Cold agglutinin disease (CAD) is a subtype of autoimmune hemolytic anemia (AIHA) characterized by the production of cold agglutinins. Disease severity is in part determined by thermal amplitude, which is the warmest temperature at which antibodies can properly bind to antigens. If this exceeds a temperature of about 30°C, the acral circulation may experience erythrocyte agglutination. 

Studies have demonstrated that four-fold differences in prevalence and incidence occur in relation to the climate in which the patient lives. These findings are complemented by another study that suggests seasonal flux impacts the prevalence of case reports. 

In this article, we will explore more closely the impact of the climate and seasonal changes on the clinical outcomes of patients with CAD. 

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Diseases Affected By Seasonal Changes 

Aside from CAD, there are a number of conditions known to be impacted by seasonal changes. One is seasonal affective disorder, which is a form of depression that tends to get worse in the winter. The prevalent theory for why this is the case is that the longer nights and colder days have a negative impact on patients’ mental state. In a sense, it is the opposite of going on a “sunny tropical vacation”; just as some people find relief and ease from warmer weather, others find the cold to be oppressive. 

Another prominent disease affected by seasonal changes is Raynaud’s disease. The typical presentation is patients feeling their extremities go numb in response to cold temperatures. The severity of symptoms experienced by patients during cold seasons varies, but patients who experience more severe forms of the disease can visibly see their fingers and toes whiten; in extreme cases, amputation may be required.

Patients who have seasonal affective disorder or Raynaud’s disease often feel a sense of dread as the seasons change from autumn to winter, since this heralds the start of a new cycle of hardship. Some patients are so affected by the winter season that they choose to leave their respective countries for warmer climates during the entire duration of the season. Of course, not all patients can afford to move away for months on end, and many patients have no choice but to take the necessary precautions and brave the season. 

The point here is that seasonal changes are not simply a matter of preference for some patients. In the modern world, seasonal changes have an impact on clothing choice, and usually not much more. For patients with illnesses that are influenced by the climate and the seasons, the change in seasons is largely robbed of its beauty as real mental or physical suffering sets in. 

CAD and Seasonal Changes 

Let’s return to the subject of CAD. Patriquin and Pavenski wrote, “It has long been assumed that all aspects of CAD worsen in colder climates or seasons. Case reports by Dacie and Lyckholm support this, with documentation of more profound anemia and higher [lactate dehydrogenase] in the winter.” 

Read more about CAD etiology

Let’s take a look at the case report from Lyckholm (and Edmond). They detailed the case of a 61-year-old patient who presented with hemolytic anemia and acrocyanosis. He was found to have CAD and was prescribed plasmapheresis, prednisone, and chlorambucil. The patient was then followed for 2 years without therapy, during which he continued to work, spending most of his time outdoors. 

The research team reported that the patient’s cold-agglutinin titer exceeded 1:524,288 with a therapeutic maximum of 37°C. By plotting out a graph of his lactate dehydrogenase concentration against temperature over the course of 3 years, it became abundantly clear that the severity of his symptoms was related to temperature: troughs in temperature levels corresponded with peaks in lactate dehydrogenase concentration, and vice versa. 

Although the relationship between lactate dehydrogenase concentration and temperature in this patient was crystal clear, Patriquin and Pavenski wrote that there is “considerable variation among patients.” They reported that while median lactate dehydrogenase values tend to be modestly raised in the winter and spring, individual lactate dehydrogenase levels could be as low as 88-8403 u/L. This indicates that there is great heterogeneity in the severity of CAD among patients as a result of temperature changes.

Clinical Approaches

What can physicians do to manage CAD worsened by seasonal changes? Besides advising the temporary move to warmer climates, physicians have a few tools to counter CAD symptoms (although patients with a milder phenotype may not need additional therapy).

Read more about CAD therapies 

Patriquin and Pavenski wrote, “For patients requiring pharmacologic intervention, the focus should be on targeting the underlying clonal lymphoproliferative disorder and addressing persistent complement-mediated hemolysis.” This can include targeting B-cells or the complement system. Severe anemia can be treated with red cell transfusions. 

Another step that physicians can take is to offer support when their patients report the worsening of their symptoms due to seasonal changes. Because seasonal changes are a part of life and the modern world grinds on almost indifferently, we might make the mistake of thinking that all of our patients are able to do so too. By taking immediate investigative action, we can make a real difference in reducing season-related morbidity. 


Patriquin CJ, Pavenski K. O, wind, if winter comes … will symptoms be far behind?: exploring the seasonality (or lack thereof) and management of cold agglutinin diseaseTransfusion. 2022;62(1):2-10. doi:10.1111/trf.16765

Lyckholm LJ, Edmond MB. Images in clinical medicine. Seasonal hemolysis due to cold-agglutinin syndromeN Engl J Med. 1996;334(7):437. doi:10.1056/NEJM199602153340705