I Want To...
I Want To...
Find Research Faculty
Enter the last name, specialty or keyword for your search below.
School of Medicine
I Want to...
Infection after infection. Bedridden days. Pain-wracked nights. Adult primary immunodeficiencies bring suffering to more adults than you’d think—and too often go undiagnosed. Enter Antoine Azar.
Photos by Justin Tsucalas; Illustration by Stuart Briers
Funding a Path to a Cure
Tara Sakraida Parker has been so inspired by her experience with Antoine Azar that she is now putting her philanthropy background to work on behalf of the Adult Primary Immunodeficiency Center. She recently brought a group of potential donors and adult PI patients together for an event at The George Town Club in Washington, D.C., where Azar introduced his work and laid out the case that philanthropic support will be critical to realizing his plans to grow the center’s clinical and research capabilities.
One such gift arrived recently. Through the Johns Hopkins Center for Innovative Medicine (CIM), Sakraida Parker and her husband have funded a multiyear gift to make Azar the Tara Sakraida Parker and Richard Parker CIM Scholar. David Hellmann, who serves as director of the CIM, likens Azar’s funding to a prestigious MacArthur Fellowship, or “genius grant.” He thinks Azar is on his way to building the “largest, most highly respected center of its kind, anywhere.
“This is a center that will be blazing trails in scientific learning and collaboration in the years ahead,” Hellmann says. “With Dr. Azar at the helm, it’s going to be leading the way as we learn how to treat and, hopefully, cure these patients.”
Watch a video featuring Tara Sakraida Parker and Antoine Azar.
The crisis that landed Tara Sakraida Parker in the hospital four years ago was a lifetime in the making. As a child growing up in Oregon, Sakraida Parker had endured chronic infections one after another—sinusitis, tonsillitis, strep throat and others.
Each time, recovery was agonizingly slow. Relapses were the rule. When she was 11, an inner ear infection that would have been merely a fleeting annoyance for most other kids left her without hearing in one ear.
She soldiered through the hearing loss and countless stretches of bedridden down time. She made it through college and law school, then into the practice of real estate transactional law while living in Denver. She moved to Los Angeles to take a position in philanthropy as director of gift planning at UCLA. Through it all, the infections kept on coming. “My whole life, it’s pretty much been antibiotics all the time,” she says with a sigh.
“My whole life, it”s pretty much been antibiotics all the time.”
—Patient Tara Sakraida Parker
Early in 2015, a particularly vicious virus invaded her central nervous system and left her writhing in the worst pain she’d ever been through. The hospital stay stretched on for a week.
“I’d been through a lot by this point, but it was different now—life-changing stuff, in a devastating way,” she says. “It was a dark time.” She’d grown tired of seeing doctor after doctor and never getting a firm diagnosis. Would the infections ever stop invading? Would the sicknesses they caused ever stop going from bad to worse?
That crisis marked the start of a new chapter in Sakraida Parker’s journey—one that would ultimately bring her to Johns Hopkins allergist and immunologist Antoine Azar.
What she would learn from him is that she and many of the physicians she’d visited over the years had never really asked the right questions. In reacting to each new infection that arose, they were doing battle with proverbial trees while missing the forest. Those outside invaders were as much symptoms as diseases.
The real problem had been lurking inside of Sakraida Parker’s body the whole time.
Delays in Diagnosis
Whenever Azar gets the opportunity to talk about his work, he starts with the “fun fact” that we humans are really only 10 percent human. Nine of every 10 cells in our bodies are microbial.
“It sounds strange, doesn’t it?” he asks. “But most of us live very well in this 10 percent situation. The reality is, we need these microbes, and they need us.”
The job of maintaining a state of peaceful, productive coexistence among these cells falls to our immune system. The job sounds straightforward enough: Leave the “good” cells alone to do their thing, and go after the “bad” and disruptive ones. In reality, of course, this is an incredibly complex operation, akin to conducting an orchestra comprising billions of instruments.
“It’s is a very, very, very tight situation inside the immune system,” Azar says. “The smallest little bit of imbalance can cause all kinds of serious problems.”
Azar’s focus on this system dates to his days at the University of Iowa’s Carver College of Medicine, where he completed his residency in 2004. While doing rotations, the native of Beirut found himself fascinated by the work of immunologist Zuhair Ballas and by the intricate puzzles that arise when the immune system is out of kilter.
“By the second day of Dr. Azar’s internship, I knew I wanted to mentor him,” says Ballas. “He had all the things that make the difference between a good physician and a great one.”
Azar spent eight years on the faculty at Iowa. By the time he joined the Division of Allergy and Clinical Immunology at Johns Hopkins in 2015, he had focused his professional attention on a range of diseases called primary immunodeficiency disorders (PIs, or sometimes PIDDs). He is now the director of a new Adult Primary Immunodeficiency Center housed on the Johns Hopkins Bayview Medical Center campus.
