By Manish J. Butte, MD, PhD
SOMETIMES IN MEDICINE WE ARE PRESENTED WITH A CASE THAT CONFOUNDS OUR YEARS OF TRAINING, EXPERIENCE AND EXPECTATIONS. Not long ago, I was confronted with such a case. It began last year when a family traveled 150 miles to UCLA from their home in Santa Maria, along California’s Central Coast, with their 4-year-old son Abraham, who was infected by Coccidioides immitis, the fungus commonly found in soil that causes Valley fever. Of the 8,000 Californians who contract Valley fever each year, most recover without treatment; those with more serious cases will require an antifungal medication that clears the infection. But a few patients will experience a life-threatening form of the disease that ravages the body for reasons unknown.
Abraham’s case was the latter.
The child’s infection was invasive, having spread throughout his soft tissue, skull, bones, arms, legs and spine. He could not walk and required around-the-clock pain medication. He was too sick to eat and had to be fed through a tube. To help Abraham’s immune system clear the infection, our team administered a powerful combination of antifungal medications.
This therapy should have been enough, but the infection was persistent and continued to spread. It became clear that standard medications were insufficient. To try to determine what was going on with the boy, our research lab began looking for clues about why Abraham’s body had such difficulty fighting the infection. Using genome sequencing and RNA sequencing, our team performed experimental tests on Abraham’s T cells and analyzed the genetic pathways that were turned on in his immune cells.
The results revealed that Abraham’s immune response was not producing enough interferon gamma, an essential infection-fighting molecule. An inadequate supply of interferon gamma made Abraham highly susceptible to a host of bacterial and fungal infections and hindered his ability to fight them.
We treated Abraham with multiple injections of interferon gamma to supplement the deficiency and boost his immune system. The spread of the infection slowed, but even these treatments were not enough.
His immune system just wasn’t responding adequately. To save his life, we needed to find out why. A suggestion came from a colleague in pediatric allergy and immunology, Maria Garcia-Lloret, MD (RES ‘00, FEL ‘98, ‘03), to consider an alternative approach. Perhaps, rather than trying to simply supplement the work of Abraham’s immune system, it needed to be rebooted altogether.
The immune system responds to different organisms it perceives as harmful by activating one of several different types of immunities, similar to how a computer runs a program to complete a certain function. Type 1 immunity, for instance, is the program the immune system runs to fight most bacteria, viruses, fungi and other such harmful microorganisms that cause infections. Type 1 immunity uses interferon gamma to coordinate its attack. Type 2 immunity is the program the immune system runs to fight certain parasites, such as worm or tick infections, or in response to allergens. When the immune system responds to a threat by running a particular program, all the immune cells tune in to that same program. In order to adequately fight an infection, the immune system must run the correct program.
While type 1 immunity was the program that needed to run to attack Abraham’s Valley fever infection, our lab experiments consistently showed that his immune system was somehow tuned to type 2 immunity. Here, Dr. Garcia-Lloret’s contribution proved to be invaluable. She proposed that the drug dupilumab — which was approved by the U.S. Food and Drug Administration to treat eczema and asthma — might help reprogram Abraham’s immune system and run type 1 immunity instead. Dupilumab has been shown to effectively block the type 2 immune response that causes the skin to react with an eczema flare-up.
In addition to her medical expertise, Dr. Garcia-Lloret became a bridge for us with the family. The parents spoke no English and very little Spanish; their primary language was a regional dialect from Mexico. But Dr. Garcia-Lloret, who originally is from Argentina — coincidentally, the country in which the first case of coccidioidomycosis was described, in the 1890s — was able to develop a communication channel with the family, so they would be informed about what we were thinking and doing.
Further lab experiments using Abraham’s cells demonstrated that dupilumab showed promise in pushing his cells toward the infection-busting type 1 pathway, so Dr. Garcia-Lloret and I administered treatments of the drug — in addition to injections of interferon gamma — for Abraham.
Within a few weeks, Abraham showed signs of starting to clear the infection. While at one point his survival seemed unlikely, he was finally able to leave the hospital for the first time in 11 months — walking, playing and restored to health.
While steroids have been a go-to, non-specific tool for blocking immune responses, this new generation of medicines like dupilumab offer a way to block type 2 immunity specifically, which offers hope for some difficult-to-treat allergies and asthma. This case was the first time anyone has tampered with type 2 immunity for the purposes of fighting an infection.
Maybe this approach has the potential for broader applications against such diseases as tuberculosis and severe viral infections. As physicians, we always are thinking about how to reduce suffering, and my colleagues and I are happy to have found a potential new treatment for these serious infections. In return, these cases of rare immune diseases offer us new knowledge about how the immune system works and why it chooses to run various programs to fight different infections. With this new knowledge, I hope that our studies will help to identify which patients are at increased risk of life-threatening infections, so we can offer them hope before they get severely ill.