TRALI or Transfusion Related Acute Lung Injury is the most common cause of transfusion-associated death in the US. As a critical care physician, TRALI is a diagnosis we commonly consider but rarely diagnose and its pathogenesis befuddled me until now. Newly armed with new immunologic background I retackled the topic – and it is fascinating!
The clinical phenomenon
Within hours of receiving blood products, approximately one in 20,000-50,000 patients develops shortness of breath, low oxygen levels and a chest X ray with diffuse patchy consolidation (too much whiteness!). This is TRALI, a form of non-cardiogenic pulmonary edema (a life-threatening leak of fluid into the airspaces or alveoli.) Between 5-25% of patients with TRALI die as a consequence. TRALI can occur after transfusion with any product derived from blood (such as packed red cells, platelets, cryoglobulin) but risk is higher with products that contain greater proportions of plasma.
Why does TRALI occur?
TRALI appears to be due to due to donor antibodies to three major recipient leukocyte antigens. In up to 90% of cases donor antibodies to recipient MHC I, MHC II and human neutrophil antigens have been identified.
The proposed mechanisms are a bit different for each type of antigen:
• Anti-neutrophil antibodies – the donor antibody directly binds to antigen on the neutrophil surface. Activation of complement and release of neutrophil vasoactive peptides damages the pulmonary endothelium and leads to “capillary leak.”
• Anti-MHC I antibodies – the donor antibody is thought to bind to pulmonary endothelium. As neutrophils squeeze through the tiny pulmonary vessels, neutrophils bind via their Fc receptors and cross link.
• Anti-MHC II antibodies – this mechanism was a mystery until recently because neither endothelial cells nor neutrophils have MHC II! A recent article suggested the mechanism is indirect. Circulating monocytes (which do display MHC II) are activated by when bound by specific anti-MHC antibodies. The supernatant from these activated monocytes stimulates neutrophils to produce reactive oxygen species (ROS). The ROS produced by neutrophils disturbs the pulmonary endothelial barrier resulting in greater permeability and fluid leakage.
Is one hit alone sufficient?
The above mechanisms are pretty neat, but experimentally antileukocyte antibodies alone are not sufficient to result in TRALI. For rats to develop TRALI with infusion of antileukocyte antibodies, the pulmonary endothelium must first be “primed” with lipopolysaccharide (LPS) an intensely immunogenic component of the cell wall of gram negative bacteria. This experimental data is consistent with the observation that critically ill patients appear to be at greater risk of developing TRALI than otherwise healthy patients. Presumably critical illness is associated with pulmonary microvascular injury that provides the first hit. The transfusion of antileukocyte antibodies is the second hit.
But why would blood donors have anti-MCH or anti-neutrophil antibodies anyway?
Almost always the donor has been alloimmunized during pregnancy. In recent study of 5,000 US woman, alloimmunization rates were directly correlated with parity. Antileukocyte antigens were identifiable in 1.7% of nulliparous women but rose to 29.8% among woman with three or more pregnancies.
You feeling lucky?
The bad luck part comes in receiving a blood product from a donor who has been alloimmunized by a person who has MCH or neutrophil antigens that match yours. Recall that despite the fact that antileukocyte antibodies are relatively common, TRALI is rare because the antibodies only cause disease if there is a specific cognate antigen.
What can be done to prevent TRALI?
Traditionally, blood banks have attempted to identify donor who are “responsible” for TRALI and prevent them from donating again. This means that once TRALI has occurred, blood bank staff must investigate to identify the donor. The problem with this approach is that TRALI can be difficult to identify definitively as these patients often have other reasons for having diffuse lung problems.
A more effective strategy would be to use only male donors for plasma donation. The UK implemented this approach and reports of TRALI fell by 75%. The challenge is that this is one more restriction that compromises an already stretched blood supply.