Several promising research projects are in the works at the Adult Primary Immunodeficiency Center.
Preliminary results are already in for a study on a subset of patients with chronic obstructive pulmonary disease (COPD), the nation’s number three cause of death.
Many COPD patients stay relatively stable for long stretches after diagnosis, relying only on their inhalers to provide an occasional boost. But some patients suffer through dangerous “exacerbations,” episodes that leave them so short of breath they end up in the hospital. These exacerbations tend to hit the same patients over and over again. They lose ground with each new episode and often go downhill quickly.
“If you look at the 12-month prognosis for COPD patients, an exacerbation is actually worse than having a heart attack,” Antoine Azar says.
The cause of these episodes has not yet been clearly identified, but Azar and his colleagues at the University of Iowa speculated that some exacerbation episodes might be happening in patients with undiagnosed adult PIs. They went looking for such cases—and found them.
“Then we treated them for their immune system problems,” Azar says. “So many of them did so much better after that. Some patients who had been hospitalized almost every month, they stayed out of the hospital after getting these treatments for a year or more.”
Azar and his collaborators are looking to build on those results, published in PLOS ONE, going forward.
These immunodeficiencies arise in two main ways. External forces are the culprits in secondary immunodeficiencies. The AIDS virus is one infamous example here. Various cancers can throw the immune system out of whack in some patients. So, too, can the radiation and chemotherapy regimens used to treat those cancers.
Primary immunodeficiencies, on the other hand, are inborn affairs rooted in genetic abnormalities. More than 300 variations of primary immunodeficiency have been identified to date, and that number gets bigger as scientists learn more about genes and the role they play in the immune system.
The adjective adult is key in Azar’s work. The field of pediatric PI is a robust, well-established affair focused on immune system flaws that manifest in infancy. Screening at birth for the deadliest of those risks is now routine for newborns around the country.
By comparison, the field of adult PI is a mere fledgling. Azar’s clinic is the first such facility in Maryland and one of just a handful nationwide. The work he and his team perform there is built on a wealth of quite recent discoveries about the prevalence, course and impact of later-in-life immunodeficiencies.
“Too many physicians have outdated misconceptions about this,” Azar says. “They’re out there thinking, ‘Well, if it was an immunodeficiency, it would have shown up early in childhood.’”
One problem with this assumption is patients like Sakraida Parker, whose issues arise in childhood but aren’t diagnosed in a timely way. A second problem is that many primary immunodeficiencies don’t manifest at all until later in life. Some of the genetic flaws involved operate like time bombs, set to go off at certain points in life. Others come into play only if they receive a nudge from an environmental cofactor that may or may not appear.
The bottom line: More than half of primary immunodeficiencies are diagnosed after age 18. Fully 40 percent aren’t identified until after age 30. Azar recently made such a diagnosis in an 86-year-old patient.
That delay in diagnosis can have a grave impact on quality of life, he says, noting that half of newly identified adult PI cases involve patients who have endured two or more hospitalizations prior to their diagnosis. In 15 percent of cases, there have been six or more hospitalizations.
“We need to keep diagnosing more patients, but we also we need to move up the diagnostic clock,” Azar says. “Right now, by the time people get to us, we’re saying, ‘Oh, wow, you’ve been through so much already.’”
“We need to keep diagnosing more patients, but we also need to move up the diagnostic clock. Right now, by the time people get to us, we’re saying, ‘Oh, wow, you’ve been through so much already.’”
—Immunologist Antoine Azar
The Worst Flu Ever
The run of medical misadventures that Ed Rodatus has endured for two decades now began on a night in 2000 when he was driving home from a camping trip with his wife and kids, when a stabbing pain in his neck landed him in the emergency room.
He was 46 years old, with no serious health problems in his history. In the months that followed, that neck pain creeped downward and spread into his back. Six months went by before he was diagnosed with a rare, bone-only variety of non-Hodgkin lymphoma, which required an aggressive chemotherapy regimen. It worked, but Rodatus has been in a wheelchair ever since, suffering from nerve damage associated with peripheral neuropathy as well as fatigue and dizziness most likely caused by dysautonomia, a nervous system malfunction. It’s possible that both conditions were brought on by that chemotherapy.
Those physical challenges—he couldn’t type on a keyboard anymore, for example—left Rodatus unable to continue his career as a software engineer. From his wheelchair, he remained as active as possible in raising the kids and tackling household chores. But the medical challenges kept coming. He was diagnosed with bladder cancer in 2003. Fortunately, an experimental treatment put this new cancer into remission, too.
In more recent years, Rodatus has suffered from the same sort of frequent, recurring and stubborn infections that afflict Sakraida Parker. “Imagine the worst flu you’ve ever been through,” he says. “These were worse than that. I’d be sick for weeks at a time, sometimes months.”
