Editorials

TRALI
A New Case Definition, a New Epidemic?
Transfusion-related acute lung injury (TRALI) represents acute
lung injury (ALI) after the transfusion of one or more plasmacontaining blood products and is now the leading cause of
transfusion-related morbidity and mortality (1). The incidence
of TRALI is frequently reported as 1 occurrence for every 5,000
blood component transfusions (2, 3); however, this is thought to
be a vast underestimate of the true incidence, resulting from
lack of recognition or underreporting. Two hypotheses have
emerged to explain the mechanisms responsible for TRALI.
One involves an interaction between passively transferred
donor human leukocyte antigen (HLA) antibodies and recipient HLA antigens (3, 4). The cognate antibodyantigen interaction leads to leukocyte activation and subsequent lung injury.
Alternatively, a two hit hypothesis has been proposed in
which biologically active substances, such as lysophosphatidylcholine species of bioactive lipids, accumulate in the red cells
as the blood is stored and are transfused passively (5). These
inflammatory lipids can subsequently induce neutrophil priming
capable of producing lung injury in the setting of systemic inflammation from another insult, such as trauma or sepsis (6, 7).
Despite its frequency and morbidity, we have an incomplete
understanding of the epidemiology and basic mechanisms of
TRALI. Like other critical illness syndromes, this is due, in part,
to unreliable and inconsistent definitions. Most TRALI studies
exclude cases in which another ALI risk factor is present. While
this is a justifiable decision, such a restrictive definition will prevent any evaluation of the two-hit hypothesis because patients
primed by systemic inflammation would be excluded. To address
the lack of a common TRALI definition, the National Heart,
Lung, and Blood Institutes Working Group on TRALI published a consensus definition in 2005 (8). According to this report, TRALI is now recognized as new-onset ALI occurring within
6 hours of transfusion of a plasma-containing blood product.
ALI is largely defined according to the 1994 ALI/ARDS North
AmericanEuropean consensus conference definition (9). Notably,
unlike the prior definition, the new consensus definition allows
for a possible diagnosis of TRALI if other classic ALI risks are
present yet the clinical setting makes TRALI likely.
In this issue of the Journal (pp. 886891), Gajic and coworkers (10) evaluated the incidence of TRALI among a cohort
of transfused medical intensive care unit (ICU) patients using
the 2005 TRALI definition to better understand the implications of this case definition. By using electronic surveillance
methods, coupled with a clinical expert review panel, they capture both suspected TRALI cases (with no identifiable preexisting ALI risk factor) and possible TRALI cases (with an
additional ALI clinical risk factor present). The authors report
74 new TRALI cases arising from 901 observed patients and
6,558 associated blood products (inclusive of packed red blood
cells, platelets, and fresh frozen plasma) transfused. This incidence is about 50 times higher than previous estimates. However, it is important to place this finding in context. This study

Am J Respir Crit Care Med Vol 176. pp 839842, 2007

Internet address: www.atsjournals.org

was conducted in a single-center medical ICU with a generous

proportion of patients having gastrointestinal (GI) and/or liver
disease. Of their TRALI cases, 62% had another ALI risk
factor, thus highlighting the close interaction between transfusion, classic ALI risk factors, and the subsequent development of ALI. This finding supports more contemporary epidemiologic studies indicating that transfusion of even a single unit
of blood to critically ill patients with other preexisting ALI risks
is independently associated with a greater risk of subsequent
ALI and death (11, 12). Although the TRALI definition allows
the investigators to explore the two-hit hypothesis, teasing out
the independent effect of blood products from the indications
for blood products, which may be multiple, in patients at risk for
ALI remains a challenge. The authors concede that potential
misclassification of cases (i.e., ALI brought on by the traditional
ALI risk factor and not transfusion) as well as some degree of
residual bias, including indication bias, may be present.
This study used a nested case-control design well suited to
evaluating the interaction between clinical and biologic factors
in patients as well as the donor blood products. The authors
perform a multivariable logistic regression analysis showing that
both specific clinical donor characteristics (donor gender and
parity) and blood product characteristics (HLA class II antibodies and bioactive lipids) have independent effects on the
development of ALI. This supports the notion that soluble
bioactive agents in the plasma compartment, comprising what is
collectively referred to as the storage lesion, are associated
with the development of TRALI. Interestingly, the age of blood
did not differ between cases and control subjects. Current data
support the idea that soluble bioactive agents, including inflammatory lipids, accumulate in the plasma compartment as blood
products are stored (5, 13, 14).
Observational data have linked the storage time of red cell
units with multiple organ failure, death, and other adverse
clinical outcomes (15). By analyzing the storage time as the
median duration of blood storage time, the authors may have
diluted the effect of one older blood unit on TRALI development among the several transfused. Furthermore, the phenomenon of transfusion-related immunomodulation (TRIM) might
predispose to infection, creating an associative link between
transfusion and ALI (through sepsis) (16). In a randomized
controlled trial of trauma patients, we found no advantage to
leukoreduction in preventing infection (17); however, other
biologically active modifiers in stored blood could be responsible for TRIM. Gajic and colleagues study does not provide
us with information to temporally link transfusions with the
development of sepsis, but sepsis was the most common risk
factor associated with ALI and might confound the relationship
between transfusion and lung injury. Finally, it is important to
point out that around 50% of the associated units in TRALI
cases and over 25% of the associated units in control subjects
did not have analyses for the stated potentially bioactive factors,
which could introduce bias into these biomarker estimates.
Gajic and colleagues have provided us with data that draw
attention to the frequency with which TRALI occurs in the
medical ICU. If the true incidence of this syndrome is even half
of that estimated by this study, the associated morbidity and

