Despite early comparisons between COVID-19 and influenza, coronavirus was never going to be just another flu. It comes from a different family of viruses and it has proven far more pernicious and unpredictable. Even so, “cytokine storms,” where the immune system turns on the body by overreacting to a virus, were widely regarded as playing a critical role in 1918 influenza pandemic.
Not all historians and health professionals agree that cytokine storms led to as many deaths a century ago with the 1918 flu, and now a new study questions just how critical a factor they have been in COVID-related fatalities. So how large a part have these potentially fatal hyperinflammatory immune responses played in the coronavirus pandemic?
“ Fewer than 5% of the COVID-19 patients in a new study, including some of the sickest individuals, had the life-threatening, hyperinflammatory immune response known as a ‘cytokine storm.’ ”
Some 500 million people, or one-third of the world’s population, became infected with the 1918 Spanish flu. An estimated 50 million people died worldwide, with about 675,000 deaths occurring in the U.S., according to the Centers for Disease Control and Prevention. As of Saturday, 53.7 million people worldwide contracted COVID-19, with 1.3 million deaths, 245,453 of which were in the U.S.
These scientists aimed to find out. Most adults with moderate-to-severe COVID-19 have a suppressed viral immune response when compared to those suffering from influenza, according to research published Saturday by scientists at St. Jude Children’s Research Hospital in Memphis, Tenn., and Washington University School of Medicine in St. Louis, Mo.
“Fewer than 5% of the COVID-19 patients in this study, including some of the sickest individuals, had the life-threatening, hyperinflammatory immune response known as cytokine storm syndrome. Cytokines are small proteins secreted by blood cells that help coordinate the immune response and trigger inflammation,” it found.
“We did identify a subset of COVID-19 patients with the broadly upregulated array of cytokines, which is a hallmark of cytokine storm,” said co-author Paul Thomas, Ph.D., a member of the St. Jude Department of Immunology. “But, overall, the average person with COVID-19 — even patients with moderate-to-severe disease — had less inflammation than the average person with flu.
He said patients would benefit from a rapid, reliable and inexpensive test to measure cytokines and identify those most likely to benefit from immunosuppressive treatment. “The findings suggest that treatment suppressing inflammation might only be effective in that minority of patients with the hyperinflammatory profile,” Thomas added.
Medical staff treat a patient with coronavirus in the COVID-19 intensive care unit at the United Memorial Medical Center on Nov. 10, 2020 in Houston, Texas. COVID-19 infections are on the rise in Houston, Texas has surpassed 1 million cases.
Go Nakamura/Getty Images
A hallmark of some viruses: A surge of immune cells and their activating compounds (known as “cytokines”) effectively turned the body against itself, led to an inflammation of the lungs, severe respiratory distress, leaving the body vulnerable to secondary bacterial pneumonia. It was seen as one reason why seemingly healthy people were so hard hit by the 1918 flu.
The research included 168 adults with COVID-19, 26 adults with influenza and 16 healthy volunteers. More than 90% of the COVID-19 patients were hospitalized, about half in the intensive care unit; 23% of those hospitalized died. More than half of flu patients were hospitalized, 35% in the ICU, and 8% of flu patients hospitalized died.
The study found that the antiviral-immune response was “profoundly suppressed” in COVID-19 patients versus flu patients. In most cases, COVID-19 was not caused by broad hyperinflammation from a cytokine storm, it said. (However, the researchers noted that lack of hyperinflammation in most of these coronavirus patients did not mean they had less disease.)
Doctors and members of the public, as of now, were spooked by how otherwise strong, healthy people who fell victim to the 1918 influenza, also known erroneously as the “Spanish flu.” Many historians today attribute that to the “cytokine storm,” the process where the immune system in healthy people reacts so strongly as to hurt the body.
