Medically Attended Anxiety or Depression Is Increased Among Newly Diagnosed Patients with Cold Agglutinin Disease (CAD)
Authors: Patel Parija , Jiang Xiaohui , Nicholson Gina , Frankenfeld Cara , Iglesias-Rodriguez Melitza , Fryzek Jon P , Su Jun 
Published: February 2021

CAD is a rare form of autoimmune hemolytic anemia (AIHA) that accounts for approximately 20% of all AIHA and is characterized by classical complement pathway-activated hemolysis. Clinical manifestations of CAD can include complement-mediated chronic hemolytic anemia, profound fatigue, as well as transient agglutination-mediated circulatory symptoms (Berentsen et al. Hematol Oncol Clin North Am. 2015; Swiecicki et al. Blood. 2013). Recent research has shown that patients with anemia are more likely to develop depression and anxiety (Shafi et al. J Coll Physicians Surg Pak. 2018; Vulser et al. Acta Psychiatr Scand. 2016), but this has not been previously studied in patients with CAD.
We conducted a matched-cohort comparison study evaluating the risk of medically attended anxiety or depression in patients with and without CAD. All patients with CAD were identified in the Optum Claims-Clinical dataset by reviewing clinical notes for CAD terms. Patients with CAD were matched (1:10) to non-CAD patients by age (±3 years), sex, race, region of residence, and active time and season and year of entry date in the Optum health plan. Inclusion criteria included 25 years of age or older with no history of anxiety or depression. Medically attended anxiety or depression was defined using International Classification of Diseases (ICD-9 and ICD-10) codes for inpatient stays and outpatient hospital visits, medication class, and procedure codes for psychotherapy. Cox regression models were built to estimate time to hospitalizations without medications or psychotherapy, medications or psychotherapy without hospitalization, hospitalization with medication or psychotherapy, or any of these outcomes adjusted for age, sex, race, region, comorbidity score, and cluster (matched CAD and non-CAD cohorts). As patients with both primary CAD (not due to secondary causes) and secondary cold agglutinin syndrome (coexisting diagnosis of malignancy or infection) were included in the primary analysis, subset analyses also were performed for patients with primary CAD.
A total of 384 patients with CAD (mean [standard deviation {SD}] age: 70.0 [13.0] years) and 2789 patients without CAD (comparisons; mean [SD] age: 69.6 [12.7] years) were identified between 2006 and 2016. The mean (SD) time to event for any hospitalization, medication use, or psychotherapy was 27.7 (24.4) months for patients with CAD and 38.2 (25.6) months for comparisons with patients with CAD being 60% more likely to have medically attended anxiety or depression (adjusted hazard ratio [aHR]: 1.6; 95% confidence interval [CI]: 1.3-2.1). Patients with CAD were almost twice as likely to be prescribed medication or psychotherapy for anxiety and depression after their CAD diagnosis (aHR: 1.8; 95% CI: 1.2-2.9) or to be hospitalized for a depression or anxiety-related event along with medication or psychotherapy (aHR: 2.0; 95% CI: 1.4-2.9). There was also a nonsignificant risk for patients with CAD being hospitalized for anxiety and depression without medication or psychotherapy (aHR: 1.2; 95% CI: 0.8-1.9).
Subanalysis of patients with primary CAD also were at a statistically significant increased risk for medically attended anxiety or depression (aHR: 1.8; 95% CI: 1.4-2.4) with the largest risk for prescription medication or psychotherapy (aHR: 2.7; 95% CI: 1.6-4.6).
To our knowledge, this is the first study to evaluate anxiety or depression among patients with CAD. Our study indicates that medically attended depression and anxiety manifest at a higher rate in patients with CAD compared with a matched non-CAD cohort. These findings suggest that patients with CAD may experience extra-hematologic manifestations of the disease that potentially have a broader impact on their overall mental health, physical health, and quality of life. Further investigation on this topic is warranted.

Disclosures
Patel: Sanofi: Current Employment. Jiang:EpidStrategies: Current Employment. Nicholson:EpidStrategies: Current Employment. Frankenfeld:EpidStrategies: Current Employment. Iglesias-Rodriguez:Sanofi: Current Employment. Fryzek:EpidStrategies: Current Employment. Su:Sanofi: Current Employment.