Even now 100 years on, the 1918 influenza pandemic stands as one of the most devastating public health events in world history. This global disaster, which led to the deaths of an estimated 50 to 100 million people, is still offering lessons to public health experts, clinicians, and researchers, according to two eminent scientists who have studied the 1918 strain extensively.

In a series of articles reflecting on the 1918 influenza pandemic and its implications for the 21st century, David Morens, MD, and Jeffery Taubenberger, MD, PhD, underscore the need to develop better vaccines and to identify biomarkers that early on would signal a patient’s impending deterioration. As work on these aims progresses, clinical laboratories should be ready and available to provide rapid test results in emergency, inpatient, and outpatient settings, advised Morens, senior advisor to the director of the National Institute of Allergy and Infectious Diseases (NIAID), and an officer in the United States Public Health Service. 

Timing is everything in the treatment of flu-related complications, according to Morens. “The decisions doctors face in admitting patients and treating them with antibiotics have to be made quickly. You need to know what’s happening before it happens,” stressed Morens. Individuals with flu usually present similarly and as the infection progresses it’s nearly impossible to predict which patients will recover and which will face serious complications, including death. Epithelial tissue killed by the virus allows bacteria to invade the cells below the epithelium and cause damage—which may not be visible until late-stage illness. “It’s a tidal wave—and you can’t stop it,” he said.

The pathology that indicates whether an influenza patient will develop serious pneumonia is not always visible on an X-ray or computed tomography scan, nor is it easily detectable by clinical signs. A lung puncture or bronchoalveolar lavage wouldn’t necessarily find anything, either. According to Morens, the right types of biomarkers would translate into more efficient tests that clinical laboratories could use to assist physicians in making earlier diagnoses of secondary bacterial bronchopneumonias, which are the real culprits behind severe flu and subsequent deaths related to flu.

Morens and Taubenberger’s call for better flu-related biomarkers came as part of two retrospectives they wrote on the 1918 pandemic that also considered what a pandemic today with 1918 severity would look like. Almost all flu-related mortalities during the 1918 pandemic were traced to complications from bronchopneumonias such as Streptococcus pneumoniae, Streptococcus pyogenes, and Staphylococcus aureus.

“In 1918, progression to bronchopneumonia usually began several days after the onset of otherwise unremarkable symptomatic influenza; onset of lower respiratory involvement was typically subtle, with chest X-rays often being normal and chest auscultation unremarkable right up to the beginning of a rapid downhill course, leaving a very narrow window for beginning lifesaving treatment,” Morens and Taubenberger wrote in The New England Journal of Medicine (NEJM).

This scenario could manifest today, crippling a healthcare system unprepared to deal with a huge volume of patients experiencing such a rapid onset of illness. Not enough antibiotics, antiviral drugs, ventilators or other medical supplies would be available to address a pandemic of 1918 proportions. “As many as 2 or more million Americans could die in the span of a few weeks without early diagnosis of impending bronchopneumonia, immediate hospitalization, and critical care, including intravenous antibiotics and mechanical ventilation,” cautioned Morens and Taubenberger,  chief of the viral pathogenesis and evolution section at NIAID.

The avian virus that caused the 1918 outbreak is similar to currently existing wild waterfowl influenza A viruses. “These will presumably continue to exist far into the future, capable of re-emerging when human population immunity to H1N1 influenza A virus wanes. Moreover, 4 of the 15 other extant waterfowl HAs (H6, H7, H10, and H15) are, like the 1918 H1, highly pathogenic in mammals and could potentially cause similar extreme pandemic fatality,” wrote Morens and Taubenberger.

Avoiding such a pandemic calls for the development of universal influenza vaccines to ward off all incarnations of influenza A virus. However, this is easier said than done. “Since the genetic and antigenic makeup of future influenza viruses cannot be predicted from the nearly infinite number of possibilities, developing a truly protective universal vaccine will be a significant challenge that has not yet been met,” explained Morens and Taubenberger.

In an interview with CLN Stat, Morens acknowledged that it’s unclear which biomarkers would fit the bill to set off early warnings on cases likely to deteriorate rapidly.  Some biomarkers might be useful in indicating severe bacterial pneumonia in the downhill course of acute respiratory distress syndrome, but “they’re not all that sensitive or that specific,” he said.

Looking forward, researchers might turn their eyes on analyzing the predictive power of combinations of biomarkers  such as white blood count, C-reactive protein, X-ray, and procalcitonin, or developing tests that look at host gene response patterns for pneumonia, Morens suggested. “People also should be thinking about imaging techniques that could help us diagnose bronchopneumonia that’s progressing.”

It’s too soon to tell what the 2018-2019 flu season will bring in the United States, but illnesses have been ramping up, according to the Centers for Disease Control and Prevention. The agency reported that between October 1, 2018 and January 5, 2019 an estimated 6.2 and 7.3 million people in the U.S. had symptomatic flu and that 27 states had either high or moderate influenza activity.

Several efforts are underway to improve flu monitoring through advanced technologies. This flu season, CDC will be getting a little help from an influenza-tracking model developed by biostatistician Nicholas Reich, PhD, an associate professor at the University of Massachusetts, Amherst (UMass) and his colleagues. Five teams under this collaborative model incorporate data from internet sources such as Twitter, Google, and Wikipedia to create influenza forecasts using different methodological approaches. “All six teams submit their models to an online repository each week. Once all the models are submitted, my team at UMass runs a short software program that combines all of the forecasts. We then submit this single forecast to the CDC,” Reich told CLN Stat.

And, at Houston Methodist, a healthcare system in Greater Houston, Texas, pathologists developed a continually updated real-time flu tracker website that assisted doctors in treating patients in a timely manner in past flu seasons. The website actively reports on a number of different pathogens, including influenza A, influenza B, respiratory syncytial virus (RSV), and rhinovirus/enterovirus.