Impact of Primary Graft Failure on Outcomes Following Lung Transplantation

Christie, Jason D.; Sager, J.S.; Kimmel, Stephen E.; Ahya, Vivek N.; Gaughan, Christina; Blumenthal, Nancy P.; Kotloff, Robert M.

doi:10.1378/chest.127.1.161

Cited by 199 publications

(159 citation statements)

References 18 publications

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“…These findings are consistent with reported mortality rates and relative risks in single-center studies for the most severe forms of PGD, including our own (1,2,5). In addition, a recent ISHLT registry report describes PGD as accounting for greater than 30% of mortality in the first 30 days, according to listed cause of death (14,19).…”

Section: Discussionsupporting

confidence: 89%

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The Effect of Primary Graft Dysfunction on Survival after Lung Transplantation

Christie

Kotloff²,

Ahya³

et al. 2005

Am J Respir Crit Care Med

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302

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Rationale: Primary graft dysfunction is a severe acute lung injury syndrome after lung transplantation. Long-term outcomes of subjects with primary graft dysfunction have not been studied. Objectives: We sought to test the relationship of primary graft dysfunction with both short-and long-term mortality using a large registry. Methods: We used data collected on 5,262 patients in the United Network for Organ Sharing/International Society of Heart and Lung Transplantation registry between 1994 and 2000. We assessed outcomes in all subjects; to assess potential bias from the effects of early mortality, we also evaluated subjects who survived at least 1 year, using Cox proportional hazards models with time-varying covariates. Main Results: The overall incidence of primary graft dysfunction was 10.2% (95% confidence intervals [CI], 9.2, 10.9). The incidence did not vary by year over the period of observation (p ϭ 0.22). All-cause mortality at 30 days was 42.1% for primary graft dysfunction versus 6.1% in patients without graft dysfunction (relative risk ϭ 6.95; 95% CI, 5.98, 8.08; p Ͻ 0.001); among subjects who died by 30 days, 43.6% had primary graft dysfunction. Among patients surviving at least 1 year, those who had primary graft dysfunction had significantly worse survival over ensuing years (hazard ratio, 1.35; 95% CI, 1.07, 1.70; p ϭ 0.011). Adjustment for clinical variables including bronchiolitis obliterans syndrome did not change this relationship. Conclusion: Primary graft dysfunction contributes to nearly half of the short-term mortality after lung transplantation. Survivors of primary graft dysfunction have increased risk of death extending beyond the first post-transplant year.Keywords: acute lung injury; lung transplantation; outcomes; primary graft dysfunction; reperfusion injury Primary graft dysfunction (PGD), also known as primary graft failure, is a form of lung allograft ischemia-reperfusion injury (1, 2). Occurring in the first hours to days after transplantation, the clinical course and pathophysiology of the most severe forms are most similar to the acute respiratory distress syndrome (1,3,4). With an incidence reported between 10 and 25%, and a high mortality (5), PGD represents the leading cause of early death after transplantation (1, 2, 5-8).However, the long-term outcomes of PGD have not been (Received in original form September 20, 2004; accepted in final form March 3, 2005) Supported by grants NHLBI K23 HL04243 and the Craig and Elaine Dobbin Pulmonary Research Fund.Correspondence and requests for reprints should be addressed to

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Section: Discussionsupporting

confidence: 89%

“…systematically studied because of the low numbers of survivors at single centers (2,3,5). In one study, it was suggested that severe ischemia-reperfusion injury increases the risk of chronic rejection and long-term mortality (9); however, others have found no such relationship (3).…”

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confidence: 99%

The Effect of Primary Graft Dysfunction on Survival after Lung Transplantation

Christie

Kotloff²,

Ahya³

et al. 2005

Am J Respir Crit Care Med

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302

212

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“…In part, this is due to the high incidence (11-25%) of PGD, even in well-preserved ''ideal organs'' (23)(24)(25)(26). The use of the Pa O 2 /FI O 2 index, or P/F ratio, for assessing acute lung dysfunction from acute lung injury (index < 300) and adult respiratory distress syndrome (index < 200) is the accepted standard (27), and the use of the P/F ratio in assessing PGD has recently been established (23,28).…”

