Wall Street Journal title: Rethinking the Origins of Inflammatory Diseases
WSJ subtitle: Research on how the immune system can go wrong is changing the way medicine thinks about everything from Covid-19 to heart disease
By: Shilpa Ravella
Date: 6 October 2022
“When the Covid pandemic took hold in late 2019, an urgent question soon emerged: Why did some individuals experience worse outcomes than others? A few patterns made intuitive sense. The elderly tended to fare worse. So did those with certain health conditions, including obesity, heart disease, hypertension, diabetes and lung or kidney disease. But severe infections were not exclusive to the elderly, those with pre-existing health conditions or healthcare and other essential workers. As scientists scrambled to better understand why this was so, inflammation and the immune system appeared to play a fundamental role.
With Covid-19 and many other infections, the germ itself or a measured immune reaction to it triggers most symptoms—like a fever, which alerts the body to the attack, or the coughs and loose stools that expel microscopic infectious particles. But if the immune system doesn’t succeed in managing the germ, it can later resort to a flood of inflammation, where immune cells churn out reams of cytokines—small proteins that act as messengers in an attempt to fight the germ.
Many people with Covid-19 in intensive care units succumb to a burst of inflammation rather than to the germ itself.
Many people in intensive care units succumb to this burst of inflammation rather than to the germ itself. An overzealous immune reaction might help to explain why some young and ostensibly healthy individuals suffer severe illness or death during pandemics like Covid-19.
The word inflammation comes from the Latin verb inflammare, “to ignite”—a kindling, a setting on fire, as the ancient Romans described it. It is an ancestral response that evolved to protect the body from threats and contain damage, be it from a microbe, chemical or trauma—the same defense employed by animals as primitive as starfish. Flaring up, tackling a problem and dying away, inflammation is a fundamental immune response that has served us well through most of human history.
But in modern times, the threats we face are more insidious than those our ancestors faced. Today we find that inflammation can persist, with or without a known trigger, destroying healthy tissue. Autoimmune diseases like arthritis or lupus, which turn inflammation against the body, can be devastating and sometimes fatal. Many patients come to my gastroenterology practice inflamed. Some suffer from inflammatory bowel disease, an autoimmune condition in which severe intestinal inflammation can result in surgery to remove most or all of the intestines. Others cope with inflammation from acid reflux, food sensitivities, celiac disease, irritable bowel syndrome and more.
he main force behind acute inflammation is our immune system. When the body detects damaged tissue, cells called phagocytes rush to the site, ingesting germs or damaged cells and other foreign materials. Other types of white blood cells may join the fray. This is usually accompanied by the four cardinal signs of inflammation first noted by the Greek physician Celsus in the 2nd century A.D.—redness, heat, swelling and pain. In injured tissues, blood vessels widen and blood flow surges, causing redness and heat. The walls of inflamed vessels become more porous, allowing inflammatory cells, protein and fluid to leak into tissues, creating swelling and putting painful pressure on nerve endings.
There is a yin and yang to inflammation that is analogous to using a fire hose. Too little water pressure in the hose and the fire—be it a germ or another intruder—wins. Too much and the body can turn on itself, drowning in autoimmunity. But sometimes the hose simply leaks, and a low-level inflammation simmers quietly in the body. We cannot see hidden inflammation with our naked eye—as we can the swollen joints of patients with rheumatoid arthritis and the rashes of those with lupus—or with the tools we typically use to diagnose inflammatory diseases. Otherwise healthy people walking around with this type of inflammation are entirely unaware that it exists within them. There may be no obvious signs or symptoms.
Hidden inflammation can be found adorning specific spots in organs or traveling through the body’s vessels—usually it does both. We are not accustomed to routinely diagnosing and treating most cases of hidden inflammation despite the damage it is known to cause, but it is far from benign. Hidden inflammation, silent and sinister, lurks in heart disease and smolders beneath developing tumors. It is tied to many other chronic conditions as well, including obesity, diabetes and neurodegenerative and psychiatric diseases.
The biomedical framework of the 19th century is no longer effective for most health conditions that plague us today.
Even worse, it increases the likelihood that our immune system will mount an overwhelming, inappropriate attack against infections, leading to grim outcomes. In fact, hidden inflammation may shed light on why ostensibly healthy individuals can succumb to severe illness during epidemics and pandemics.
The biomedical framework of the 19th century—divided by organ systems and an understanding that a specific cause results in a specific disease—is no longer effective for most health conditions that plague us today. Effectively combating hidden inflammation begins with delving deeply into its root causes. Human genetics, which have remained relatively constant, or longer lifespans cannot alone explain the steep rise in chronic inflammatory diseases over the last decades. Our destinies are largely shaped by lifestyle.
Ironically, the modern world’s discovery of the importance of hygiene may have contributed to the rise of inflammatory disease. Exposure to a wide variety of germs in the first few days and years of life is essential to cultivating a diverse, anti-inflammatory microbiome. Studies show that when children are exposed to greater numbers of microbes during infancy, their risk of hidden, chronic inflammation in adulthood may decrease. Without these timely exposures, they may go on to develop immune systems that overreact to benign germs, foods and other matter, such as pollen or household dust. They have a higher risk of becoming silently inflamed and succumbing to chronic inflammatory illnesses, including overt autoimmune diseases.
A child needs to interact not only with the right quantity of microbes but also with the right quality. In 2003, microbiologist Graham Rook of University College London considered a new hypothesis. He knew that common childhood infections—colds, flus, measles and others—manifested relatively recently in human evolution, after the Neolithic agricultural revolution around 10,000 B.C., when human populations grew larger and started to live close together. These “crowd infections” had not taken hold in hunter-gatherer communities, where they either killed an individual or induced quick immunity.
In contrast, ancient microbes that had formed mutually beneficial partnerships with humans, evolving alongside them in mud and water and rotting vegetation, are crucial for molding the immune system. These “old friends”—as Dr. Rook proposed—are indispensable to optimal immune function. They activate a variety of immune pathways that dampen inflammatory responses. They prevent the body from attacking its own tissues or harmless airborne particles like dust, dander and pollen. The most vital exposures for children are not infections—exceptions rather than the rule in microbial interactions with the immune system—but rather the missing conversations with old friends.
The burden of hidden inflammation and chronic inflammatory diseases forces us to reckon with all elements of our modern environment, to view health not simply as the presence or absence of one or multiple distinct diseases but as a state of being that allows for maximal fulfillment of human potential. As our environment continues to transform, the interdependence at the core of this equation is increasingly manifest: that the health of humans, microbes and the planet are inextricable.
—Dr. Ravella is a gastroenterologist and an assistant professor of medicine at Columbia University Medical Center. This essay is adapted from her new book, “A Silent Fire: The Story of Inflammation, Diet and Disease,” which will be published on Oct. 11 by W.W. Norton. “