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((more citations needed|date=January 2017))
((Infobox medical condition (new)
| name            = Transfusion-related acute lung injury
| synonyms        = TRALI
| image           = Hyaline membranes - very high mag.jpg
| caption         = [[Micrograph]] of [[diffuse alveolar damage]], the histologic correlate of TRALI; [[H&E stain]]
| pronounce       =
| field           = pulmonology
| symptoms        =
| complications   =
| onset           =
| duration        =
| types           =
| causes          =
| risks           =
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'''Transfusion-related acute lung injury''' ('''TRALI''') is the serious [[Complication (medicine)|complication]] of [[blood transfusion|transfusion]] of [[blood products]] that is characterized by the rapid onset of excess fluid in the [[lung]]s.<ref>((cite journal |last1=Gajic |first1=Ognjen |last2=Moore |first2=S. Breanndan |title=Transfusion-Related Acute Lung Injury |journal=Mayo Clinic Proceedings |volume=80 |issue=6 |pages=766–770 |year=2005 |pmid=15945528 |doi=10.1016/S0025-6196(11)61531-0 |doi-access=free ))</ref> It can cause dangerous drops in the supply of [[oxygen]] to body tissues. Although changes in transfusion practices have reduced the incidence of TRALI, it was the leading cause of transfusion-related deaths in the [[United States]] from fiscal year 2008 through fiscal year 2012.<ref>[[U.S. Food and Drug Administration]], Center for Biologics Evaluation and Research. [https://www.fda.gov/downloads/BiologicsBloodVaccines/SafetyAvailability/ReportaProblem/TransfusionDonationFatalities/UCM346856.pdf Fatalities Reported to FDA Following Blood Collection and Transfusion: Annual Summary for Fiscal Year 2012]. Bethesda, Md: U.S. Food and Drug Administration.</ref>

==Signs and symptoms==
It is often impossible to distinguish TRALI from [[acute respiratory distress syndrome]] (ARDS). The typical [[presentation (medical)|presentation]] of TRALI is the sudden development of [[shortness of breath]], severe [[hypoxemia]] (O<sub>2</sub> saturation <90% in room air), [[hypotension|low blood pressure]], and [[fever]] that develop within 6 hours after transfusion and usually resolve with supportive care within 48 to 96 hours. Although low blood pressure is considered one of the important signs for diagnosing TRALI, in some cases [[hypertension|high blood pressure]] can occur.<ref name=":0">((Cite journal |pmc = 3134874|year = 2009|last1 = Silliman|first1 = C. C.|title = Transfusion-related acute lung injury (TRALI): Current Concepts and Misconceptions|journal = Blood Reviews|volume = 23|issue = 6|pages = 245–255|last2 = Fung|first2 = Y. L.|last3 = Ball|first3 = J. B.|last4 = Khan|first4 = S. Y.|pmid = 19699017|doi = 10.1016/j.blre.2009.07.005))</ref>

Delayed TRALI occurs 6 to 72 hours after transfusion completion. It is associated with a higher rate of [[Mortality rate|mortality]].<ref>Cho MS, Modi P, Sharma S. Transfusion-related Acute Lung Injury. 2020 Jul 26. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan–. ((PMID|29939623))</ref>

