The Development of Transfusion-Related Acute Lung Injury for the Second Time: A New Awareness for Daratumumab?

Abstract

Transfusion-related acute lung injury (TRALI) is an undesired and potentially fatal complication of blood transfusion. Besides human neutrophil and leukocyte antigens of the donor blood; especially for red blood cell transfusions, nonantibody-mediated mechanisms seem responsible. Among these patients, pulmonary neutrophils have increased sensitivity to initiate TRALI. It is a very rare event for a patient to develop a second reaction. Comorbid conditions such as kidney failure and cardiovascular diseases may pose a risk. Daratumumab, an anti-CD38 monoclonal antibody, seems unrelated because it only causes indirect Coombs positivity without triggering transfusion complications. However, its role in recipient–donor interactions causing TRALI is less clear. Here, we report a relapsed multiple myeloma-diagnosed patient who developed TRALI under daratumumab treatment.

Introduction

Transfusion-related acute lung injury (TRALI), which has been suggested to be associated with donor neutrophil and leukocyte antigens (human neutrophil antigen (HNA) and human leukocyte antigen (HLA), respectively) and nonantibody substances, is a potentially fatal complication of blood transfusion. ¹ The incidence varies 0.01 to 1.12% per product transfused and increases for critically ill patients. ² TRALI presents with the onset of acute respiratory distress (hypoxemia) within 6 h of a blood transfusion and demonstrates infiltrates on a frontal chest radiograph indicative of the presence of pulmonary edema. ³ Daratumumab is an immunoglobulin G₁ kappa monoclonal antibody directed against cluster of differentiation (CD) 38, which is overexpressed on multiple myeloma (MM) cells. ⁴ Here, we present a patient with relapsed MM who developed a second TRALI under daratumumab therapy.

Case Report

A 76-year-old male patient has been followed with MM diagnosis (lambda light chain) for 3 years. His blood type was O Rh (−). He had no comorbidity except coronary artery disease with a preserved ejection fraction. He was admitted to the clinic because of deterioration of kidney functions, attributed to myeloma relapse. His direct/indirect Coombs tests were negative. Daratumumab (16 mg/kg weekly) + dexamethasone therapy was initiated with close follow-up regarding any sign of cardiac failure. 1 day later, due to anemia (8.4 g/dL); 1 unit of packed red blood cell (RBC) transfusion with diuretics was performed, which elevated hemoglobin to 11 g/dL without any sign of hemolysis. Within 3 h, new-onset dyspnea was observed and endotracheal intubation was performed due to hypoxia. There were bilateral infiltrates on the chest radiograph (Figure 1). No sign of cardiac failure was observed; including hypertension, dilated neck veins, and S₃ gallop, or obvious response to diuretics. Body weight was monitored and no increase was detected. Also, no infectious/septic condition was present. TRALI type 1 was considered for the patient according to the updated criteria. ⁵ After supportive therapy including high-dose steroids, he was extubated within days and continued to antimyeloma therapy, which supplied benefit to his disease course and renal functions. The infiltration of the lungs was also regressed (Figure 2). Two-and-a-half months later, another RBC transfusion was required for the patient, and he received 1 unit of packed RBC from a different donor, which caused another respiratory collapse within 2 h. Endotracheal intubation was performed due to hypoxia, and bilateral pulmonary infiltrates were observed (Figure 3). Transfusion-associated circulatory overload (TACO) and other acute respiratory distress syndrome (ARDS) causes were eliminated as before and TRALI was diagnosed accordingly. ⁵ The patient benefitted from supportive therapy, which again included high-dose steroids (40 mg/day), and was discharged from the intensive care unit within days after extubation.

Figure 1.

Chest radiograph demonstrating bilateral pulmonary infiltrates after RBC transfusion (first TRALI).

Figure 2.

Chest radiograph demonstrating the regression of infiltrates after the first TRALI.

Figure 3.

Chest radiograph, again demonstrating bilateral pulmonary infiltrates (second TRALI).

Discussion

TRALI develops from activation of pulmonary endothelium of the host; which is triggered by HNA and HLAs of the donor's blood. Nonantibody-mediated mechanisms are also involved in the pathogenesis. ⁵ Hematological malignancies, especially leukemia and lymphoma, are reported to have more TRALI, due to a higher number of transfusions. ⁶ Data regarding MM and TRALI are limited, and to the best of our knowledge, this is the second case reported to have TRALI for the second time.^7-9 Daratumumab has no proven effects on the development of TRALI because its hematological adverse effects are limited with the detection of minor antigens and indirect Coombs positivity without causing any transfusion-related adverse events.^10,11 However, TRALI is generally associated with neutrophil/leukocyte antigens or nonantibody substances within the serum of the donor, not the recipient. However, it is assumed that fewer than 10% of TRALI cases are triggered by anti-HLA or anti-HNA antibodies in the patient's plasma (reverse TRALI). ¹² Other host-related factors might contribute to the susceptibility to develop a second TRALI reaction for our patient; such as advanced age, having a hematological malignancy, cardiovascular disease, and kidney failure, which can increase host pulmonary neutrophil sensitivity to recipient's HLA, HNA, or nonantibody substances. ² The role of the complement in TRALI has been investigated in models of antibody-mediated TRALI and daratumumab-induced complement activation may also have a role in the pathogenesis.^13,14 This activation is suggested to be increased by anti-major histocompatibility complex class I antibody “34 to 1-2S” (anti–H-2Kd), which is known to induce TRALI.^15-18 The presence of CD38 expression on pulmonary endothelial cells and its binding to CD31, another molecule highly expressed on endothelial cells, may represent another explanatory mechanism.^19,20 It is possible that soluble CD38 in the blood product binds to CD31 after transfusion.20 When the pulmonary endothelium couples with daratumumab, drug-mediated complement activation may trigger endothelial cell damage and thereby inducing a “reverse antibody-mediated” TRALI.^3,19 Also, daratumumab has been demonstrated to have a depleting effect on T-regulatory cells, increasing sensitivity to TRALI in mouse models.^21,22 In conclusion, daratumumab may contribute to the development of TRALI. These associations between the drug and TRALI should be clearly illustrated with further clinical trials to reduce TRALI and related mortality.