Association of pulmonary function testing abnormalities and severe veno-occlusive disease of the liver after marrow transplantation

Abstract

Summary:We investigated an association between pulmonary function testing (PFT) before bone marrow transplantation and the development of severe veno-occlusive disease (VOD) of the liver. We previously noted that reductions in diffusing capacity of the lung for carbon monoxide (corrected for hemoglobin) (D L CO c ) were associated with mortality after transplantation, but this was not caused by respiratory failure. We performed a case-series review of prospectively collected data from 307 marrow recipients who underwent PFT within 2 weeks of transplantation. Of these, 170 (56%) developed VOD; 39 (13%) mild, 81 (26%) moderate, and 50 (16%) severe or fatal. Both total lung capacity (TLC) and D L CO c were associated with severe VOD in univariate analysis (P = 0.006 for each). However, D L CO c entered logistic regression models that contained variables for all known risk factors for severe VOD, while TLC did not contribute additional predictive information. The odds ratio (OR) associated with a D L CO c below the lower limits of normal (70% of predicted) was 2.4 (95% CI, 1.0 to 5.4; P = 0.04). We conclude that reduced diffusion capacity of the lung measured before marrow transplantation is an independent risk for severe hepatic VOD. We speculate that the decreased D L CO c indicates pre-existing systemic endothelial cell damage and a susceptibility to severe hepatic injury from chemotherapy. Keywords: bone marrow transplantation; hepatic venoocclusive disease; pulmonary function tests; diffusing capacity; risk factors Pulmonary function testing (PFT) is frequently performed before marrow transplantation.1-3 These results are used as a baseline for comparison with future studies, 4-6 and to predict development of respiratory complications. 7,8 Recent data from this center suggested that decreased diffusion capacity of the lung for carbon monoxide (corrected for hemoglobin) (D L CO c ), and an increased alveolar-arterial oxygen difference (P(A-a)O 2 ) before marrow transplan- tation are associated with an increased risk of death during the first 6 months after transplantation. Surprisingly, the D L CO c and the P(A-a)O 2 acted independently of each other as risk factors, suggesting that they indicate separate mechanisms leading to death.9 Furthermore, the increased incidence of death associated with a reduced D L CO c could not be accounted for by an increase in the incidence of respiratory failure.We therefore hypothesized that a reduced D L CO c may be associated with another common organ failure leading to death after marrow transplantation, such as severe venoocclusive disease (VOD) of the liver. We postulated that a decreased D L CO c measurement, which is influenced by capillary blood volume in the lung, could reflect systemic endothelial damage due to previous chemotherapy or irradiation. Therefore, the increased mortality associated with low D L CO c may be due to non-pulmonary complications related to further endothelial injury during the cytoreductive conditioning chemotherapy.Since VOD of the liver has be...

Hepatic veno-occlusive disease after hematopoietic stem cell transplantation: update on defibrotide and other current investigational therapies

“…3,[34][35][36] Recognized pretransplant risk factors for the development of VOD include older transplant recipient age, poor performance status, female gender, donor-recipient HLA disparity, advanced malignancy, prior abdominal radiation, second myeloablative transplant, reduced pulmonary diffusion capacity (DLCO) and prior liver disease including elevated AST prior to conditioning or preexisting cirrhosis. 3,34,37,38 In the pediatric literature, younger age at transplant (o6.5 years) also appears to be a risk factor for the development of hepatic VOD. 39 The type and intensity of the transplant conditioning regimen is probably the greatest determining factor of risk for developing severe VOD.…”

Pulmonary function testing prior to hematopoietic stem cell transplantation

“…In a slightly smaller study, Schwarer et al 60 found no significant association between Table 3 Previous studies that included pretransplant pulmonary function tests pretransplant lung function and the development of 'lateonset pulmonary syndrome,' defined as the presence of signs and symptoms of a respiratory illness associated with the development of abnormal PFTs with no evidence of an infectious etiology. An interesting study assessing the relationship between lung function abnormalities and severe veno-occlusive disease (VOD) of the liver after marrow transplantation was conducted by Matute-Bello et al 61 In a prospective study of 307 patients, they found that a pretransplant DL CO o70% of normally predicted was associated with a significant risk for developing VOD (OR 2.4, 95% CI 1.0-5.4; P ¼ 0.04), with the incidence of severe hepatic VOD being 36.4% among patients with a pretransplant DL CO o65% of predicted, compared to an incidence of 11.9% among patients with a pretransplant DL CO 465% of predicted (P ¼ 0.001). Studies from our group have been mainly focused on the development of AFO after HCT, which represents the most common noninfectious pulmonary complication after HCT.…”

The hemochromatosis C282Y allele: a risk factor for hepatic veno-occlusive disease after hematopoietic stem cell transplantation

“…The more frequent use of these regimens for allogeneic HSCT conditioning may explain why some (but not all) studies report a higher risk of HVOD in recipients of allogeneic as compared to autologous HSCT. [11][12][13] Nonmyeloablative regimens cause considerably less acute organ toxicity, but this benefit may be offset by higher disease relapse rates. 10,14 High-dose chemoradiotherapy rapidly depletes intracellular antioxidants and represents a significant oxidative challenge to the liver.…”