Transfusion‐associated adverse pulmonary sequelae: widening our perspective

In the daily practice of transfusion medicine, encountering a suspected adverse reaction in the administration of blood products is a well-appreciated frequent event. Although an abundant amount of literature (both primary and secondary sources) exists regarding this topic, much of the discussion and focus of investigations revolves around a “short list of the usual suspects” in the causation of such events. Owing to its significant morbidity and mortality and the historical origins of modern blood banking in serology, concern regarding hemolysis (whether immune or nonimmune) is usually the focus of an initial evaluation by the blood bank. Federal and state regulatory agencies and professional accreditation organizations have also shaped this approach with reporting requirements and procedures that spotlight hemolytic reactions. Increasingly, interest in a variety of nonhemolytic adverse occurrences associated with blood transfusion has become a focus of clinical research and discussion within the transfusion medicine community. In this context, transfusion-associated adverse pulmonary sequelae challenge traditional perspectives. Included in this spectrum of adverse occurrences are a variety of clinical entities, many of which lack any pathognomomic feature or definitive laboratory test to help transfusion medicine practitioners in their evaluation. Although their nosology awaits full clarification, their etiologic roots extend into both immunologic and nonimmunologic realms. The pulmonary compartment appears particularly sensitive to immunologic mediators.1-3 This observation may be due in large part to its content and distribution of the various cells of the innate and adaptive arms of the immune system, as well as trafficking of these cells from the peripheral circuit through the pulmonary space. Respiratory manifestations induced by allergic foreign plasma proteins can vary widely in severity ranging from mild discomfort to life-threatening anaphylactoid or anaphylactic presentations.4 The potential contributions of active biologic response modifiers to the disease process may be practically approached by targeted laboratory testing in the assessment of such transfusion reactions. Testing for select analytes, such as total IgE, IgA, and C3 and C4 complement protein levels, may be useful in this regard but there is no “right” way to make a laboratory diagnosis. Testing for other analytes of interest include levels of the two IgA subclasses, IgA1 and IgA2 as well as antibodies directed against them, various cytokine mediators, and activated forms of the C3 and C5 complement proteins. Although the differential diagnosis of transfusion complications involving the respiratory tree includes allergic and anaphylactic reactions, as well as intravascular hemolysis, bacterial contamination, and intercurrent illness, the most important diagnoses are transfusion-related acute lung injury (TRALI) and transfusion-associated circulatory overload (TACO). In most cases, these are readily distinguishable. In TRALI, moderate hypotension and low to normal pulmonary artery wedge pressure are prominent features.5 With TACO, hypertension (with widened pulse pressure), tachycardia, and elevated central venous and pulmonary artery wedge pressure are typical.6 There is overlap, however, between these two entities, which represents a challenge to the clinician. Most instances of TRALI occur within 2 hours of transfusion, a timeline approximating that of TACO. Onset of signs and symptoms, however, may be as late as 6 hours. Hypertension is found at the outset of up to 15 percent of TRALI cases. Finally, TRALI and TACO can occur in the same patient; one can precede the other or manifest concurrently. For all these reasons, TACO and TRALI can be either misdiagnosed or unrecognized. Although both circulatory overload and TRALI have been recognized as complications of hemotherapy for many years, both were formerly considered too uncommon to be important. The frequency of TRALI and TACO has not been firmly established. The reported incidence rates vary widely. As described recently by the Canadian TRALI Consensus Panel, differences in definition, methods of surveillance, and methods of tabulation of denominator data clearly influence the data for TRALI.5 The same can be said for TACO. In two multicenter, but retrospective, analyses of patients undergoing total knee or total hip replacement surgery, TACO was observed in 1 and 8 percent of cases, respectively.7,8 If these studies even approximate the true frequency, TACO has been severely underrecognized in routine settings. At one tertiary-care medical center that used nurses specifically trained to recognize transfusion reactions, Popovsky