Case of severe CAD emphasizes importance of early diagnosis: Study
Woman, 57, had symptoms like bluish skin color, Raynaud's phenomenon
A middle-aged woman in Iran with a history of Raynaud’s phenomenon was found to have cold agglutinin disease (CAD) after developing blue-tinged skin, known medically as acrocyanosis, and other severe symptoms, according to a case report highlighting the importance of early diagnosis and treatment in CAD.
Raynaud’s phenomenon — when the body’s extremities become numb and/or discolored in response to cold — can occur as a CAD symptom. However, the cause of the symptom in this patient was not determined at the time she arrived at the hospital, the researchers noted.
The woman, 57, died five days after being hospitalized for her symptoms, which included acrocyanosis, a bluish discoloration of the skin, especially in the hands and feet.
The fact that the patient had been experiencing symptoms for two weeks before her admission, combined with the resulting delayed start of rituximab, a therapy commonly used off-label for CAD, may have contributed to her poor response and subsequent death, the researchers noted.
“Early identification [of CAD] through appropriate laboratory tests is crucial,” the investigators wrote. “In severe cases, prompt initiation of proper treatment is necessary to prevent fatal outcomes.”
The study, “A middle-aged woman with the initial symptom of acrocyanosis diagnosed with cold agglutinin disease: A case report,” was published in SAGE Open Medical Case Reports.
In CAD, self-reactive antibodies called cold agglutinins mistakenly bind to red blood cells at cold temperatures, causing them to clump together and ultimately be destroyed. Such red blood cell destruction is known as hemolysis, and often leads to anemia, or low counts of red blood cells, and fatigue. It also can lead to the formation of blood clots that can block vessels and cause acrocyanosis.
Another CAD symptom is Raynaud’s syndrome, in which blood vessels narrow when exposed to cold temperatures. This most commonly occurs in the fingers and toes, which turn pale, red, or blue, and become numb or develop a tingling sensation.
Woman had developed Raynaud’s phenomenon 2 years earlier
In this report, the researchers detailed the case of a woman who developed severe CAD after experiencing Raynaud’s phenomenon two years earlier.
The woman was referred to the hospital due to a lack of energy and jaundice, or a yellowing of the skin and the whites of the eyes. Jaundice can occur in CAD due to hemolysis and the associated buildup of a yellowish waste product, called bilirubin, in the body.
The patient had also been experiencing darkening of the urine, another potential symptom associated with high bilirubin levels, for two weeks, during which time she gradually developed acrocyanosis in the extremities and tip of her nose.
Additionally, the woman had a pale appearance and had netlike blue-to-purple discoloration of the skin on the arms and legs, the report noted. Her heart rate was higher than normal and she had slightly lower blood oxygen levels.
She reported a history of Raynaud’s phenomenon, and was found to have intermittent pallor, acrocyanosis, and redness of the extremities after exposure to cold temperatures or stress.
Blood tests performed before hospital admission indicated low levels of hemoglobin, the protein that carries oxygen in red blood cells, as well as elevated levels of lactate dehydrogenase (LDH) and bilirubin, two markers of hemolysis. The woman also tested positive on a direct Coombs test, which detects antibodies and/or other immune proteins bound to red blood cells.
Multiple tests needed to make CAD diagnosis, which delayed treatment
Based on lab results and her symptoms, the woman was diagnosed with autoimmune hemolytic anemia (AIHA), a group of autoimmune diseases that includes CAD and is marked by attacks on red blood cells.
She was admitted to the intensive care unit, and further tests, including for the presence of cold agglutinins, were conducted to understand the cause of her condition. Her blood also showed the clumping of red blood cells on a microscope.
In the meantime, the woman was given the corticosteroid methylprednisolone together with intravenous immunoglobulin (IVIG). Corticosteroids are a type of anti-inflammatory and immunosuppressive medication, while IVIG delivers healthy antibodies to neutralize the self-reactive antibodies that drive CAD.
However, the patient’s condition deteriorated, with worsening anemia and the development of shortness of breath. Her blood oxygen levels decreased even further. A warmed blood transfusion also did not ease her condition.
CAD is a chronic condition that can start with mild symptoms but lead to fatal complications, so early diagnosis is essential.
Results from blood tests on the third day of hospitalization showed high levels of cold agglutinins, confirming a CAD diagnosis. She was then started on rituximab, an antibody-based therapy that targets the immune cells that produce self-reactive antibodies. This medication is frequently used off-label in CAD, and is known to be more effective than corticosteroids in CAD.
The researchers planned to give rituximab once weekly for four to eight weeks. However, the woman’s breathing issues worsened and, on the fifth day of hospitalization, she experienced a cardiorespiratory arrest and died.
This case highlights the importance of quickly diagnosing CAD in patients, the researchers noted.
“CAD is a chronic condition that can start with mild symptoms but lead to fatal complications, so early diagnosis is essential,” the team wrote.
In addition to jaundice, “other factors indicating the severity of the disease in this patient include elevated levels of LDH and [bilirubin], contributing to a poor prognosis,” they added.
“One of the limitations of this case was the late administration of rituximab, given the AIHA diagnosis,” the team concluded. “However, the patient was initially admitted to another hospital and was referred to our facility on the second day of admission.”
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