Patients with cold agglutinin disease (CAD) may be at a higher risk of mortality during the winter months, according to a letter published in Transfusion.

The letter showed evidence of a 4.5 (95% CI, 2.00-10.08) times increased risk of death in patients from Denmark during the winter months (December, January, and February) when data were adjusted for age, sex, and year of diagnosis. Even unadjusted, the risk of death was 3.2 (95% CI, 1.43-7.18) times higher during the winter months.

The authors of the letter were writing in response to a previously published article that said that patients with CAD in the US had evidence of symptoms year-round. The letter’s authors had also previously published a study of patients in Norway, Denmark, and Italy that showed seasonal variations in the incidence of CAD with a higher rate during the colder months.

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“Our results indicate that CAD is associated with an increased risk of death during the colder months. However, our observational data does not allow for a direct causal inference,” the authors said.

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The authors pointed out that biochemical data were not available to them so it was impossible to address whether constant seasonally independent hemolysis was present in the patients or not. If it was present, they suggested that the increase in mortality could be due to short-term increases in hemolysis or impaired microcirculation that could aggravate comorbidities. They also mentioned that general frailty and the use of immunosuppressants could lead to increased rates of infection during the colder months and subsequent mortality.

A similar increase in seasonal mortality was not observed in age- and sex-matched comparators nor patients with more general autoimmune hemolytic anemia (AIHA).

“Consequently, these findings should seek confirmations in other cohorts and preferably other climatic areas, as this could potentially inflict on results,” the authors said.

A total of 114 patients with CAD and 5311 comparators were identified for the study through the analysis of the Danish National Patient Register. This group accumulated 45 and 1074 deaths, respectively, during the study period. An additional 2889 patients with AIHA and 143,269 comparators were also identified which accumulated 1809 and 64,954 fatalities, respectively.


Hansen DL, Möller S, Berentsen S, Frederiksen H. Mortality in cold agglutinin disease shows seasonal pattern. Transfusion. Published online May 9, 2022. doi:10.1111/trf.16894