Review study highlights challenges in CAD treatment, diagnosis
AIHA manifestations can vary widely, researchers note
Establishing a diagnosis of autoimmune hemolytic anemia (AIHA), a group of conditions including cold agglutinin disease (CAD), is sometimes difficult, due to the high variability in signs and symptoms and the possibility of a secondary cause, a review study showed.
“Additionally, therapy is poorly evidence-based and mainly funded on consensus of experts,” the researchers wrote.
The review study described several cases highlighting challenges in diagnosis and/or treatment of CAD and other AIHA types. One case, concerning a 76-year-old woman with CAD secondary to a blood cancer, showed the increased risk of life-threatening infections with several courses of immunosuppressive treatment until and after achieving a correct diagnosis.
The study, “Autoimmune Hemolytic Anemias: Challenges in Diagnosis and Therapy,” was published in Transfusion Medicine and Hemotherapy.
AIHA comprises a group of diseases in which self-reactive antibodies bind to the body’s own red blood cells, marking them for destruction. It is generally divided into three types: CAD, in which the abnormal antibodies, called cold agglutinins, are active at low temperatures; warm AIHA, where antibodies are active at higher temperatures; and mixed AIHA, where antibodies are active at a range of temperatures.
In CAD, red blood cell destruction causes symptoms including anemia, fatigue, blue-tinged skin (acrocyanosis), and Raynaud’s phenomenon, when body extremities become numb and/or discolored in response to cold temperatures.
CAD treatment complex as symptoms, causes vary
“AIHAs are highly [variable], from mild/compensated to life-threatening/fulminant, and may be primary or [secondary, when] associated with infections, [cancers], autoimmune diseases, transplants, immunodeficiencies, and drugs,” the researchers wrote.
The pair of researchers in Italy reviewed current knowledge on how these different forms of AIHA are diagnosed and treated, highlighting complexities that may be encountered by clinicians caring for patients.
Diagnosing any type of AIHA generally involves a direct Coombs test, which assesses for antibodies and other immune proteins bound to red blood cells. It’s crucial to distinguish between the different forms of AIHA, however, because treatments for warm AIHA generally aren’t effective in CAD and vice versa.
In addition, “the diagnosis of an underlying disease may be particularly complex, as it involves several conditions,” the researchers wrote.
The nature of the underlying condition in secondary AIHA may also have an “impact on treatment choices and outcome,” even though most of secondary AIHAs “are excluded from clinical trials thus limiting treatment approach,” the researchers wrote.
CAD treatment generally focuses first and foremost on steps to minimize cold exposure, which can help prevent symptoms from becoming a problem. In more severe cases, immunosuppressive medications may be used to stop the production of disease-driving antibodies.
But while these therapies can be effective for controlling CAD, suppressing the immune system can also make patients vulnerable to infection.
This tradeoff was highlighted in one of the cases described in the study.
Woman’s case shows ‘pitfalls’
A 76-year-old woman was followed by an immunologist for five years due to a disease mimicking an autoimmune condition called scleroderma and associated also with anemia and Raynaud’s phenomenon. She received several immunosuppressive treatments, including steroids, azathioprine, and cyclophosphamide.
The woman was referred to a hematologist because markers of blood cell destruction were getting steadily worse without clear cause. A positive Coombs test and higher-than-normal levels of cold agglutinins ultimately led to a diagnosis of CAD.
At first, the patient’s CAD was assumed to be primary. She received a blood transfusion for her severe anemia, and started treatment with rituximab, a mainstay CAD treatment that works by depleting B-cells, the immune cells that make antibodies.
Rituximab was partly effective for managing the woman’s symptoms, but after a few months she again developed severe anemia and acrocyanosis, as well as dark urine — a sign of excessive blood cell destruction.
Further testing revealed a previously undetected blood cancer in the bone marrow, and her diagnosis was reclassified from primary CAD to secondary CAD.
Following the new diagnosis, the woman was given further rounds of treatment with rituximab in combination with the chemotherapy bendamustine. But after two months on these immunosuppressive therapies, she developed a severe fungal infection that ultimately proved to be fatal.
“This case highlights the pitfalls in the differential diagnosis between [primary and secondary CAD] and how disease [profile] may evolve over time,” the researchers wrote. “Additionally, it points at the infectious risk of prior and subsequent immunosuppressive treatments in elderly and frail CAD patients.”
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