Cold agglutinin disease (CAD) is a chronic illness that imposes a significant disease burden, depending on the severity of symptoms experienced. While we have made considerable progress in our understanding of CAD over the last decade, very few studies have centered on understanding the patient’s perspective of this condition.

Patients with CAD show hallmarks of anemia during cold seasons: fatigue, cold/painful extremities, chest pain, dark urine, and headaches. A small percentage of patients will have more extreme symptoms, such as hepatomegaly and lymphadenopathy. 

One of the more prominent ways in which CAD is managed is simply clinical observation, or the “watch and wait” approach. Patients are advised to keep warm and protect themselves against cold exposure when they need to be outside during the winter months. 

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The reason the “watch and wait” approach is so commonly used is that it does not rely on any pharmacological management, meaning it is the most conservative of treatments. And for patients who do not experience severe episodes of CAD, this method usually works. 

Read more about CAD etiology 

However, problems arise when a patient’s pain tolerance is low and if a patient wishes to completely eliminate any chance of experiencing CAD symptoms during cold weather. Patients who have flexible jobs or are retired may be able to move to a warmer climate to wait out the cold, and some patients indeed spend months away from home just to escape the cold weather. 

Patients who cannot move away from the cold can suffer tremendously during the winter, especially those who have more significant episodes of anemia during cold weather. These patients need to contend with having to stay warm as a matter of necessity and not luxury, and to do so for a long duration. In addition, they have to deal with this annually when the winter months return. This challenge is amplified in patients who live in countries where it is fairly cold year-round. 

The Psychological Impact of CAD

Joly and colleagues conducted a study to understand the burden of CAD on the daily lives of patients. Their findings were published in JMIR Formative Research.

“To enhance diagnosis and clinical management, it is necessary to better understand the symptom severity and impact of CAD from the patient’s perspective,” they wrote.

Joly et al created a web-based questionnaire to ask patients about the impact of the disease on their daily lives. It consisted of 39 close-ended questions and 5 open-ended questions. The inclusion criteria were having a confirmed diagnosis of CAD, being aged 18 or more years, and currently residing in the United States. 

Fifty participants fulfilled the inclusion criteria and completed the questionnaire. The researchers reported that 34% of them were diagnosed 2 years or longer after their initial symptoms. Why the long delay? Respondents revealed that it was because of a lack of awareness of the disease (32%) or misdiagnosis by initial physicians (30%). 

Read more about CAD treatment 

Around 54% of patients described their disease as moderate/severe and approximately 42% of patients reported their disease has worsened over time. In addition, 88% of patients reported experiencing increasingly intense symptoms over time, and that their sensitivity to CAD symptoms has grown. Among the most common triggers were cold temperature (83%), winter (68%), and air conditioning (55%). 

The most commonly reported symptoms were fatigue (90%) and shortness of breath (66%). One patient wrote, “Anything I need to routinely do, such as laundry, cooking, and light to moderate housework, leaves me completely drained.” 

Many patients reported a deterioration in their quality of work, either because their illness prevented them from being productive, or because they had to take time off work. In addition, patients reported that transportation for medical appointments and hospital/supportive care often resulted in out-of-pocket costs. 

Another patient wrote, “I have always been a very active person. Not being able to do the same activities is very hard emotionally. We look normal to most people, but we are not and that explanation is very hard for most people to understand and I get frustrated trying to explain CAD to people.”

Tailoring Our Treatment Approach

It is clear from this study that the disease burden of CAD goes far beyond cold-related symptoms and touches every aspect of a patient’s life. In addition, CAD can be said to be an “invisible” disease, meaning the condition is not obvious to an acquaintance or a bystander. 

This study from Joly et al is clear evidence that patients with CAD need to be psychologically supported. This means physicians should routinely ask questions relating to patients’ mental health and take action when needed. In addition, poor public awareness of CAD needs to be tackled so that patients are diagnosed as early as possible and appropriate management steps can be taken. 

“Patients with CAD experienced difficulty in receiving proper diagnosis and treatment owing to their rare disease; hence, they should be diagnosed earlier and, then, closely monitored and advised by a health care provider with knowledge of how to treat the disease,” Joly and colleagues wrote. 


Joly F, Schmitt LA, Watson PAM, Pain E, Testa D. The burden of cold agglutinin disease on patients’ daily life: web-based cross-sectional survey of 50 American patientsJMIR Form Res. 2022;6(7):e34248. doi:10.2196/34248

Berentsen S, Röth A, Randen U, Jilma B, Tjønnfjord GE. Cold agglutinin disease: current challenges and future prospectsJ Blood Med. 2019;10:93-103. doi:10.2147/JBM.S177621