Abstract
Quantifying the phenotypic features of rare diseases such as inborn errors of immunity (IEI) helps clinicians make diagnoses, classify disorders, and objectify the disease severity at its first presentation as well as during therapy and follow-up. Furthermore, it may allow cross-sectional and cohort comparisons and support treatment decisions such as an evaluation for transplantation. On the basis of a literature review, we provide a descriptive comparison of ten selected scores and measures frequently used in IEI and divide these into three categories: (1) diagnostic tools (for Hyper-IgE syndrome, hemophagocytic lymphohistiocytosis, and Wiskott-Aldrich syndrome), (2) morbidity and disease activity measures (for common variable immune deficiency [CVID], profound combined immune deficiency, CTLA-4 haploinsufficiency, immune deficiency and dysregulation activity [IDDA], IPEX organ impairment, and the autoinflammatory disease activity index), and (3) treatment stratification scores (shown for hypogammaglobulinemia). The depth of preclinical and statistical validations varies among the presented tools, and disease-inherent and user-dependent factors complicate their broader application. To support a comparable, standardized evaluation for prospective monitoring of diseases with immune dysregulation, we propose the IDDA2.1 score (comprising 22 parameters on a 2–5-step scale) as a simple yet comprehensive and powerful tool. Originally developed for use in a retrospective study in LRBA deficiency, this new version may be applied to all IEI with immune dysregulation. Reviewing published aggregate cohort data from hundreds of patients, the IDDA kaleidoscope function is presented for 18 exemplary IEI as an instructive phenotype–pattern visualization tool, and an unsupervised, hierarchically clustered heatmap mathematically confirms similarities and differences in their phenotype expression profiles.
Highlights
In clinical oncology and rheumatology, staging, grading, and diagnostic criteria are routinely applied to define the diagnosis or a subtype of a disorder and to determine the appropriate management of a patient and the treatment of a disease
A standardized, quantitative definition of the clinical phenotype of an inborn errors of immunity (IEI) in its entirety and its consequences on the patient’s quality of life, need for supportive care, and disease burden is relevant both in disease- or drug-specific studies as well as in prospective patient registry studies to learn about the natural course of the disease
In order to propose a clinical score that covers more than one distinct disease and likewise measures disease activity, several obstacles must first be overcome
Summary
In clinical oncology and rheumatology, staging, grading, and diagnostic criteria are routinely applied to define the diagnosis or a subtype of a disorder and to determine the appropriate management of a patient and the treatment of a disease. Certain other distinct inborn errors of immunity (IEI), where a clear genotype–phenotype correlation and the therapeutic consequences of a (mostly genetic) diagnosis (e.g., a targeted therapy, gene therapy, or hematopoietic stem cell transplantation [HSCT]) have been established. This management is especially challenging in immunodeficient patients with accompanying syndromic or complex features, such as immune dysregulation with autoimmunity. Three examples of tools assisting diagnosis-making are the Hyper-IgE syndrome (HIES) score, which was originally designed for autosomal dominant STAT3-LOF syndrome [4, 5], and the ‘diagnostic guidelines’ and the ‘H score’ used for primary and secondary hemophagocytic lymphohistiocytosis (HLH), respectively [6,7,8]
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