Immune Dysregulation Program: for Patients Who ‘Don’t Read the Textbook’

Edward M. Behrens, MD

We all learned some simple patterns for diseases of the immune system when we were in training: immunodeficiency is “too little immune system,” autoimmunity is “too much immune system,” atopy is a “allergic immune system,” and lymphoproliferation is “a rapidly expanding immune system.” Medicine is complex and these simple buckets help us put complex disease into contexts we can understand and remember.

On the other hand, we all have taken care of patients who “don’t read the textbook.” Sometimes we rewrite the textbook a bit, like the newly created category of “autoinflammatory” disease, where patients have an overactive immune system, but don’t lose tolerance to self and so don’t make autoantibodies. But many patients don’t even fit cleanly into a single category. Sometimes patients present with a history of susceptibility to infections and organ-specific autoimmunity, sometimes we see combinations of 3 or 4 of these different categories.

Medical specialization has also historically organized around these buckets: Immunology sees immunodeficiency, Allergy sees atopy, Rheumatology sees autoimmunity, lymphoproliferation goes to Oncology. For patients who don’t fit neatly, this is a far-from-perfect system. It means seeing multiple doctors, often hard-to-coordinate appointments, delays in diagnosis, and imperfect therapies. Advances in molecular diagnostics have allowed us to realize that these diverse symptoms can often be unified under a single genetic diagnosis, and even when a gene isn’t known, it has become clear that we need a different type of categorization for complex immune-driven syndromes.

First in Nation to Break Down Silos

It is in this context that the field of “immune dysregulation” was born. The concept of immune dysregulation disorders includes both genetic and nongenetic syndromes of disordered immunity that typically crosses the traditional silos of immune diseases.

Children’s Hospital of Philadelphia, through its Frontiers Program, was first hospital to launch a truly collaborative, multidisciplinary clinical team to address the need in immune dysregulation care. The Immune Dysregulation Frontiers Program, founded in 2018, consists of rheumatologists, immunologists, oncologists, hematologists, infectious disease physicians, and a host of other disciplines. We offer both outpatient and inpatient consultation at CHOP. Our 2 dedicated nurse practitioners perform medical intake on all outpatient referrals to make sure patients see exactly the right combination of specialists from our team in a single visit to CHOP.

Leveraging cutting-edge diagnostics—including genetics, cellular, and cytokine profiling—functional immunology, and expert anatomic pathology consultation, our aim is to diagnose and treat patients with these complex syndromes who might otherwise have a much longer diagnostic odyssey.

What Exactly Is Immune Dysregulation?

How to recognize and refer immune dysregulation disorders remain a challenge for all involved. Perhaps it is easiest to start with what is NOT immune dysregulation.

Questions regarding classical immune mediated diseases still belong to the relevant subspecialty: lupus referrals should go to Rheumatology, malignancy questions to Oncology, and frequent infections to Immunology. It is really when the symptoms blur and overlap between these things when immune dysregulation should be invoked. On the other hand, sometimes patients present with difficult-to-diagnose symptoms like fatigue, headache, and pain, but without objective evidence of inflammation such as fever, rash, or elevated acute phase reactants. These patients are likely better served in different clinics, such as CHOP’s Pediatric Headache Program or the Center for Amplified Musculoskeletal Pain Syndrome (AMPS) within the Division of Rheumatology.

However, when the immune system is clearly involved, either because of a lab or exam finding, or because the symptoms are clearly inflammatory—like fever, rash, or swollen nodes—yet the patient also has a confusing array of symptoms that cross the line between our classical referral buckets, an immune dysregulation disorder should be considered. Our Immune Dysregulation Program team is happy to consider these referrals. Part of our intake process is to decide who might best benefit from the program. Sometimes we may decide based on the patient’s chart that the child might be better served by another CHOP program, and we make that referral directly in hopes we shorten the time to diagnosis and treatment. Either way, we hope that our program can help serve patients and providers by providing a more streamlined experience for complex patients.

More information can be found on our webpage at: www.chop.edu/immune-dysregulation.