Unexplained anemia in seniors may signal autoimmune disease CAD
Case series highlights why CAD is often missed or misdiagnosed in the elderly
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A new case series urges clinicians to keep cold agglutinin disease (CAD) on their radar when treating elderly patients with unexplained anemia.
Researchers say that because the rare autoimmune condition often occurs with “clinically subtle” or atypical symptoms, it can easily be missed, delaying essential treatment for underlying causes like blood cancer.
The report, “Their Blood Ran Cold: A Case Series on Cold Agglutinin Disease,” was published in the journal QJM. The study details two cases in Singapore where older adults were diagnosed with CAD only after detailed laboratory testing overrode their lack of typical symptoms.
CAD occurs when the immune system wrongly produces self-directed antibodies, called cold agglutinins, that bind to red blood cells at cold temperatures, causing them to agglutinate (clump) and be marked for destruction (a process called hemolysis). The complement cascade, a part of the immune system, is known to contribute to CAD-related hemolysis.
The challenges of identifying a rare condition
Without sufficient red blood cells, people experience anemia, which can cause fatigue, weakness, pale skin, shortness of breath, headaches, and dizziness. Because these symptoms are non-specific and similar to those of other conditions, CAD diagnosis is often delayed.
The disease can also be classified as primary, when it develops on its own, or secondary, when it is triggered by an underlying condition, such as infections, blood cancers, or other autoimmune conditions.
In the report, a team of researchers in Singapore described the diagnostic challenges of CAD in two older adults, reminding clinicians to consider it when examining elderly patients with anemia.
The first case was an 86-year-old man without a personal or family history of cancer or autoimmune diseases. He was admitted to the clinic due to incidental macrocytic anemia, which is characterized by larger-than-normal red blood cells, leading to fewer healthy red blood cells to carry oxygen throughout the body.
He had no symptoms, and physical examination found no abnormalities or significant issues. Yet, blood tests revealed signs of CAD. These included low levels of hemoglobin, the protein in red blood cells that carries oxygen, red blood cell agglutination that was reduced at warmer temperatures, and elevated blood levels of lactate dehydrogenase, a marker of hemolysis.
The man also tested positive on the Coombs test, indicating the presence of both antibodies and complement proteins bound to red blood cells, a hallmark of CAD.
Further blood tests found excessive levels of abnormal antibodies, which may be a sign of multiple myeloma, a type of blood cancer, and hypocomplementaemia, or abnormally low levels of complement proteins.
“Hypocomplementaemia in CAD could be due to consumption of complements in activating the haemolytic cascade, with evidence suggesting repletion of these complement levels leading to further precipitation of haemolysis,” the researchers wrote.
Clinicians planned to test for possible multiple myeloma, but the man declined a bone marrow biopsy. Further testing to assess other autoimmune conditions as a possible cause for his hypocomplementaemia came back negative.
Recurrent falls and unintended weight loss
The second case involved a 92-year-old woman who was admitted to the hospital for recurrent falls. She had normochromic normocytic anemia, a poor appetite, and had unintentionally lost 6 kgs (13 lbs) over a year. Normochromic normocytic anemia refers to low red blood cell counts, with cells of normal size and color and normal hemoglobin content.
Further testing confirmed several CAD signs, including low hemoglobin levels, lessened red blood cell agglutination at warmer temperatures, elevated lactate dehydrogenase, and a positive Coombs test for both antibodies and complement proteins. She received blood transfusions to address multiple drops in hemoglobin levels.
Examination of the upper gastrointestinal tract to look for other potential causes of anemia showed an abnormal growth protruding from the stomach lining and an ulcer without active bleeding. Tissue analysis showed a benign thickening of the stomach lining.
Because of recurrent drops in hemoglobin, clinicians recommended rituximab (sold as Rituxan and Mabthera, with biosimilars available), a therapy that depletes antibody-producing B-cells. Although not specifically approved for CAD, it’s widely accepted as a treatment option.
However, the family declined further tests and treatment in line with the patient’s wishes. As a result, she was subsequently admitted to the hospital four more times for worsening heart failure, “possibly due to worsening anemia,” the team wrote.
“Early identification of CAD is crucial as it can be the sole presenting complaint in a malignancy,” the researchers wrote. “Moreover, this would also allow for early [blood-related tests and management] to prevent the complications of debilitating haemolysis.”