and Taswell9 found that 1 in 708 patients receiving red blood cell (RBC) products developed TACO. In the same report, 20 percent of the TACO cases involved single-unit RBC transfusion. These studies suggest that relatively small volumes of blood administered to an at-risk patient can trigger a life-threatening event. In reports to the FDA, circulatory overload is one of the most common causes of transfusion-associated mortality.10 In the Massachusetts Medicare study of orthopedic surgery transfusion recipients, TACO added to the length of stay and increased the intensiveness of care.7 Therefore, TACO increases morbidity and costs to the health-care system. Professional associations have highlighted TRALI and TACO and have encouraged surveillance for those events among other causes of noninfectious serious hazards of transfusion.11 In this context, the work by Zhou and colleageus12 in this issue of TRANSFUSION needs to be examined. These investigators used a rapid immunoassay for the cardiac marker B-natriuretic peptide (BNP) in their evaluation of patients with suspected transfusion reactions presenting with acute respiratory distress and/or other signs and symptoms suggestive of TACO. A member of a family of proteins involved in sodium excretion and fluid volume regulation, BNP is a cardiac-derived neurohormone synthesized and secreted from the ventricular myocardium in response to ventricular volume and pressure distension.13-15 This 32-amino-acid peptide with a molecular weight of 3472 Da is initially synthesized as a preprohormone that undergoes cleavage in the myocardial cells into its active form (BNP) and a biologically inert 76-amino-acid N-terminal fragment (NT-ProBNP). Originally identified in the central nervous system and termed brain-type natriuretic peptide, it was introduced into the clinical laboratory 4 years ago after the FDA approved its use as an aid in the evaluation of patients with dyspnea for the presence of congestive heart failure.15-17 In congestive failure, BNP levels are elevated. Since its entry into clinical medicine, off-label uses of the assay for BNP have expanded from its originally intended use into a number of areas. Such applications include evaluation of patients with acute coronary syndromes, prognostic assessment after myocardial infarction, and in the diagnosis of heart transplant rejection.18-20 The use of BNP as a diagnostic marker in the differential diagnosis of TACO is also a new area of inquiry for this assay. In the nested case-control study by Zhou and coworkers, the selection of a posttransfusion-to-pretransfusion BNP ratio of 1.5 as a cutoff point yielded a sensitivity of 81 percent and a specificity of 89 percent for the determination of TACO in the patients studied with an accuracy of 87 percent. Of the clinical data examined, only acute dyspnea, posttransfusion systolic blood pressure elevations greater than 30 mmHg, and elevated BNP were statistically different between the patients with TACO and the controls. As noted by the authors, high levels of BNP favor a TACO diagnosis. Such elevations, however, do not exclude other causes of transfusion associated adverse pulmonary sequelae because other conditions can coexist in the same patient. The value of BNP in the differentiation of TACO from TRALI remains an unsettled issue since no cases of TRALI were encountered in the authors’ cohort. Although we agree with the authors’ assessment of the adjunctive value of BNP along with clinical judgment in the evaluations of suspected cases of TACO, a relatively small number of patients were analyzed and the establishment of “reference intervals” for BNP in the uncomplicated transfusion setting needs further examination. Reference intervals for various patient subcategories, for example, pregnancy and coexisting pulmonary disorders, also need to be performed. Additionally, in light of work showing minimal baseline variations in mean vital sign values in patients undergoing uncomplicated transfusions, further examination correlating BNP levels with systolic BP measurements below the arbitrary limit of 30 mmHg selected by the authors may be of use in assessing TACO in less-obvious presentations.21 It is a sobering thought that in essence all transfusion reactions are iatrogenic in origin. The challenge for transfusion medicine is to improve diagnosis and treatment and ultimately to prevent these reactions. TACO falls into this category. Its significance has only recently been appreciated. Diagnostic strategies with analytes such as BNP integrated with a more refined clinical judgment will allow us to better understand and predict the impact of blood transfusions on our patients, especially those patients at high risk of complications.

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