Navigating primary and secondary immunodeficiency intersections: how to find IEI hidden within SID

Primary immunodeficiencies, also known as inborn errors of immunity (IEIs), and secondary immunodeficiencies (SIDs) present a multitude of challenges for clinicians due to their overlapping clinical features and diverse underlying aetiologies. IEIs mainly arise from inherited genetic defects, while SIDs are acquired conditions. IEIs are associated with an increased risk of cancer, particularly haematological malignancies, which have been linked to SID, highlighting an area of overlap. It is being increasingly recognised that in the context of cancer, immune deficiencies initially attributed to secondary causes were in fact due to an underlying IEI. This article aims to provide a comprehensive guide for recognising the subtle, yet pivotal clues that may help identify an underlying IEI in patients with haematological malignancies. Combinations of clinical features aligned to the manifestations of IEI, laboratory markers, functional studies, IEI experienced histological assessment, and genetic studies, alongside recognition of atypical responses to therapy for autoimmune and inflammatory features of IEI, and atypical features of the malignancy and its response to therapy and recurrence, can help unmask the IEI hidden within SID. This distinction is of critical importance for patients and their families, as it alters both the treatment of the underlying IEI as well as potentially the approach to the treatment of malignancy.