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mortality occurring in the more than 4 million estimated recipients of blood products each year is enormous. Future studies
should focus on other at-risk cohorts, including those with severe trauma, sepsis, and GI-related hemorrhage. These analyses
will serve to further confirm and define the epidemiology of this
syndrome and to establish the etiologic role of storage age, HLA
antibodies, bioactive lipids, and other potential components of
the storage lesion. In addition, the effect of alternative blood processing strategies, including red blood cell washing and targeted
donation based on gender and parity, need to be investigated.
Whether TRALI carries unique mechanisms of lung injury, setting it apart from those pathways responsible for ALI attributable to other risks, is unknown. This new case definition and the
resultant higher disease incidence will provide the impetus to
more thoroughly evaluate the relationship between transfusion
and lung injury.
Conflict of Interest Statement: Neither author has a financial relationship with a
commercial entity that has an interest in the subject of this manuscript.

TIMOTHY R. WATKINS, M.D.

University of Washington
and
Harborview Medical Center
Seattle, Washington
AVERY B. NATHENS, M.D.
University of Toronto
and
St. Michaels Hospital
Toronto, Ontario, Canada
References
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MA. Proceedings of a consensus conference: towards an understanding
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Podlosky L, Clarke G, Ambruso DR. Transfusion-related acute lung
injury: epidemiology and a prospective analysis of etiologic factors.
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in transfusion-related acute lung injury. Transfusion 1985;25:573577.
4. Kopko PM, Marshall CS, MacKenzie MR, Holland PV, Popovsky MA.
Transfusion-related acute lung injury: report of a clinical look-back
investigation. JAMA 2002;287:19681971.

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DOI: 10.1164/rccm.200708-1169ED

Them and Us
The Two Worlds of Tuberculosis?
On a sunny Friday last May, I left the Montreal Public Health
Department after a research meeting. As I stepped into my car,
I was summoned back for an urgent conference call with the
Public Health Agency of Canada. Montreal authorities had just
been alerted that a young man with suspected extensively drugresistant tuberculosis (TB) had landed from Prague at Montreals airport the previous afternoon, then rented a car and
crossed into New York State. Public health staff scrambled to
trace and screen passengers from the PragueMontreal flight.
Thanks to extensive media coverage, Andrew Speakers name,
face, and story came to symbolize TBs ability to cross borders
quickly and undetected (1).
Anyone involved in TB management or control needs no
reminder of the key role played by human movementacross

oceans, within rapidly industrializing countries, from war zones

to refugee camps. We see it in the composition and trajectories
of our patients, and in countless reports (2, 3).
The Norwegian study reported by Dahle and colleagues in
the current issue of the Journal (pp. 930935) is no exception
(4). From 1994 to 2005, Norwegian annual TB incidence increased 11%, from 5.6 to 6.2 cases per 100,000. By 2005, foreignborn individuals (7.9% of the population) accounted for 78% of
Norwegian TB casesversus 46% in 1994. This striking finding
reflected declining case numbers among Norwegian-born persons, a near-doubling of the foreign-born population, and increased incidence within this group.
The data suggest that the incidence of culture-positive disease decreased by over 50% among Norwegian-born individuals,