Primary Immune Regulatory Disorders (PIRD): Tools for Diagnosis and Disease Activity Assessment to Guide Therapy

Primary immune regulatory disorders (PIRDs) are an expanding group of inborn errors of immunity that predominantly have features of immune-mediated disease rather than infection. These disorders arise from defects in pathways that regulate immune homeostasis, resulting in diverse clinical manifestations including autoimmunity, hyperinflammation, lymphoproliferation, and severe atopy. A combination of genetics-forward (early use of genetic testing) approaches, immunologic laboratory testing, imaging, and phenotype-based diagnostic frameworks can help guide the evaluation of patients with suspected PIRDs. In addition, clinical scoring systems can potentially assist in quantifying disease activity, monitoring disease burden, and assessing treatment responses over time. In this review, we summarize diagnostic frameworks and clinical scoring systems relevant to PIRDs and discuss how these tools can support clinical management. We also highlight approaches that may help optimize patients for definitive therapies such as hematopoietic stem cell transplantation. As recognition of PIRDs increases, standardized disease assessment will be essential to refine diagnostic criteria and approaches, assess disease activity, and improve therapeutic outcomes for patients with immune dysregulation.