Unraveling the Natural History of Good's Syndrome: A Progressive Adult Combined Immunodeficiency.

BACKGROUND: Good's syndrome (GS) is a rare immune deficiency described almost 6 decades ago. Despite numerous published individual case reports and data collected in cross-sectional studies of small cohorts, the natural history and long-term outcomes of this disease remain unknown. OBJECTIVE: We aimed to determine the clinical and laboratory evolution of 8 adults diagnosed with GS and consecutively evaluated between 1983 and 2023. METHODS: In this prospective, longitudinal cohort study, newly diagnosed patients with GS were followed through repeated measures of clinical, immune, and hematologic changes, as well as targeted genetic screening. RESULTS: All patients reported a healthy childhood and adolescence with symptom onset during the third or fourth decade of life. All presented to our center with recurrent bacterial sinopulmonary infections, thymoma, hypogammaglobulinemia, and absence of B cells. The median age of GS diagnosis was 57 years. During follow-up, immunoglobin replacement therapy effectively minimized sinopulmonary infections. However, the majority experienced severe and systemic viral or fungal infections, 3 developed basal cell carcinomas, and 5 had progressive bronchiectasis and persistent splenomegaly. The most notable clinical feature was opportunistic infections and in vitro evidence of cellular immune deficiency, which resulted in the death of 2 individuals. We also report a statistically significant, multidecade progressive decline in lymphocytes, platelets, hemoglobin, and red blood cells in our cohort, suggesting gradual bone marrow failure. CONCLUSIONS: Knowledge of the unique phenotype and temporal evolution of GS has allowed us to develop a more comprehensive diagnostic framework. It can be investigated as part of broader research into disease pathophysiology.

Good's Syndrome: Time to Move on From Reviewing the Past.

For seven decades, the pathophysiology of Good's syndrome (GS) has remained a mystery, with few attempts to solve it. Initially described as an association between hypogammaglobulinemia and thymoma, controversy exists whether this is a unique disease, or a subgroup of Common Variable Immune Deficiency (CVID). Recently, some distinguishing aspects of both syndromes have come to light reflecting fundamental differences in their underlying pathophysiology. GS and CVID differ in demographic features and immune phenotype. GS is found almost exclusively in adults and is characterized by a significantly reduced or absence of peripheral B cells. In CVID, which also occurs in children, most patients have normal or slightly reduced peripheral B cells, with a distinguishing feature of low memory B cells. Similarly, differences in T cell dysregulation and manifestations of hematologic cytopenias may further distinguish GS from CVID. Knowledge of the clinical phenotype of this rare adult immune deficiency stems from individual case reports, retrospective, and cross-sectional data on a few cohorts with a limited number of well characterized patients. The understanding of pathophysiology in GS is hampered by the incomplete and inconsistent reporting of clinical and laboratory data, with a limited knowledge of its natural history. In this mini review, we discuss current state of the art data and identify research gaps. In order to resolve controversies and fill in knowledge gaps, we propose a coordinated paradigm shift from incidence reporting to robust investigative studies, addressing mechanisms of disease. We hope this novel approach sets a clear direction to solve the current controversies.