Stem cell transplantation and lung dysfunction.

PURPOSE OF REVIEW: To identify factors that impact the incidence and severity of lung dysfunction after haematopoietic stem cell transplantation (HSCT) for preventive and therapeutic purposes. RECENT FINDINGS: Respiratory failure from lung dysfunction after HSCT is a serious and often fatal transplant-related complication, but recent data reveal decreasing incidence and improving outcome over time. Idiopathic pneumonia syndrome (IPS) and bronchiolitis obliterans are now recognized as part of a spectrum of post-HSCT lung diseases involving both aspects of innate and adaptive immune responses, but may differ in the main lung structure affected: alveolar versus airway epithelium. There exists a strong association between acute graft-versus-host disease (GVHD) and IPS, and bronchiolitis obliterans is pathognomonic of chronic GVHD. Experimental models of IPS and bronchiolitis obliterans have proven useful to test strategies designed to limit lung injury including the effects of allogeneity, chemoradiotherapy and stem cell therapy. Recent advances in critical care practices, early diagnosis and utilizing ARDS Network ventilatory and conservative fluid management recommendations have also contributed to better outcome from lung dysfunction after HSCT. SUMMARY: Understanding the factors that contribute to post-HSCT lung injury should lead to safer transplant practices that will allow the broader use of HSCT for sicker children with comorbidities.

An official American Thoracic Society research statement: noninfectious lung injury after hematopoietic stem cell transplantation: idiopathic pneumonia syndrome.

RATIONALE: Acute lung dysfunction of noninfectious etiology, known as idiopathic pneumonia syndrome (IPS), is a severe complication following hematopoietic stem cell transplantation (HSCT). Several mouse models have been recently developed to determine the underlying causes of IPS. A cohesive interpretation of experimental data and their relationship to the findings of clinical research studies in humans is needed to better understand the basis for current and future clinical trials for the prevention/treatment of IPS. OBJECTIVES: Our goal was to perform a comprehensive review of the preclinical (i.e., murine models) and clinical research on IPS. METHODS: An ATS committee performed PubMed and OVID searches for published, peer-reviewed articles using the keywords "idiopathic pneumonia syndrome" or "lung injury" or "pulmonary complications" AND "bone marrow transplant" or "hematopoietic stem cell transplant." No specific inclusion or exclusion criteria were determined a priori for this review. MEASUREMENTS AND MAIN RESULTS: Experimental models that reproduce the various patterns of lung injury observed after HSCT have identified that both soluble and cellular inflammatory mediators contribute to the inflammation engendered during the development of IPS. To date, 10 preclinical murine models of the IPS spectrum have been established using various donor and host strain combinations used to study graft-versus-host disease (GVHD). This, as well as the demonstrated T cell dependency of IPS development in these models, supports the concept that the lung is a target of immune-mediated attack after HSCT. The most developed therapeutic strategy for IPS involves blocking TNF signaling with etanercept, which is currently being evaluated in clinical trials. CONCLUSIONS: IPS remains a frequently fatal complication that limits the broader use of allogeneic HSCT as a successful treatment modality. Faced with the clinical syndrome of IPS, one can categorize the disease entity with the appropriate tools, although cases of unclassifiable IPS will remain. Significant research efforts have resulted in a paradigm shift away from identifying noninfectious lung injury after HSCT solely as an idiopathic clinical syndrome and toward understanding IPS as a process involving aspects of both the adaptive and the innate immune response. Importantly, new laboratory insights are currently being translated to the clinic and will likely prove important to the development of future strategies to prevent or treat this serious disorder.

Impact of a Standardized Treatment Guideline for Pediatric Iatrogenic Opioid Dependence: A Quality Improvement Initiative.

OBJECTIVES: To determine whether utilization of a hospital-based clinical practice guideline for the care of pediatric iatrogenic opioid dependence (IOD) would promote a decrease in opioid exposure and improve management of opioid abstinence syndrome (AS). METHODS: This study is a retrospective chart review of critically ill patients from a tertiary care children's hospital. Inclusion criteria included mechanically ventilated patients up to 18 years of age who received continuous opioid infusions for at least 7 days and any length of methadone administration. Data on IOD patients from January 2005 to June 2010 was divided into 3 periods: baseline, phase 1, and phase 2. Primary outcome was decrease in opioid exposure, measured by methadone duration of use and any additional opioid bolus doses used in AS management. Documentation of additional opioid bolus doses was regarded as a surrogate measure of AS. Secondary outcomes included total cumulative fentanyl dose, continuous fentanyl infusion duration of use, and hospital and pediatric intensive care unit length of stay. RESULTS: There was a significant decrease in methadone duration of use in IOD patients from 15.3 ± 8.7 days at baseline to 9.5 ± 3.7 days during phase 1 (p = 0.002), to 8.1 ± 3.7 days on phase 2 (reduction not significant, p = 0.106) of this evaluation. Additional opioid bolus doses were significantly lower from baseline to phase 1 (5.5 ± 5.1 vs. 1.8 ± 2.3, p = 0.001) and from phase 1 to phase 2 (1.8 ± 2.3 vs. 0.2 ± 1.5, p = 0.003). For the remaining outcomes, differences were not observed among the evaluation periods, except for the total cumulative fentanyl dose, which was reduced from 2.8 ± 3.7 mg/kg at baseline to 1 ± 1 mg/kg only during phase 1 (p = 0.017). CONCLUSIONS: Introduction of a standardized, hospital-based clinical practice guideline for children with IOD reduced the length of exposure to opioids and improved opioid AS management.