==Cause==
The cause of TRALI is currently not fully understood. 80–85% of cases are thought to be [[immune system|immune]] mediated.<ref>((Cite web|url=https://professionaleducation.blood.ca/en/transfusion/publications/transfusion-related-acute-lung-injury-trali|title=Transfusion-related acute lung injury (TRALI)|website=Professional Education))</ref><ref name="muller_15894508">((cite journal |last1=Muller |first1=J.Y. |title=Le TRALI : du diagnostic à la prévention |trans-title=TRALI: from diagnosis to prevention |language=French |journal=Transfusion Clinique et Biologique |volume=12 |issue=2 |pages=95–102 |year=2005 |pmid=15894508 |id=((INIST|16924693)) |doi=10.1016/j.tracli.2005.04.007 ))</ref> [[Antibodies]] directed toward [[human leukocyte antigen]]s (HLA) or human [[neutrophil]] antigens (HNA) have been implicated, with transfused antibodies shown to bind antigens expressed on pulmonary endothelial cells to initiate acute inflammation in the lungs.<ref>((cite journal |last1=Cleary |first1=Simon J. |last2=Kwaan |first2=Nicholas |last3=Tian |first3=Jennifer J. |last4=Calabrese |first4=Daniel R. |last5=Mallavia |first5=Beñat |last6=Magnen |first6=Mélia |last7=Greenland |first7=John R. |last8=Urisman |first8=Anatoly |last9=Singer |first9=Jonathan P. |last10=Hays |first10=Steven R. |last11=Kukreja |first11=Jasleen |last12=Hay |first12=Ariel M. |last13=Howie |first13=Heather L. |last14=Toy |first14=Pearl |last15=Lowell |first15=Clifford A. |last16=Morrell |first16=Craig N. |last17=Zimring |first17=James C. |last18=Looney |first18=Mark R. |title=Complement activation on endothelium initiates antibody-mediated acute lung injury |journal=Journal of Clinical Investigation |date=5 October 2020 |volume=130 |issue=11 |pages=5909–5923 |doi=10.1172/JCI138136|pmid=32730229 |doi-access=free |pmc=7598054 ))</ref><ref>((cite journal |last1=Dykes |first1=A. |last2=Smallwood |first2=D. |last3=Kotsimbos |first3=T. |last4=Street |first4=A. |title=Transfusion-Related Acute Lung Injury (Trali) In A Patient With A Single Lung Transplant: Correspondence |journal=British Journal of Haematology |date=June 2000 |volume=109 |issue=3 |pages=674–676 |doi=10.1046/j.1365-2141.2000.01999.x|pmid=10886228 |s2cid=42922617 |doi-access=free ))</ref> Women who are [[multiparous]] (have carried more than one pregnancy to [[Fetal viability|viable gestational age]]) develop these antibodies through exposure to fetal blood; transfusion of blood components obtained from these donors is thought to carry a higher risk of inducing immune-mediated TRALI.<ref name=muller_15894508/> Previous transfusion or [[organ transplantation|transplantation]] can also lead to donor sensitization. To be at risk of TRALI via this mechanism, the blood recipient must [[gene expression|express]] the specific HLA or neutrophil receptors to which the implicated donor has formed antibodies. A two-hit hypothesis has been suggested<ref>((Cite journal|last=Silliman|first=Christopher C.|date=2006|title=The two-event model of transfusion-related acute lung injury|journal=Critical Care Medicine|volume=34|issue=5 Suppl|pages=S124–131|doi=10.1097/01.CCM.0000214292.62276.8E|issn=0090-3493|pmid=16617256|s2cid=36068011))</ref> wherein pre-existing pulmonary pathology (i.e., the first-hit) leads to localization of neutrophils to the pulmonary microvasculature. The second hit occurs when the aforementioned antibodies are transfused and attach to and activate neutrophils, leading to release of [[cytokine]]s and [[vasoactivity|vasoactive]] substances that induce non-cardiac [[pulmonary edema]].<ref>((cite book |last=Harmening |first=Denise |date=2019 |title=Modern Blood Banking & Transfusion Practices |location=Philadelphia |publisher=F.A. Davis Company |page=381 |isbn=9780803668881))</ref>

A proposed mechanism for non-antibody-mediated TRALI involves the accumulation of bioactive lipids in stored blood components ([[red blood cell|red cells]], [[platelets]], or [[blood plasma|plasma]]) that are capable of priming neutrophils.<ref name=":0" />