Sachs UJ, et al Mechansim of transfusion-related acute lung injury induced by HLA class II antibodies. Blood 2010 [Epub ahead of print]
Triulzi DJ. Transfusion-related Acute Lung Injury: Current concepts for the clinician. Anesthesia and Analgesia. 2009; 108: 770-6.
Stafford-Smith M. Many, but not all, outcome studies support exclusion of female plasma from the blood supply. Expert Reviews in Hematology. 2010;3:551-8.
Wow, this is really interesting. TRALI sounds like a graft versus host disease, especially when the recipient is already immunologically compromised due to previous injury. However, I'm confused about a few points. If the donor antibodies are anti-neutrophil, anti-MHCI and anti-MHCII, then why isn't the whole body attacked? Why would TRALI present only in the lungs? Or does it present elsewhere too, and the most severe effects are lung-related? I'm going to assume that the donor antibodies are tissue specific, so if they only affect the lungs, then it sounds like Type II immunopathology because the actions of the antibodies are directed against a specific target tissue. However, it doesn't make sense to me that a mother would make antibodies to lung leukocytes, unless she is pregnant with a fetus that has pulmonary defects (for example leaky epithelium vessels), and so the mom is making specific antibody to the baby's normally sequestered antigens. Is this what's going on?
ReplyDeleteThanks for your comments! I think that there is a lot that is unknown about TRALI (hopefully this is not a cop-out!). I am going to reflect/speculate/confabulate about the points you raised…
ReplyDeleteAlthough I have not seen it described as such, it really makes sense that TRALI should be considered a graft versus host phenomenon.
Really interesting point you raise about why patients present with pulmonary symptoms. As you point out, the mechanisms should not be lung-specific if the antibodies are to leukocyte antigens. After all, every cell in the body has MHC-I. I went back to my articles looking for clues. Some observations:
• Patients become acutely systemically ill –in addition to their pulmonary symptoms, they become tachycardic and febrile and often hypotensive. They can also become acutely leukopenic, neutropenic, monocytopenic and hypocomplememic. So at least in this regard, TRALI is not “lung-limited” and the whole body may be responding.
• Agglutinated granulocytes become trapped in pulmonary microvasculature – this is the concept that sticky activated granulocytes become “stuck” in the tiny pulmonary vessels (so tiny that granulocytes have to squeeze to fit through them even when not activated. However, as you suggest, we don’t see disease manifestations in other microvascular beds like the kidney. So it seems to me that this mechanism should not explain the pulmonary specificity of TRALI.
• Injured pulmonary endothelium is reactive and “primed” - this concept suggests that critically ill patients have abnormal pulmonary endothelium and it may be this “second hit” that causes them to develop clinically apparent TRALI. This might sound like hand-waving but abnormal pulmonary endothelial biology is an extremely important issue in critical care. Altered endothelial cell responses are presumed to be the cause of the acute respiratory distress syndrome (ARDS) which is another non-cardiogenic diffuse pulmonary process (distinct from and much more common than TRALI) that occurs as a result of a variety of non-pulmonary illnesses (such as sepsis from a non-pulmonary organ).
• Large population of granulocytes marginated in pulmonary microvasculature – apparently granulocytes are “pre-positioned” in the pulmonary microvasculature, presumably waiting to respond to the multitude of potential pathogens we continually inhale. Perhaps it is this disproportionate population of granulocytes that leads to disproportionate injury to the lungs rather than other tissues?
So, although TRALI is not typically described as a systemic or “whole-body” process, it may be. It is possible that we focus on it as a pulmonary issue because the delicate pulmonary parenchyma is the easiest place to discern an acute change in vascular permeability. Perhaps the effects of TRALI in other tissues are non-specific or less easily recognizable in severely ill patients.
I just heard an interview on NPR with a military surgeon at a huge trauma center in Afghanistan. She mentioned that they had fewer complications with whole blood than with fractionated products in their severely injured patients. It wasn't clear why, but maybe people so injured need many things, not all of which we know about and which might not be present in just plasma, or packed RBC, etc.
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