Section: Discussionmentioning

confidence: 99%

Th-17, Monokines, Collagen Type V, and Primary Graft Dysfunction in Lung Transplantation

Bobadilla¹,

Love²,

Jankowska‐Gan³

et al. 2008

Am J Respir Crit Care Med

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Rationale: The pathogenesis of primary graft dysfunction (PGD), a serious complication of lung transplantation, is poorly understood. Human studies and rodent models have shown that collagen type V (col [V]), stimulates IL-17-dependent cellular immunity after lung transplantation. Objectives: To determine whether patients with end-stage lung disease develop pretransplant col(V)-specific cellular immunity, and if so, the impact of this response on PGD. Methods: Trans-vivo delayed-type hypersensitivity (TV-DTH) assays were used to evaluate memory T-cell responses to col(V) in 55 patients awaiting lung transplantation. Pa O 2 /FI O 2 index data were used to assess PGD. Univariate risk factor analysis was performed to identify variables associated with PGD. Rats immunized with col(V) or irrelevant antigen underwent lung isografting to determine if prior anti-col(V) immunity triggers PGD in the absence of alloreactivity. Measurements and Main Results: We found that 58.8% (10/17) of patients with idiopathic pulmonary fibrosis, and 15.8% (6/38) of patients without idiopathic pulmonary fibrosis tested while on the wait list for a lung transplant were col(V) DTH positive. Col(V) reactivity was CD4 + T-cell and monocyte mediated, and dependent on IL-17, IL-1b, and tumor necrosis factor (TNF)-a. Pa O 2 /FI O 2 indices were impaired significantly 6-72 hours after transplantation in col(V)-reactive versus nonreactive patients. Univariate risk factor analysis identified only preoperative TV-DTH to col(V) and ischemic time as predictors of PGD. Finally, in a rat lung isograft model, col(V) sensitization resulted in significantly lower Pa O 2 /FI O 2 , increased local TNF-a and IL-1b production, and a moderate-to-severe bronchiolitis/ vasculitis when compared with control isografts. Conclusions: The data suggest that activation of innate immunity by col(V)-specific Th-17 memory cells represents a novel pathway to PGD after lung transplantation.Keywords: lung transplantation; primary graft dysfunction; collagen type V; autoimmunity; memory T cellThe historic paradigm of allograft failure due primarily to humoral and cell-mediated immune responses to foreign major histocompatability complex (MHC) antigens has recently been challenged by additional hypotheses (1-3). Although it is clear that immunity to donor human leukocyte antigen (HLA) serves a significant role in mediating allograft rejection, recent evidence suggests that self-antigens exposed during ischemiareperfusion injury may, under some circumstances, present an equal, if not greater, barrier to graft acceptance (4-6). In lung transplantation, one such cryptic self-antigen is collagen type-V (col[V]) (2). Col(V) is classified as a minor fibrillar collagen and, in the human lung, the ratio of matrix collagens is 86:28:8:1.6 (for collagens I, III, IV, and V, respectively) (7). Under normal physiologic conditions, col(V) coassembles into heterotypic fibrils with the major fibrillar collagen type I (8, 9). In fact, the majority of the col(V) monomer is normally partitioned ...

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“…Primary graft dysfunction, which can occur in up to 20% of patients, has been directly attributed to IR injury. (Christie, Sager et al 2005) In addition to this, the lungs are more readily affected by the abundance of fluids that are typically given in end of life situations. (Arcasoy and Kotloff 1999) Current thinking is that non-heart beating donors (NHBD) are ill suited for the harvesting of lungs due to the perceived damage that warm extended periods of ischemia would incur.…”

Section: Other Donor Factorsmentioning

confidence: 99%