Contributed by Andrew Freeman, MD and Lirong Qu, MD, PhDFINAL DIAGNOSIS
Cold agglutinin disease secondary to acute EBV infection
DISCUSSION
This patient's symptoms were due to cold agglutinin disease, a rare type of autoimmune hemolytic anemia, triggered by her acute EBV infection. Cold agglutinin disease (CAD) is a rare type of autoimmune hemolytic anemia (AIHA), accounting for approximately 16-32% of all cases of AIHA [1]. While CAD can be a primary disease, it may also be seen secondary to a variety of autoimmune disorders, lymphoproliferative disorders, or underlying infections, and is classically associated with mycoplasma pneumoniae or EBV infections [1-3]. Other rare causes of secondary CAD have been identified, including a recent case of COVID-19 vaccine associated CAD reported in Saudi Arabia [2]. CAD secondary to an underlying infection is often acute in onset and transient, while CAD secondary to malignancy is often chronic [1].
While the mechanism by which the autoantibody forms in CAD remains unknown, some hypotheses have been developed [1, 3]. In primary CAD, the hypothesis is that the autoantibody forms due to an underlying indolent clonal lymphoproliferative disorder, while in secondary CAD the autoantibody may arise from immune dysfunction, molecular mimicry, or infection related changes in antigenicity [1, 3]. Nonetheless, the pathophysiology of the underlying hemolytic anemia is well described. CAD is characterized by an underlying IgM autoantibody, often with specificity against the I or i red blood cell (RBC) antigen, that causes agglutination of RBCs at an optimal temperature of 3-4 °C [1, 3]. This cold reactivity is why this antibody is referred to as a cold agglutinin. Interestingly, seasonal patterns of hemolytic anemia have been described [3]. A recent study comparing CAD populations in 2 different climates found a four-fold higher prevalence and incidence of CAD in Norway compared to Northern Italy, where there is an average difference in climate by 7°C [3]. These autoantibodies can vary in the temperature at which they are active. To be considered clinically significant (i.e., capable of causing hemolysis and agglutination in vivo) the IgM autoantibody must be present at a significant titer and reactive at or near body temperature (>30C) [1, 3]. To determine this, a thermal amplitude test is performed where the patient's plasma (containing the cold agglutinin) and reagent RBCs are separately incubated at various temperatures between 4C to 37C, and then combined. The reaction is visually assessed for agglutination in vitro. Cold agglutinin titers are also performed to assess the concentration of antibody present [1].
Clinically significant cold agglutinins are capable of causing hemolysis (both intravascular and extravascular), as well as agglutination in vivo [1, 3]. Intravascular hemolysis is caused by the IgM autoantibody fixing complement to the surface of the RBC, leading to formation of the membrane attack complex via the classical complement cascade, which ultimately lyses the RBC [1]. Extravascular hemolysis occurs through opsonization of the RBCs by C3b complement protein leading to phagocytosis by macrophages of the reticuloendothelial system [1]. Agglutination can also occur in vivo, often in the cooler acral circulation of the fingers and toes, leading to symptoms of local ischemia [1, 3].
CAD can present with mild to potentially fatal hemolytic anemia, often worsened by cold exposure [1, 3]. Laboratory studies reflect the degree of hemolysis and may show elevated plasma free hemoglobin, lactate dehydrogenase, bilirubin, hemoglobinuria, and hemosiderinuria, as well as decreased haptoglobin [1]. Other tests that are useful in the diagnosis of CAD include the direct antiglobulin test (DAT) and peripheral blood smear, and in cases of primary CAD, bone marrow biopsy and flow cytometry [1, 2]. The DAT will show a positive reaction with C3, but not with IgG [1]. A peripheral blood smear will show the classic findings of agglutinated red blood cells, as seen in the images from this case above [1, 2]. Symptoms may include those typically seen in hemolytic anemia, including jaundice, dark urine, dyspnea, fatigue, lightheadedness, dizziness, and malaise [1, 2].
In milder cases of CAD, often the only treatment needed is avoiding exposure to cold environments to reduce triggering activation of the cold agglutinin [1]. More severe or chronic forms of CAD may require treatment with immune-modulating drugs and chemotherapy, such as rituximab, prednisone, fludarabine, chlorambucil, and cyclophosphamide [1, 3]. Optimal therapeutic regimens have yet to be identified and these medications come with both short and long-term risks that need to be considered [3]. Treatment of secondary CAD is focused on addressing the underlying associated disorder or infection [1]. Overall health maintenance and regular vaccinations are recommended in these patients, as infections may exacerbate CAD through increased complement protein production [1].
Patients with CAD may develop severe hemolytic anemia prompting a need for RBC transfusion. In CAD, the underlying IgM autoantibody will react at room temperature with the majority of reagent RBCs (due to the presence of the I/i antigen) and can complicate the blood bank's pretransfusion workup. For patients with CAD, the blood bank requires the use of "pre-warmed" reagents and samples to avoid interference by cold-reacting autoantibodies and to correctly identify any underlying RBC alloantibodies [1]. Identifying underlying RBC antibodies, and avoiding the corresponding antigens, is essential in order to avoid additional hemolysis and optimize the CAD patient's blood transfusion therapy. Pre-warmed RBC crossmatches may need to be performed depending on the thermal range of the autoantibody [1]. Additionally, it is very important to know the thermal range of the cold agglutinin in patients with CAD who are undergoing cardiac surgery. During cardiac surgery, the patient's body temperature is often dropped below 37°C during cold cardioplegia. Knowledge of the thermal range in these cases is essential for determining safe and appropriate decision making in the operating room. Other considerations during transfusion of patients with CAD, includes the use of blood warmers and warm blankets to avoid unnecessary cold exposures [1]. Close communication with the blood bank and transfusion medicine physician, when caring for a patient with CAD, is paramount to ensure safe and appropriate blood transfusion therapy.
REFERENCES
Contributed by Andrew Freeman, MD and Lirong Qu, MD, PhD
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