Impact of Cold Agglutinin Disease on Daily Life Seen in New Survey


Symptoms associated with cold agglutinin disease fluctuated throughout the course of the disease, and many patients were not satisfied with management measures.

Although studies have explored the impact of cold agglutinin disease (CAD) on daily life, the patient perspective represents a gap in research. A study published in JMIR Formative Research surveyed patients to provide novel insights into the impact of fatigue and overall disease severity as perceived by individuals with CAD.

CAD is a rare condition that affects 15% to 25% of patients with autoimmune hemolytic anemia (AIHA), which is characterized by red blood cell destruction by antibodies and results in anemia and other related conditions. CAD is typically identified by the presence of hemolytic anemia, reticulocytosis, hyperbilirubinemia, elevated lactate dehydrogenase, and a positive Coombs test for anti-C3d and classically negative anti–immunoglobulin G. Because most agglutinins are not clinically significant, antibody titer and thermal activity should be established to prevent overdiagnosis.

Symptoms of CAD include those consistent with hemolytic anemia: paleness, shortness of breath, rapid heart rate, fatigue, weakness, dark urine, or pain. Symptoms and overall CAD severity can fluctuate significantly, and conditions like febrile illness, trauma, and surgery can aggravate hemolytic anemia and increase the risk of thrombotic events or death.

Considering their rarity, the ability to conduct large-scale studies of AIHA and CAD is limited. The current study aimed to provide patient-centric input that could improve the diagnosis and clinical management of CAD.

Fifty patients fulfilled study inclusion criteria and filled out a questionnaire by the September 2020 deadline. The mean participant age was 66 years, and the average age at diagnosis was 59 years. Of the patients who experienced symptoms before diagnosis (88% of the overall cohort), 34% were diagnosed more than 2 years after symptom onset. For the most part, delays in diagnosis were due to a lack of awareness that these symptoms are associated with CAD or due to consulting multiple physicians before receiving a correct diagnosis.

Fatigue (including tiredness, lack of stamina, or weakness), shortness of breath, and acrocyanosis were the most commonly reported symptoms. Fifty-four percent of patients considered their disease moderate or severe, and those with severe symptoms were generally dissatisfied with their disease management. Sixty-two percent of patients reported disease progression since diagnosis, 42% of whom thought it worsened and 20% who thought it improved.

Most respondents (90%) reported experiencing fatigue, and 44% of those patients reported fatigue on a daily basis. Some patients (31%) who experienced fatigue reported that their fatigue fluctuated throughout the course of the day, 29% reported constant fatigue, and 22% reported more intense fatigue in the afternoon. Patients reported that the CAD-related symptoms with the greatest impact on daily life were fatigue, shortness of breath, and joint pain, headaches, or acrocyanosis (90%, 58%, and 44%, respectively). These symptoms were most affected during episodes of increased symptom intensity.

When asked about the day-to-day impact of CAD in an open-ended format, patients reported that their physical well-being, emotional well-being, social lives, and household finances were affected. Thirty-eight of patients reported experiencing at least 1 CAD episode within the 12 months prior to the study. The average number of episodes was 4 to 5 in the year prior, and episodes were most frequently brought on by cold, air conditioning, the winter months. Cold avoidance, rituximab treatment, and blood transfusions were the most-reported symptom management methods at the time of the survey.

Study limitations include the web-based nature of the survey, which could produce bias toward younger patients, and recruitment from the CAD Unraveled website, which introduces selection bias. However, the results confirm and supplement findings from other studies on the day-to-day effects of CAD.

“Additional studies are necessary to better understand the burden of CAD-related symptoms, especially fatigue, and the patient’s needs regarding symptom management,” the authors concluded. “It is also important to raise awareness among health care professionals regarding CAD-related symptoms to appropriately diagnose and support these patients. Specifically, health care professionals should proactively discuss ways to manage fatigue, which is not often discussed during consultations.”


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 patients. JMIR Form Res. Published online July 22, 2022. doi:10.2196/34248

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