International Clinical Consensus on Leukocyte Adhesion Deficiency-I: A Modified Delphi Analysis

Background Leukocyte adhesion deficiency (LAD-I) is a rare autosomal recessive inborn error of immunity (IEI) caused by mutation of ITGB2, encoding for CD18, which is essential for leukocyte endothelial adhesion and migration to tissues. LAD-I is predominantly characterized by severe infections, inflammation and periodontitis, with significant pediatric mortality in the absence of allogeneic hematopoietic stem cell transplantation. Historically, diagnosis and disease severity classification has been centered on the expression of CD18 in polymorphonuclear neutrophils. Given improved knowledge of prognostic factors and an evolving treatment landscape, contemporary guidance for diagnosis and management of this complex IEI is needed. Objective To formulate international, expert-led recommendations for the diagnosis and severity classification of LAD-I, and to characterize standard of care and burden of illness for patients with severe LAD-I. Methods Twelve geographically diverse experts (steering committee n=3; Delphi participants n=9) were recruited to participate in a modified Delphi study. Two rounds of online questionnaires were conducted, with statements rated according to a 7-point Likert scale, with one indicating ‘strongly disagree’, and seven, ‘strongly agree’, to assess the level of consensus. Responses were discussed during a virtual consensus workshop and final recommendations were approved by all experts. Results A strong degree of consensus was achieved across topics to generate 26 recommendations regarding the diagnosis and treatment of patients with LAD-I. Participants agreed LAD-I should be considered as either moderate or severe, and LAD-I severity classification should consider both clinical phenotype and laboratory assessment within a comprehensive diagnostic framework. We therefore developed a set of criteria to assist clinicians in diagnosing and classifying moderate versus severe LAD-I. As part of the laboratory assessment criteria, for patients that present with a family history, clinical history and/or symptoms consistent with LAD-I, polymorphonuclear leukocyte expression of CD18, CD11a and CD11b should also be evaluated when diagnosing patients and assessing disease severity. Participants agreed that a patient's condition should be classified according to the clinical phenotype and/or laboratory assessment criteria that are indicative of greater severity. In addition, we established consensus on the best practice for the treatment of severe LAD-I with definitive therapy, if available, or with best supportive care. All participants agreed that best supportive care was insufficient to prevent patients with severe LAD-I from experiencing significant morbidity, mortality and poor health-related quality of life. Furthermore, without definitive therapy, participants considered the annual risk of life-threatening infections, infection-related complications, and death to increase or persist in severe LAD-I patients who survive beyond two years of age. Conclusions The diagnostic and severity classification framework developed by the Delphi panel will aid clinicians in the diagnosis, classification and treatment of patients with LAD-I. Recommendations support best clinical practice and will lead to improved clinical outcomes among patients with LAD-I.