“Imagine the worst flu you’ve ever been through. These were worse than that. I’d be sick for weeks at a time, sometimes months.”
—Patient Ed Rodatus
Worried that he had another cancer, Rodatus made the rounds of doctors near his home in rural Frederick County, Maryland. One made a seemingly offhand mention of the fact that he had low levels of several immunoglobulins, proteins that are key players in the immune system.
By this point, Rodatus had become quite the amateur detective when it came to his health issues. He gathered up his voluminous test results from years of dealing with his cancers, dysautonomia, peripheral neuropathy and frequent infections. The database he built showed that his levels of IgG, IgA and IgM immunoglobulins had been low for quite some time.
“Nobody noticed this, or nobody thought it might be important,” he says. He took those numbers to a local immunologist, who suggested he make an appointment at the new Adult Primary Immunodeficiency Center at Johns Hopkins.
In the Right Place, at Last
Still in its infancy, with a full-time clinical staff that includes one nurse and a nurse practitioner, Azar’s center is already drawing patients from all over the country and even overseas. At times, the waitlist for initial consultations has stretched to seven months.
That was the case for Sakraida Parker. Soon after her 2015 crisis, she saw a specialist in Los Angeles, who reported that her levels of the immunoglobulin IgG were running low. “It was the first time I’d heard anything about that,” she says.
Sakraida Parker moved to Washington, D.C., in late 2015. Her search for a new array of specialists brought her to Johns Hopkins, where infectious disease specialist Christopher Lippincott told her about a “rock star” colleague who specialized in adult immunodeficiencies.
She had to wait until October to see Azar. When that appointment arrived at long last, Sakraida Parker’s sense of relief was immediate. “When you’re someone who gets sick chronically, the medical history becomes, honestly, a routine and exhausting thing,” she says. “But this man spent three hours with me that first day. He kept asking questions I’d never been asked before.”
Nurse Dawn Borst has grown accustomed to meeting patients like Sakraida Parker during her two years at the center. These patients have been through the wringer with scads of specialists. They’re exhausted, frustrated and, quite likely, not feeling well.
“I feel excited for them,” says Borst. “I can’t wait to get started because I know that they’re finally in the right place and they’re finally going to get the right information and the right treatments.”
David Hellmann, vice dean of Johns Hopkins Bayview and director of its Department of Medicine, heard good things in advance of Azar’s arrival in Baltimore, but it wasn’t until the two shared patients that he got a sense for the skills Azar was bringing to the Division of Allergy and Clinical Immunology.
Hellmann specializes in vasculitis, an autoimmune disorder that can strike in adult PI cases. (Other common ones include rheumatoid arthritis, lupus and pernicious anemia.)
“Dr. Azar is one of the most gifted diagnosticians I’ve ever seen,” Hellmann says. “You can find a lot of doctors here who are exceptional with patients. You can find a lot of doctors who are exceptional at science. He excels at both, and that combination is actually quite rare.”
That’s exactly the combination Rodatus needed after he built that database to sort through his immunoglobulin levels. By that point, he’d lost a lot of faith in the medical profession.
“I needed somebody who is a thinker, but also someone who could really engage with me and listen to what I was saying,” he says. “So much of what other doctors had been telling me for so long, it all sounded like scripts they were reading. Dr. Azar is a gem.”
The puzzles that Azar seeks to solve for patients like Rodatus and Sakraida Parker are intricate, with clues hiding in nearly every corner of the body. “I know it’s a truism that the most important part of diagnosing a patient is taking a good history,” he says, “but it’s really true in these immunodeficiencies.”
Delay in diagnosis can have a grave impact on quality of life.
Newly identified adult PI cases that involve patients who have endured two or more hospitalizations prior to their diagnosis.
Cases in which there have been six or more hospitalizations prior to their diagnosis.
Sakraida Parker’s lengthy first appointment with Azar unfolded in fits and starts. He peppered her with questions for 30 or so minutes, then left to see other patients until he could find a way to squeeze out a few more minutes for her. At times, the questions reached a level of detail Sakraida Parker found astonishing.
“He asked question about infections I’d had in the 1990s,” she recalls. “He wanted to know things like how many milligrams of some medication they gave me. Was it 40? Was it 100?” Afterward, Azar ordered an array of what sounded to Sakraida Parker like “really unusual” lab tests.
What Azar is looking for in these histories are little abnormalities that often serve as markers of adult PI. The frequency, severity and duration of infections can be important, as can any out-of-the-ordinary twists and turns those infections take. The details of the cancers and autoimmune diseases that patients suffer sometimes present key clues. Inflammation issues are on the watch list as well.
The list just keeps going. Has the patient had two or more pneumonias? Lost teeth at a premature age? Do they have stubborn skin warts? Shingles? Have they had a myringotomy tube put in for an ear infection, especially at an age where that treatment is uncommon?
