ways to prepare for, and battle, future outbreaks.

A monster virus emerges every several decades

"Not only is another influenza pandemic possible, but it's certain to eventually happen. Influenza mutates annually -- we call that 'antigenic drift.' That low, constant rate of mutation, however, isn't really the problem when it comes to pandemics. The real problem that leads to a pandemic is a major 'antigenic shift,' which takes place when several different viruses infect the same cell and recombine, creating a Frankenstein-like virus that's very different from viruses that have recently circulated. These major antigenic shifts occur every several decades. When these shifts happen, people have no memory immunity to the new virus, meaning that their immune systems aren't able to react swiftly to fight it.

"With the 1918-1919 flu season, older patients had some memory immunity to the virus because a similar strain had circulated years before. Younger patients, who didn't have that memory immunity, fared much worse. About half of the people who died from the Spanish flu were between the ages of 20 and 40.

"Vaccination, which helps boost memory immunity, and good hygiene practices are the best tools we have to prevent and combat the threat. People think the flu is like a cold. It's not. The flu is much worse than a cold and it can be deadly."

Brad Spellberg, MD, is an expert in infectious disease and a 2017-18 American Association for the Advancement of Science (AAAS) Public Engagement Fellow. He is the chief medical officer at Los Angeles County + USC Medical Center and professor of clinical medicine at the Keck School of Medicine of USC.

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Seasonal flu vaccines may have power to protect during a pandemic

"The seasonal flu vaccine is designed to protect you against strains of viruses that are predicted to be the most common of the season. The vaccine can be very effective against some virus strains and less effective against others. Studies have shown that flu vaccines work better at protecting against influenza B or influenza A H1N1 viruses than influenza A H3N2. The 1918 flu pandemic was caused by H1N1.

"A variable that's hard to predict is how our immune systems are going to react to influenza. Sometimes in the effort to fight off an infection, our immune systems get too revved up and can inadvertently cause harm to our own organs. This may have contributed to the 1918 flu pandemic's high mortality rate. Vaccination may mitigate your immune system's reaction in this situation.

"If the flu vaccine works well against a virus causing a pandemic, it could reduce your chance of getting a severe episode of the flu or getting the flu at all. As was seen in the 1918 pandemic, young, healthy people can die from the flu. Getting the seasonal flu vaccine may be the difference between feeling a little under the weather and having to be hospitalized in the intensive care unit."

Santhi Iyer Kumar, MD, is an expert in critical care. She is director of the medical intensive care unit at Keck Hospital of USC, chief quality and patient safety officer at Keck Medical Center of USC and assistant professor of clinical medicine at the Keck School of Medicine of USC.

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Weather, geography and age are factors in influenza patterns

"Interestingly, temperature and humidity determine when influenza peaks -- in temperate climates, flu peaks one month after the lowest humidity, while in tropical areas it peaks in the rainy season. In temperate areas like North America, flu activity is higher during the winter months, and in tropical countries, there is low-level flu activity year-round.

"Different influenza strains are predominant in different parts of the world and the strains themselves behave differently. For example, influenza A H3N2, which was the culprit in the Hong Kong flu pandemic of 1968, spreads more quickly than influenza A H1N1 or influenza B because it mutates more quickly than the others.

"The people who are most vulnerable to complications of influenza can also vary. In recent years, influenza deaths have tended to be more common in children younger than 5 and in adults older than 50. Epidemiologists describe this type of age distribution as 'U-shaped.' The Spanish flu, however, had an unusual 'W-shaped' distribution, with the peak being people between the ages of 20 and 35.

"The CDC recommends taking three actions to fight the flu: get vaccinated, follow preventive measures every day and take antiviral drugs if your doctor prescribes them."

Neha Nanda, MD, is a hospital epidemiologist and medical director of infection prevention and antimicrobial stewardship at Keck Medicine of USC. She is also clinical associate professor of medicine at the Keck School of Medicine of USC.

Meeting the challenge of delivering much-needed medicine

"When a pandemic strikes, having the right medicines and treatments at the right location and in the right quantity is vital. Almost 100 years after the Spanish flu pandemic, these continue to be immense challenges.

"There are major constraints in the medication supply chain that are primarily driven by the need for strict temperature control for vaccines from the beginning to the end of the supply chain. In countries or regions where infrastructure such as electricity, cold chain and other essential requirements are not in place, it's very hard to maintain the integrity of the medical supply chain. Along with this, there is also the risk of counterfeit drugs being introduced into the supply chain.

"The breadth and scope of the challenge depends greatly on the types of medications needed and the regions impacted. Delivering medicine in the field has different challenges than supplying existing medical facilities -- new distribution systems are probably needed and proper controls have to be in place. The commercial supply chain, which has accomplished incredible innovation and has developed highly efficient systems, could be integrated into medical delivery during a pandemic to provide urgently needed medications."