TRALI is typically associated with plasma products such as [[fresh frozen plasma]]. TRALI can also occur in recipients of [[packed red blood cells]], whether adult or pediatric patients.<ref name="pmid26126598">((cite journal |last1=Cudilo |first1=Elizabeth M. |last2=Varughese |first2=Anna M. |last3=Mahmoud |first3=Mohamed |last4=Carey |first4=Patricia M. |last5=Subramanyam |first5=Rajeev |last6=Lerman |first6=Jerrold |title=Case report of transfusion-related acute lung injury in a pediatric spine surgery patient transfused leukoreduced red blood cells |journal=Pediatric Anesthesia |volume=25 |issue=12 |pages=1294–7 |year=2015 |pmid=26126598 |doi=10.1111/pan.12696 |s2cid=5106831 ))</ref>  Due to the higher risk of TRALI resulting from donations by females, the [[AABB]] (formerly the American Association of Blood Banks) has recommended that those blood components with a high volume of plasma not be used for transfusion, but for further processing into other [[therapy|therapeutic]] products.<ref name=":1">Association Bulletin #14-02. TRALI Risk Mitigation for Plasma and Whole Blood for Allogeneic Transfusion. Bethesda: AABB; 1/29/2014</ref>

==Pathophysiology==
In TRALI, first-hit risk factors include long-term excessive alcohol use, shock, liver surgery, current smoking, higher peak airway pressure while undergoing mechanical ventilation, positive intravascular fluid balance, low levels of [[interleukin-10]], and systemic [[inflammation]]. Systemic inflammation may be reflected in the plasma cytokine profiles but also via increased levels of [[C-reactive protein]] (CRP), an [[acute-phase protein]] that rapidly increases during acute infections and inflammation and is widely used clinically as a [[biomarker]] of inflammation. CRP has been shown to be elevated in TRALI patients and, in a mouse [[model organism|model]], to functionally enable the first hit in the development of TRALI by increasing the accumulation in the lungs of a neutrophil [[homology (biology)|homologous]] to [[interleukin-8]]. Another factor that can predispose patients to TRALI is pre-existing lung injury, which causes white blood cells to localize in the lungs' blood vessels.<ref>Kleinman S, Kor DJ. “Transfusion-related acute lung injury (TRALI).” In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA. Last updated 5/11/17. Accessed via http://www.uptodate.com/contents/transfusion-related-acute-lung-injury-trali  on 6/28/17.</ref> The second hit in TRALI may be conveyed by anti-leukocyte antibodies or other factors present in the transfusion product. In approximately 80% of cases, anti-HLA class I or II or anti-HNA antibodies are implicated as involved in triggering TRALI, although that figure may be even higher depending on the detection methods used. In the remaining 20% of TRALI cases, non–antibody factors or biological response modifiers are suggested to contribute the second hit, and these may possibly include lipid mediators, [[extracellular vesicles]], and aged blood cells.<ref>((Cite journal|last1=Semple|first1=John W.|last2=Rebetz|first2=Johan|last3=Kapur|first3=Rick|date=April 25, 2019|title=Transfusion-associated circulatory overload and transfusion-related acute lung injury|journal=Blood|volume=133|issue=17|pages=1840–1853|doi=10.1182/blood-2018-10-860809|issn=1528-0020|pmid=30808638|doi-access=free))</ref>

==Diagnosis==
[[Image:Transfusion-related acute lung injury chest X-ray.gif|thumb|upright=1.5|[[Chest X-ray]] of transfusion-related acute lung injury (TRALI) compared to chest X-ray of the same person after treatment]]
TRALI is defined as an [[acute lung injury]] that is temporally related to a blood transfusion; specifically, it occurs within the first six hours following a transfusion.<ref>((cite journal |vauthors=Toy P, Popovsky MA, Abraham E, Ambruso DR, Holness LG, Kopko PM, McFarland JG, Nathens AB, Silliman CC, Stroncek D |title=Transfusion-related acute lung injury: definition and review |journal=Critical Care Medicine |volume=33 |issue=4 |pages=721–6 |year=2005 |pmid=15818095 |doi=10.1097/01.ccm.0000159849.94750.51))</ref>

It is typically associated with plasma components such as platelets and fresh frozen plasma, though cases have been reported with packed red blood cells since there is some residual plasma in the packed cells.<ref name=":1" /> Incidents have also been reported with other blood products including "[[cryoprecipitate]], [[granulocytes]], [[intravenous immune globulin]], [[allogeneic]] and [[autologous]] stem cells".<ref>Cho MS, Modi P, Sharma S. Transfusion-related Acute Lung Injury. 2020 Jul 26. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan–. ((PMID|29939623)).</ref>

