Somewhat serendipitously, before NORD announced that Dr. Lionakis was named a 2002 Rare Impact Award Honoree, we had planned to feature Dr. Lionakis and his work. We especially want to recognize him for all that he has done to advance the scientific community’s understanding of APS 1/APECED as well as for his kind and compassionate care for our community, which many of us have been fortunate to experience firsthand. We are grateful beyond words for Dr. Lionakis.
The Early Years
Dr. Lionakis obtained his M.D. and Sc.D. from the University of Crete in Greece. After completing his clinical training in Internal Medicine at Baylor College of Medicine and in Infectious Diseases at NIAID, Dr. Lionakis joined the Laboratory of Molecular Immunology at NIH (LMI) in 2008 and began to work on fungal immunology under the mentorship of Dr. Philip Murphy. At LMI, Dr. Lionakis did bench research on how chemotactic factors regulate the innate immune response in invasive candidiasis. In 2010, he was recruited as an Assistant Clinical Investigator in the NIAID Transition Program in Clinical Research (TPCR), where he established the Clinical Mycology Unit (CMU) within LMI.
In 2012, Dr. Lionakis was recruited as a tenure-track investigator in the NIAID’s intramural research program, where he established the Fungal Pathogenesis Unit (FPU) within the Laboratory of Clinical Infectious Diseases (LCID). Invasive candidiasis is the most common deep-seated human mycosis and the fourth-leading cause of nosocomial bloodstream infection in the United States.
CMC and APS 1
Chronic mucocutaneous candidiasis (CMC) is one third of the classic diagnostic triad of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) also known as autoimmune polyglandular syndrome type 1 (APS 1). As we know, APS 1 is a rare monogenic disorder characterized by development of multiorgan autoimmunity that targets several endocrine and non-endocrine tissues. APS 1 patients are susceptible to a “signature” infectious disease, chronic mucocutaneous candidiasis (CMC), which manifests with chronic, recurrent and severe infections of the mucous membranes, skin and/or nails by the commensal yeast fungus Candida.
Dr. Lionakis has sought to gain a more thorough understanding of CMC by examining APS 1 patients. Before he began his work, APS 1 was not thought to exist in the North American population. The highest prevalence of this disorder was found amongst certain historically isolated populations, such as Persian Jews (1:9,000), Sardinians (1:14,000) and Finns (1:25,000). Over the past 10 years, Dr. Lionakis has assembled a team, consisting of 20 specialists, to evaluate APS 1 patients in a comprehensive manner, by providing exams involving endocrinology, orthopedics, ophthalmology, dentistry, gastroenterology, dermatology and multiple other disciplines. To date, Dr. Lionakis’ team has worked with approximately 120-130 North American patients (and an additional 30-40 patients who reside outside of North America), and there have been over 1,000 patient visits to the NIH, with multiple patients seen several times now.
Redefining the Diagnostic Criteria
One of Dr. Lionakis’ first major research papers focused on the discovery of a second triad of manifestations that, when combined with the traditional triad, has led to much earlier diagnoses of patients in our community. This, in turn, has led to much earlier treatment, which directly results in better outcomes and greatly improved quality of life for APS 1 patients. One of the constant themes of Dr. Lionakis’ work has been to improve patients’ lives. He’s written about several manifestations of this disease which haven’t previously been described in the literature, such as pneumonitis (a potentially life-threatening manifestation), APECED associated hepatitis (also life threatening), and gastrointestinal issues. Not only has he written about these manifestations, he has also introduced effective treatments for each.
PTH Helps with Patient Procedures
Dr. Lionakis has also helped define the role of Forteo® (a synthetic parathyroid hormone) around procedures for his patient group. APS 1 patients traditionally received a “stress” dose of cortisol before procedures to protect against an adrenal crisis. The introduction of this stress dose, however, often had the unintended consequence of driving calcium levels down to dangerous levels in individuals with hypoparathyroidism (which includes most of the APS 1 patient population). Through the use of Forteo, administered under the direction of a protocol developed by Dr. Lionakis and his team (which requires in-patient hospital admission so that patients may be monitored closely through repeated bloodwork), calcium levels are stabilized, hypocalcemic crises are avoided, and patients’ health and safety are ensured.
Some of Dr. Lionakis’ most recent work has centered around understanding how COVID-19 affects our community. It was found that a large proportion of APS 1 patients are at increased risk of developing severe COVID-19 because most APS 1 patients have autoantibodies to type 1 interferons. Dr. Lionakis has helped our community understand how to protect against COVID-19 and on how to treat it. Many patients have called on him directly for advice.
A Clinician First, a Researcher Second
Dr. Lionakis works directly with each APS 1 patient and family. In my mind, he has always been a clinician first and a researcher second. He has sought to thoroughly understand each of the more than 30 manifestations of this disorder and to develop effective treatments. In fact, several manifestations are now able to be diagnosed and treated proactively before they emerge and cause irreversible damage.
His efforts serve as a model for researchers of other rare disease communities by:
- Showing how to find patients with a rare disease who are widely scattered
- Demonstrating the benefits of examining patients with rare disorders in a thorough and comprehensive fashion
- Revealing that it is possible to assemble a team of doctors who are able to communicate quickly and effectively with one another in order to devise new and better treatments
- Reinforcing the importance of publishing those findings to quickly disseminate critical information to a world-wide rare disease patient population
In His Own Words
Dr. Lionakis has provided the following brief summary of his work. In brief, we have published 32 papers related to APS1/APECED. They span the spectrum of clinical research and basic research and are related to diagnosis, pathogenesis, immunology, and treatment. The most influential papers are:
- Redefined clinical features and diagnostic criteria in autoimmune polyendocrinopathy -candidiasis-ectodermal dystrophy
This paper changed the way people think of APECED. Through a comprehensive evaluation of all patients, we proposed and redefined the diagnostic criteria and described manifestations that occur early that were largely unnoticed or ignored. This paper describes for the first time the breadth and time course of APECED in North America. We are finalizing a follow-up paper now on this topic that shows that the expanded diagnostic criteria validate in subsequent patients (>100 now in this paper) including patients from Europe. Independent of our group, multiple groups around the world have now re-examined at their cohorts and have confirmed that our criteria are permissive to early diagnosis.
