A team of Danish researchers discovered that patients with cold agglutinin disease (CAD) utilize significantly more healthcare resources than the general population, both prior to diagnosis and 1-year post-diagnosis, according to a study published in Current Medical Research and Opinion.

CAD is a rare form of autoimmune hemolytic anemia that currently has no approved treatment. Among the most common clinical manifestations of CAD are marked fatigue and cold-induced circulatory symptoms, such as Raynaud’s phenomenon. Current literature points to a profound disease burden on patients, including an increased risk of thromboembolic events as well as early mortality.

To date, there had never been a European population-level analysis of patients with CAD, which is what prompted the Danish researchers to fill in the gap. 

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The research team looked up all CAD cases registered with the Danish National Patient Registry between January 1, 1999, and June 30, 2016, and identified a subgroup of patients with primary CAD. Those patients were matched to individuals from the general population without CAD based on birth year, sex, as well as 19 disease categories. Researchers then analyzed their use of healthcare resources, such as outpatient clinic visits, inpatient hospitalizations, and blood transfusions. 

The researchers identified 104 CAD patients who were matched to 1003 comparison cohort members. They discovered that the odds of patients with CAD having at least 1 inpatient hospitalization was 17.2 times higher than comparison cohort members. In addition, CAD patients had a 5.3 times higher rate of outpatient visits compared to matched comparisons.

Blood transfusion use was also significantly higher among CAD patients, and the median number of transfusion days during the 12 months after diagnosis was 4.0 for the 43.3% of CAD patients who received blood transfusion treatment. The researchers identified high-dose immunoglobulin as the most frequently applied drug for CAD patients. 

The reason that the Danish research team matched CAD patients with 19 disease categories was to verify that the increase in healthcare resource utilization (HRU) was not due to comorbidities. In addition, researchers conducted sensitivity analyses that excluded cases with underlying conditions that can be associated with CAD, such as B-cell lymphoma and specific infections. HRU was still higher among the CAD population.

“The persistence of increased HRU across all parameters (inpatient, outpatient, emergency room, transfusion days, and expensive drug use) in the CAD cohort after making these adjustments indicates that our findings cannot be solely owing to the presence of underlying comorbidities or related disorders,” the researchers wrote.


Vágó EK, Nicholson G, Horváth-Puhó E, Hooda N, Fryzek JP, Su J. Healthcare resource utilization among patients with cold agglutinin disease in DenmarkCurr Med Res Opin. Published online August 10, 2021. doi:10.1080/03007995.2021.1960494