Seasonal Patterns of Anemia, Hemolytic Markers and Healthcare Resource Utilization Among Patients with Cold Agglutinin Disease in the United States: A Retrospective Analysis
Authors: Röth Alexander , Fryzek Jon , Jiang Xiaohui , Morales Jaime , Broome Catherine M. 
Published: October 2019

Abstract
Introduction: Cold agglutinin disease (CAD) is a rare form of autoimmune hemolytic anemia in which circulating immunoglobulin M autoantibodies bind to the "I" antigen on red blood cells (RBCs), preferentially at lower temperatures (Berentsen et al. Hematol Oncol Clin North Am, 2015). This results in both agglutination of RBCs and complement-mediated hemolysis. "Cold" typically refers to the immune biology (thermal amplitude) of the antibody and not to clinical features of the disease. Although exposure to cold temperatures may precipitate both the circulatory symptoms of CAD and hemolysis (Berentsen. Br J Haematol, 2018), seasonal variation of CAD manifestations is poorly understood (Lyckholm et al. N Engl J Med, 1996; Berentsen et al. Hematology, 2007). There are no clinical trials to support the efficacy of nonpharmacologic management of CAD by cold avoidance or relocation to warm regions (Berentsen. Br J Haematol, 2018; Swiecicki et al. Blood, 2013). Given the lack of data on clinical and laboratory effects of seasonality on the manifestations of CAD, we compared hemoglobin (Hgb) as well as markers of hemolysis and healthcare resource utilization (HRU) for patients with CAD between seasons.
Methods: Patients were identified from the Optum-Humedica database, containing de-identified information on medications, laboratory results, diagnoses, procedures, and clinical notes for more than 14 million people annually from all 50 states. Individuals with "cold agglutinin disease" in their clinical notes on at least 3 separate dates were considered patients with CAD. If "cold agglutinin disease" was documented on just 1 or 2 dates, patients were included only after an independent review and agreement by 2 hematologists. The laboratory parameters related to hemolysis, median minimum Hgb, median maximum bilirubin, and median maximum lactate dehydrogenase (LDH), were evaluated, as well as inpatient days, outpatient visits, emergency room visits, and transfusion days. Multivariate regression models were built to explore variation by season comparing the values in fall, winter, and spring to the values in the summer. Data were adjusted for age at baseline, gender, race, region, year, and Charlson Comorbidity Index prior to baseline and accounted for clustering of correlated observations.
Results: A total of 808 patients with CAD were identified from the Optum-Humedica database for analysis from 2009 to 2016. Most patients were ≥65 years of age (66%), female (63%), white (84%), and from the Midwest (43%). The median minimum Hgb value for winter as compared with summer was decreased by 0.54 g/dL (P<0.001). The median maximum bilirubin and LDH increased by 0.12 mg/dL (P=0.005) and 42.1 U/L (P<0.001) in winter versus summer, respectively. There were no differences in inpatient days, outpatient visits, emergency room visits, or transfusion days between winter and summer (Table). No significant seasonal disease pattern in HRU was noted in these patients.
Conclusions: Patients with CAD in this cohort had evidence of persistent hemolysis independent of the season. Disease manifestations as evaluated by HRU measures were fairly consistent all year long. The variations in median Hgb, bilirubin, and LDH between winter and summer were not associated with differences in clinical outcomes, as there were no significant changes in HRU or transfusion days. These data suggest that perceptions of CAD as a seasonal disorder may not be accurate and recommendations such as moving to regions with warmer climates likely provide no meaningful clinical benefit. The lack of seasonal variability in this cohort suggests that treatment considerations for patients with CAD should be season-independent.

Disclosures
Röth: Pfizer: Consultancy, Honoraria, Research Funding; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Bioverativ: Consultancy, Honoraria; Amgen: Research Funding. Fryzek:Sanofi: Research Funding. Jiang:Epidstat: Employment. Morales:Bioverativ: Employment. Broome:Bioverativ: Honoraria, Research Funding; Alexion: Honoraria.