- Dr. Fierabacci has even coined these expanded criteria the Ferre/Lionakis criteria:
This paper discovered a new paradigm by which mucosal candidiasis can occur, caused by excessive autoimmune inflammation that disrupts the epithelial barrier and permits Candida to cause disease. This paradigm shift is operational in APECED and other diseases that we will publish in the coming months/years and pave the foundation for targeted treatments for candidiasis (and beyond) in APECED. This discovery is one of those that will get into the major textbooks of immunology.
- Lymphocyte-driven regional immunopathology in pneumonitis caused by impaired central immune tolerance
This paper is critically important because it uncovered pneumonitis as a common, early onset, dangerous manifestation of APECED that had been overlooked. It defined the immunological and pathogenesis features of the entity in mice and humans with APECED and devised a treatment strategy that puts pneumonitis in remission. The paper also extended these findings beyond APECED in two other diseases, RAG deficiency and thymoma, indicating that a discovery in APECED can enlighten other diseases for pathogenesis and treatment.
- We summarized these findings in a review for physicians entitled, An AIREless Breath: Pneumonitis Caused by Impaired Central Immune Tolerance.
We have now treated many more patients and we have diagnosed this early on in many patients. At some point in the near future, we will publish our follow-up experience as we have now treated ~15 patients successfully. We are also preparing two other papers this year on the topic, one that will further expand the findings in thymoma (which we now treat successfully in that disease on the basis of what we found in APECED pneumonitis) and a second on the triggers of pneumonitis flares in APECED patients. The dire consequences of not recognizing and treating this condition early on are depicted in this case here:
- Fatal autoimmune pneumonitis requiring bilobectomy and omental flap repair in a patient with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED)
- APECED-Associated Hepatitis: Clinical, Biochemical, Histological and Treatment Data From a Large, Predominantly American Cohort
This paper is a parallel to the pneumonitis paper only for hepatitis. It is the largest assembly of APECED associated hepatitis to date and it informs clinical, diagnostic, autoantibody, histological, and treatment on this entity. It was published in Hepatology this year.
- Preexisting autoantibodies to type I IFNs underlie critical COVID-19 pneumonia in patients with APS-1: this paper described the propensity of a large proportion of APECED patients to develop severe COVID associated with the presence of autoAbs to type 1 interferons.
- Associated with the previous COVID-19 paper, the paper entitled Type I interferon autoantibodies are associated with systemic immune alterations in patients with COVID-19 helped define the immunological defects in patients with severe COVID-19.
- Temporal Dynamics of Anti-Type 1 Interferon Autoantibodies in COVID-19 Patients describes the trajectory of these autoabs before and after COVID-19 in APECED vs. non-APECED patients.
- SARS-CoV-2 Spike Protein-Directed Monoclonal Antibodies May Ameliorate COVID-19 Complications in APECED Patients showed the early delivery of anti-spike monoclonal antibodies can help ameliorate severe disease in APECED patients.
- Lessons from primary immunodeficiencies: Autoimmune regulator and autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy : this is a comprehensive review of APECED from all aspects, from basic to clinical.
Additional reviews of interest that we have written are listed here:
- Insights into immune tolerance from AIRE deficiency
- Infections in the monogenic autoimmune syndrome APECED
- Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy
Briefly, here are also other papers of note:
- We have profiled autoantibodies that are associated with Sjogren’s in APECED and have provided samples to Dr. Mark Anderson who did the same in ovarian and intestinal dysfunction in APECED.
- A follow-up paper by Dr. Anderson is submitted now that has even more patients from our cohort and from Europe. We have described novel clinical manifestations or underscored the importance of less recognized ones.
- We have defined the role of Forteo around procedures, and we recently published the largest study on treatment of hypoparathyroidism in the world.
- We have shown that resistant candida can be treated with novel antifungals (https://pubmed.ncbi.nlm.nih.gov/29040636/;https://pubmed.ncbi.nlm.nih.gov/29788070/), one of which (VT-1161) is about to get FDA-approved in the coming weeks.
- We have helped define:
Our Family’s Hero
It is difficult to find the words to express how much Dr. Lionakis has meant to our family. Our son’s journey with APS 1 can be roughly broken up into three 5-year periods.
- The first five years after his diagnosis, we assembled our team of doctors as best we were able. We were fortunate to have many fine, capable physicians, but each worked within their own specialty.
- At the end of the fifth year, we were introduced to Dr. Lionakis, and for the first time and over the next five years, we had a single doctor to turn to for each new twist and turn that APS 1 introduced into our lives.
- During these last five years, as a result of Dr. Lionakis’ work, we are addressing problems proactively rather than racing to catch up to an already established problem.
I’m sure many in our community who’ve dealt with APS 1 over many years have had a similar experience. Dr. Lionakis has provided knowledge, which has given us hope. There is still much work to be done, but we are in very capable hands.
Congratulations Dr. Lionakis on being selected to receive NORD’S 2022 Rare Impact Award.
It is certainly well earned and well deserved.