Atypical symptoms, odd lab findings delay CAD diagnosis

67-year-old endures 10-year medical journey to diagnosis of cold agglutinin disease

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by Andrea Lobo |

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Atypical symptoms, including persistent blue discoloration and skin lesions in the extremities, along with uncommon laboratory findings, delayed a cold agglutinin disease (CAD) diagnosis for more than a decade in a 60-year-old woman, a study reports.

“This case adds important context to the difficulty in diagnosis of this disease,” the researchers wrote in the study “Cold agglutinin disease: A case report with atypical clinical findings,” which was published in the journal SAGE Open Medical Case Reports.

CAD occurs when the immune system produces self-reactive antibodies, called cold agglutinins, that wrongly bind to red blood cells at low temperatures, making them form clumps that mark them for destruction.

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The complement cascade, part of the immune system, is implicated in this process, and CAD patients show significantly low levels of the complement proteins C3 and C4.

Given that activation of either protein leads to their degradation into components that trigger the next protein in the complement pathway, low levels of these proteins usually are associated with complement system activation.

Red blood cell destruction, or hemolysis, leads to anemia, or a below-normal number of red blood cells, which may affect oxygen transport throughout the body. Other symptoms include fatigue, a bluish discoloration of the skin (acrocyanosis) and Raynaud’s phenomenon, which causes fingers and toes to feel numb in response to cold.

Now, a team of researchers at University of Kansas School of Medicine described the case of 60-year-old woman whose non-classical symptoms and laboratory findings delayed a CAD diagnosis for more than 10 years.

Patient’s early history

The woman went to an allergy and immunology clinic for further investigation due to chronic skin irritation.

She had been dealing with chronic symptoms for more than a decade, including acrocyanosis, mainly in her lower left extremity, with painful ulcers in her foot that limited her mobility.

She also had several other skin problems, such as redness, pimples, and visible blood vessels in the face (rosacea), easily-bruised skin, and Raynaud’s phenomenon. Cardiovascular and gastrointestinal problems, as well as high blood pressure, anxiety, and depression also were part of her medical history.

The woman had undergone extensive workups to identify the underlying cause of her symptoms, which failed to provide a definite diagnosis.

Previous laboratory tests showed normal levels of hemoglobin — the protein in red blood cells that transports oxygen — and of bilirubin, a marker of hemolysis.

In turn, her C4 levels were persistently lower-than-normal, which could suggest CAD. However, her atypical symptoms and absence of both a drop in hemoglobin levels and rise in bilirubin levels challenged a suspicion of CAD.

“The lack of diagnosis was due, in part, to her atypical symptoms and laboratory findings that required a high level of clinical suspicion to diagnose,” the researchers wrote.

The physician at the allergy and immunology clinic sent her to the emergency room due to worsening acrocyanosis, lack of a palpable pulse, and acute blood vessel inflammation in her left leg and foot.

Physical examination revealed normal blood pressure, normal respiratory and heart rate, and low oxygen saturation in the blood, with reduced pulse detected in her wrists and absent in her feet.

The woman also presented skin redness in the left leg/foot and both hands, acrocyanosis on the toes, and cold-to-touch extremities. She also reported fatigue, weakness, dizziness, muscle pain, and chronic headache.

Lab work did not support CAD diagnosis

Lab work was unremarkable, again showing normal levels of hemoglobin and bilirubin and absence of antibodies associated with other autoimmune diseases. However, she still showed low levels of C4, and on a previous hospitalization, an analysis of her blood had revealed red blood cell clumping.

Further testing for potential blood cancers and major circulatory problems came back negative. However, other tests showed severe damage to nerves relaying sensory and motor signals in her lower left extremity, as well as muscle atrophy (shrinkage), although without evidence of muscle disease.

After her discharge, follow-up laboratory tests indicated low C3 and C4 levels, and other signs of hemolysis, including higher-than-normal levels of the enzyme lactate dehydrogenase and low levels of the protein haptoglobin.

She also was positive for cold agglutinins and tested positive on a direct Coombs test that detects antibodies and complement proteins attached to red blood cells.

Coombs test leads to CAD diagnosis

Based on these results, the patient was diagnosed with CAD, and she initiated treatment with rituximab (sold as Rituxan and MabThera, with biosimilars available). The therapy, which works by killing antibody-producing immune B-cells, often is used as first-line treatment for CAD.

The treatment improved her levels of C3 and C4 proteins and showed signs of reduced hemolysis and lack of red blood cell clumping.

However, she still experienced persistent symptoms that did not fully resolve. A second line of treatment with bendamustine, along with other potential alternative treatments, was being considered.

“We present a unique case of CAD with atypical lab findings and difficult clinical presentation,” the researchers wrote.

“CAD should be considered in a patient with [low complement protein levels] and unexplained circulatory symptoms including Raynaud’s phenomenon and ulcerations,” they added.

Also, “treatment should be tailored to the underlying cause if identified,” the team wrote, adding that “more studies are needed to identify a clear treatment regimen for CAD.”