“ In most cases, COVID-19 was not caused by hyperinflammation from a cytokine storm, a new study in Science Advances concluded. That was believed to be a feature of the 1918 influenza pandemic. ”
“There are two hypotheses to explain the 1918 strain’s high lethality: Cytokine storms and secondary bacterial infection,” according to a 2018 editorial in Nature. “In a cytokine storm, the body’s immune system overreacts, causing tissue and organ damage, and even death.” However, the editorial says it’s more likely that secondary bacterial infections played a bigger role.
The Nature editorial cites this “intriguing” 2008 paper published in The Journal of Infectious Diseases examined and reviewed over 8,400 tissue specimens from 1918–1919 influenza fatalities found that “the majority of deaths in the 1918–1919 influenza pandemic likely resulted directly from secondary bacterial pneumonia caused by common upper respiratory-tract bacteria.”
This may tally with the progress of that pandemic with the second wave hitting even harder. “The 1918 Spanish flu’s second wave was even more devastating than the first wave,” Ravina Kullar, an infectious-disease expert with the Infectious Diseases Society of America and adjunct faculty member at the University of California, Los Angeles, told MarketWatch.
Though the 1918 pandemic is forever associated with Spain, this strain of H1N1 influenza was actually discovered earlier in Germany, France, the U.K. and the U.S. But similar to the Communist Party’s response to the first cases of COVID-19 in Wuhan, China, last Decembert, World War I censorship buried or underplayed those earlier reports.
“It is essential to consider the deep connections between the Great War and the influenza pandemic not simply as concurrent or consecutive crises, but more deeply intertwined,” historian James Harris wrote about 1918. Members of the public were spooked by how otherwise strong, healthy people fell victim to the 1918 influenza. A “cytokine storm” seemed a likely explanation.
“There are two hypotheses to explain the 1918 strain’s high lethality: Cytokine storms and secondary bacterial infection,” according to a 2018 editorial in Nature.
The most recent study released Saturday, published in Science Advances, a peer-reviewed open-access journal published by the American Association for the Advancement of Science, suggests that a majority of COVID-19 patients are not candidates for treatment with steroids such as dexamethasone that, the researchers argue, can backfire in some patients.
Dexamethasone has, however, been found to be effective in treating severely-ill COVID-19 patients, according to three studies published in September in JAMA. Researchers reported in mid-June that low doses of dexamethasone played a significant role in helping to reduce deaths in hospitalized COVID-19 patients on ventilators by one-third.
“ The majority of COVID-19 patients are not candidates for treatment with steroids such as dexamethasone, the researchers argue, but it’s been effective in treating severely-ill patients. ”
And Anthony Fauci, director of the National Institute for Allergy and Infectious Diseases, also credited dexamethasone with helping patients. “We know that dexamethasone clearly diminishes the death rate in people requiring mechanical ventilation and/or people who require high-flow oxygen,” Fauci said during an interview with the American Medical Association last weekend.
Other research finds that cytokine storms do remain a risk with older patients during the coronavirus pandemic. Genes in the body that appear to be a major factor giving SARS-CoV-2 access to the heart cells that become more active with age, according to a recent study in the Journal of Molecular and Cellular Cardiology, and that can leave them more vulnerable to hyperinflammation.
The researchers found that “inflammation in older people can be more intense, causing organ damage,” Johns Hopkins University reported. “Lung tissue becomes less elastic over time, making respiratory diseases like COVID-19 a particular concern for older people.” Thus, a cytokine storm in those patients may promote the inflammation and acute respiratory distress syndrome.
Furthermore, a September 2020 paper published in the peer-reviewed Frontiers in Immunology journal concluded: “Aberrant immune host response together with cytokine storm and lymphocytopenia [a disorder where your blood does not have enough white blood cells] followed by acute respiratory distress, are still relevant problems that affect the severity of COVID-19.”
One similarities abide between 1918 and 2020: During the 1918 flu, cities that implemented non-pharmaceutical interventions such as social distancing and school closures tended to have better economic outcomes, Francis Yared, the global head of rates research at Deutsche Bank wrote in a recent note, adding, “There wasn’t such a big trade-off between economic activity and public health.”
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