“It’s all these unusual little details that are key,” Azar says. “They’re what help solve the mysteries these patients are presenting.”
In Sakraida Parker’s case, that youthful ear infection was one key clue. Azar describes her loss of hearing as “quite an unusual outcome in a patient that age.” The uncommon severity of the virus that attacked her nervous system in 2015 was another clue. “Most people in their 30s would get rid of that infection right away,” he says.
The upshot of Azar’s detective work? Sakraida Parker suffers from natural killer (NK) cell deficiency, a shortage of the NK cells that act as a sort of rapid-response vanguard in the defensive armies of the immune system. Especially important in fighting off viruses, they also play roles in the overall coordination of the immune system. (The HIV virus can cause similar NK malfunctioning, but Sakraida Parker’s condition arose differently, through a genetic abnormality at birth.)
Rodatus’ history served up its share of clues, too—bouts of pneumonia, frequent and prolonged respiratory infections, gangrene in two fingers, and shingles at a younger-than-usual age. Azar diagnosed him with common variable immune deficiency (CVID). With a prevalence of one in 25,000, CVID is the most common of the adult PIs that cause serious health problems.
Like many other PIs, CVID creates immune system weaknesses that give infections free reign to rampage through the lungs, sinuses and ears, among other organs. Over time, these infections can take a cumulative toll on those organs, especially the lungs. Azar has seen patients in their 30s who have already lost 70 percent of lung functioning.
In Rodatus’ case, it’s still a bit of a mystery when and how his disease arose. The chemotherapy he endured may have played a role, but that treatment was quite a few years before the onset of many of his key PI symptoms. Azar suspects that in this case, CVID came along on its own, sometime in the years after that chemotherapy.
Interestingly, both patients point to diagnosis alone as turning points. While enduring their decadeslong runs of physical woes, they both also battled emotional and psychological issues that arose from uncertainty over what caused their problems—and worries about what the future might hold.
“It brought such a sense of relief to me, just being able to put a name on what I’d been going through,” Sakraida Parker says.
Trial, Error and Creativity
Treatment has been a boon for both patients as well. Rodatus received immunoglobulin therapy, which involves regular injections of the key proteins to boost the immune system. This has helped to reduce the frequency and severity of his infections.
“I’m not getting sick like I used to,” Rodatus says. “I’ll have something that lasts a couple of days now and then, but not too long ago, I would have been down for a week and a half every time. It’s much less stressful now that I’m not so sick all the time. When you’re battling on several different fronts at the same time, that makes for a tough war.”
In Sakraida Parker’s case, Azar prescribed prophylactic antimicrobials to try and imbue her body with a greater capacity to fight off new infections. The treatment made a big difference right off the bat. She describes 2018 as “the best year of my life, healthwise.”
These two therapies both rank as common choices in adult PI, but a number of other techniques can be employed as well. Granulocyte colony stimulating factor, for instance, triggers the bone marrow to produce more of the white blood cells patients need to boost their immune systems. Stem cell transplants are an option in other cases. Someday soon, gene therapy techniques may become an option for some.
More Common than You’d Think
In 2004, only a few hundred new cases of adult primary immunodeficiency disease were being diagnosed nationwide. By 2015, that number was approaching 80,000 annually. This is less a reflection of rising incidence than the result of steady progress in identifying cases that previously went undiagnosed, notes Antoine Azar. He expects to see those numbers continue to climb as more clinicians get up to speed on the latest developments.
But no technique is a magic bullet here. This past winter, Sakraida Parker had a setback, getting knocked for a loop by powerful new infections in her sinus and ear. Things grew even worse when Johns Hopkins otolaryngologist Daniel Sun told her that she might well have autoimmune inner ear disease, a rare and difficult-to-diagnose condition in which a patient’s immune system goes into mistaken attack mode in the inner ear.
The hearing in Sakraida Parker’s one good ear may well be at risk going forward. As dispiriting as these developments have been, she is quick to point out that they are powerful illustrations of why Azar’s center is such an important resource for patients like her. Adult PI cases often present mind-boggling conundrums. In her case, a weak immune system needs bolstering on the one hand, but now that system also needs to be reigned in on the other hand.
“It’s going to be a balancing act to stop the attack without killing my weak immune system,” she says.
With no cure in place yet, the search for treatments in cases like Sakraida Parker’s often reaches points that involve trial, error and creativity. The first treatment Azar was trying with Sakraida Parker as of spring 2019 is unconventional: high-dose intravenous immunoglobulin, which contains a mix of IgG immunoglobulins built out of plasma from tens of thousands of donors.
Says Sakraida Parker, “Antoine has a way of pulling patients back from that dark place. It’s like he always has something else, a plan B and a plan C and then a plan D after that. To have that kind of support behind me now, it just changes my life, even when things take a turn for the worse.”