Physicians are detecting allergies in an increasing number of children. Some of that comes from quicker, somewhat better diagnosis and increased awareness, and some from an increase in allergy prevalence. But whatever the cause, many studies indicate that getting one allergy increases the odds of suffering from others, especially if the first one appears at an early age.
“It’s like turning on a switch when you get an allergy, and there will be more,” says Jonathan Malka—a childhood asthma specialist and chief of pediatric allergy/immunology at Pediatric Associates of Fort Lauderdale, FL. But it’s complicated: no one knows for sure how the switch gets turned on and how that leads to more allergies.
The progression of skin allergies to asthma and allergic rhinitis is called the allergic or atopic march. Atopic dermatitis is an itchy, inflammatory skin allergy that, before 1960, affected fewer than 3% of children; by the 2000s it had increased to around 20%. A child with atopic dermatitis is more likely to develop other allergic conditions or symptoms. For example, about 70% of people with severe atopic dermatitis have asthma, whereas in those without atopic dermatitis, only about 8% have asthma—a nearly 9-fold difference.
“From the 1950s till now, there’s been a clear, dramatic increase in the prevalence of allergies,” says Benjamin Gold, a pediatric gastroenterologist at GI Care for Kids in Atlanta, who studies the impact of gut microorganisms on inflammation and immune-related diseases. “The increase includes the frequency of childhood allergies, the variety of ways that allergies present and the frequency of children who have allergies that persist through their lives.” Now, research is revealing potential mechanisms for this increase, from genes to the earliest exposures to allergens.
Modifying the march
If it is an allergic march, what gets it started? Maybe it’s inherited. Many studies indicate that a faulty skin barrier lets in allergens that set off the atopic march. There’s a gene, FLG, that makes a protein that helps build the skin’s barrier function. If there are problems with this gene, children can get a severe case of atopic dermatitis, but not always.
Given that only about half of children with atopic dermatitis move into a complete allergic march, there is clearly more involved. For one thing, there are other genes and parts of the immune system related to the march. Molecular changes to these genes—such as adding methyl groups, known as epigenetics—can also affect the odds of being sensitive to various allergens. “There’s been too much rise in prevalence to be all due to genes,” says Jenifer Lightdale, chief of the pediatric gastroenterology and nutrition division at the University of Massachusetts Medical School in Worcester, MA. “It’s something in the environment, and probably more than one thing.”
The original description of the atopic march included only atopic dermatitis, asthma and allergic rhinitis. One of the most common allergies in infants, though, arises from what they eat. “Food allergy is one of the first types of sensitivities that the immune system can have in a young infant,” says Lightdale. “Sometimes, that starts as early as two to three weeks after birth.” Now, food allergy is also considered part of the march.
As an example, Neil Shah, global vice president of medical affairs at Mead Johnson Nutrition, notes, “Milk allergy is a disease, and it sometimes never goes away completely.” Cow’s milk allergy could be one of the first sensitivities, because it arises from one of the first foods that susceptible newborn intestines encounter.
Atopic dermatitis and food allergies with gastrointestinal (GI) symptoms have at least one other thing in common—skin and related tissues. Skin runs inside through the mouth, esophagus and then transitions to the special GI lining all the way through the gastrointestinal tract and back to the surface—interacting with the environment the whole way along. Similar skin-like surfaces can also be found through the nose and into the lungs—locations to set off allergic rhinitis and asthma.
And it is not just the structural similarity that is important, what lives on those surfaces also matters. Each human has their own microflora—bacteria and other microorganisms that live on and in them. “An infant’s microflora can predict the development of allergies later in life,” says Gold. “Any disruption of the normal microbiome—a condition called dysbiosis in the mouth, on the skin, in the gut, anywhere—can trigger inflammatory diseases, especially allergies.”
Someone with atopic dermatitis has different kinds and more importantly proportions of bacteria, both on the skin and in the gut, than someone without it. But it’s not just one kind of bacteria increasing or decreasing the risk, it’s the combination of microorganisms that matters.
From the start, more research on the atopic march revealed connections with a longer list of conditions. The march started with atopic dermatitis, asthma and allergic rhinitis, and then scientists added food allergies. But the march hasn’t stopped there, and it might trigger more than allergies, including attention-deficit/hyperactivity disorder (ADHD). Studies in various countries, starting in Germany, showed an association between atopic dermatitis and ADHD. Jonathan Silverberg and Amy Paller—experts in adult and pediatric atopic dermatitis, respectively, at the Northwestern University Feinberg School of Medicine—added further evidence, showing that children in the United States with atopic dermatitis are also more likely to have attention-deficit/hyperactivity disorder (ADHD).
Despite the seeming disparity of these disorders, Paller speculates on a possible molecular connection. Sleep deprivation in infants and young children with atopic dermatitis might influence neurodevelopment, or ADHD might arise from “a direct CNS effect of circulating type 2 cytokines on neurodevelopment,” Paller says. For example, interleukin 2, a type 2 cytokine, appears to play a role in atopic dermatitis. So, if atopic dermatitis is connected to circulating type 2 cytokines that affect brain development, then, says Paller, “it suggests that ADHD may be a downstream component of that atopic march”.
There could yet be more health problems related to the atopic march waiting to be discovered, because it arises from a fundamental imbalance. “It’s the immune system not regulating itself properly,” Shah says. So, the march doesn’t stop at the skin, and the limits remain unknown.
Nonetheless, by working out the diverse links and combining clues from various angles of research, scientists are starting to crack the steps in the atopic march. The results could really open up what is known about immune reactions, and how to control them. “Maybe in 5 or 10 years,” says Gold, “we’ll be able to use this information to minimize the risk of allergies and even other inflammatory or autoimmune diseases, and that’s where this science is heading.”
Jonathan Malka, Benjamin Gold and Jenifer Lightdale have received financial support from Reckitt Benckiser, although their comments in this piece were made independently. Mead Johnson is a Reckitt Benckiser company.
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