It is a diagnosis upon examination of clinical manifestations that appear within 6 hours of transfusion, such as acute respiratory distress, tachypnea, hypotension, cyanosis, and dyspnea. TRALI is an uncommon syndrome, that is due to the presence of leukocyte antibodies in transfused plasma. It is believed to occur in approximately one in every 5000 transfusions.<ref name=":0" /> Leukoagglutination and pooling of granulocytes in the recipient's lungs may occur, with release of the contents of leukocyte granules, and resulting injury to cellular membranes, endothelial surfaces, and potentially to lung parenchyma. In most cases leukoagglutination results in mild dyspnea and pulmonary infiltrates within about 6 hours of transfusion, and spontaneously resolves.((citation needed|date=August 2016))

Occasionally more severe lung injury occurs as a result of this phenomenon and [[acute respiratory distress syndrome]] (ARDS) results. Leukocyte filters may prevent TRALI for those patients whose lung injury is due to leukoagglutination of the donor white blood cells, but because most TRALI is due to donor antibodies to leukocytes, filters are not helpful in TRALI prevention. Transfused plasma (from any component source) may also contain antibodies that cross-react with platelets in the recipient, producing usually mild forms of posttransfusion purpura or platelet aggregation after transfusion.((citation needed|date=August 2016))

Another nonspecific form of immunologic transfusion complication is mild to moderate immunosuppression consequent to transfusion. This effect of transfusion is not completely understood, but appears to be more common with cellular transfusion and may result in both desirable and undesirable effects. Mild immunosuppression may benefit organ transplant recipients and patients with autoimmune diseases; however, neonates and other already immunosuppressed hosts may be more vulnerable to infection, and cancer patients may possibly have worse outcomes postoperatively.((citation needed|date=August 2016))

==Treatment==
The mainstay of therapy in TRALI is [[supportive care]]. Oxygen supplementation is employed in all reported cases of TRALI, and 72% of patients require aggressive respiratory support.  To support blood pressure, intravenous administration of fluids, as well as [[vasopressor]]s, are essential. In treating TRALI, [[diuretic]]s are to be avoided, although they are [[indication (medicine)|indicated]] in the management of [[transfusion associated circulatory overload]]. [[Corticosteroid]]s can be beneficial.((citation needed|date=August 2016))

==Epidemiology==
The true incidence of TRALI is unknown because of the difficulty in making the diagnosis and because of underreporting. It is estimated to occur in 1:1300 to 1:5000 transfusions of plasma-containing products. TRALI is the leading reported cause of death related to transfusion in the United States; more than 20 cases were reported per year from 2003 to 2005.((citation needed|date=August 2016)) The immune mediated form of TRALI occurs approximately once every 5000 transfusions and has a mortality of 6–9%.<ref>((cite journal |last1=Bux |first1=J. |title=Transfusion-related acute lung injury (TRALI): a serious adverse event of blood transfusion |journal=Vox Sanguinis |volume=89 |issue=1 |pages=1–10 |year=2005 |pmid=15938734 |doi=10.1111/j.1423-0410.2005.00648.x |s2cid=26023653 |doi-access=free ))</ref>

==See also==
* [[Flash pulmonary edema]]

==References==
((reflist|2|refs=
))

== External links ==
* [https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/transfusion-related-acute-lung-injury-trali  Transfusion Related Acute Lung Injury] - US [[Food and Drug Administration]] (FDA).
* [https://web.archive.org/web/20060927164834/http://www.ashi-hla.org/publicationfiles/ASHI_Quarterly/28_2_2004/Neutrophil_Ag_Ab.pdf Neutrophil Antigens and Antibodies] - American Society of Histocompatibility and Immunogenetics.
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((transfusion medicine))

[[Category:Complications of surgical and medical care]]
[[Category:Intensive care medicine]]
[[Category:Lung disorders]]
[[Category:Transfusion reactions]]
[[Category:Transfusion medicine]]

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