Safety of inhaled nitric oxide after lung transplantation.

BACKGROUND: The present study tests the hypothesis that therapy with inhaled nitric oxide (iNO) at the time of lung transplantation in patients undergoing bilateral angle lung transplantation: (i) is safe; and (ii) does not increase either the duration of mechanical ventilation or the incidence of acute graft dysfunction. METHODS: We conducted a prospective, non-randomized trial of iNO at 20 parts per million. The treatment group was comprised of 14 patients (10 females, 4 males) undergoing lung transplantation to address severe end-stage lung disease and pulmonary hypertension (mean pulmonary artery pressure > 30 mmHg). Clinical and histologic parameters were compared with 22 historical control subjects who were matched with the study population for age, diagnosis and disease severity (17 females, 5 males) and had undergone lung transplantation in the preceding 2-year time period. No significant differences were noted between the 2 study groups at baseline. RESULTS: No toxic effect of iNO treatment was evident. Although the incidence of acute graft dysfunction was the same in both groups, the occurrence of acute graft rejection in the initial 4 weeks after transplant was less frequent in the iNO group than in the control group (7% vs 32%, p = 0.05). Fifty percent of the treatment group, as compared with 22% of the control group, were discharged from the hospital within 2 weeks of the procedure (p = 0.05). CONCLUSIONS: Early initiation of iNO in lung transplant patients with pulmonary hypertension is safe and may decrease the incidence of acute graft rejection. We speculate that iNO may exert an immunomodulatory effect.

Simultaneous absence of surfactant proteins A and D increases lung inflammation and injury after allogeneic HSCT in mice.

The relative contributions of the hydrophilic surfactant proteins (SP)-A and -D to early inflammatory responses associated with lung dysfunction after experimental allogeneic hematopoietic stem cell transplantation (HSCT) were investigated. We hypothesized that the absence of SP-A and SP-D would exaggerate allogeneic T cell-dependent inflammation and exacerbate lung injury. Wild-type, SP-D-deficient (SP-D(-/-)), and SP-A and -D double knockout (SP-A/D(-/-)) C57BL/6 mice were lethally conditioned with cyclophosphamide and total body irradiation and given allogeneic bone marrow plus donor spleen T cells, simulating clinical HSCT regimens. On day 7, after HSCT, permeability edema progressively increased in SP-D(-/-) and SP-A/D(-/-) mice. Allogeneic T cell-dependent inflammatory responses were also increased in SP-D(-/-) and SP-A/D(-/-) mice, but the altered mediators of inflammation were not identical. Compared with wild-type, bronchoalveolar lavage fluid (BALF) levels of nitrite plus nitrate, GM-CSF, and MCP-1, but not TNF-alpha and IFN-gamma, were higher in SP-D-deficient mice before and after HSCT. In SP-A/D(-/-) mice, day 7 post-HSCT BALF levels of TNF-alpha and IFN-gamma, in addition to nitrite plus nitrate and MCP-1, were higher compared with mice lacking SP-D alone. After HSCT, both SP-A and SP-D exhibited anti-inflammatory lung-protective functions that were not completely redundant in vivo.

Inflammatory cytokines and the development of pulmonary complications after allogeneic hematopoietic cell transplantation in patients with inherited metabolic storage disorders.

Patients with inherited metabolic storage disorders are at a higher risk of developing pulmonary complications after hematopoietic cell transplantation (HCT). This single-center prospective study of 48 consecutive inherited metabolic storage disorder patients was performed to identify risk factors for the development of pulmonary complications after HCT. Before HCT, subjects underwent bronchoalveolar lavage (BAL) for cell count, culture, nitrite levels, and analysis of proinflammatory cytokines and chemokines. The overall incidence of pulmonary complications was 52% (infectious, 23%; noninfectious, 29%) over a period of 4 years. Diffuse alveolar hemorrhage was the most frequent noninfectious complication and occurred in 19% of patients, all of whom had a diagnosis of mucopolysaccharidosis (Hurler and Maroteaux-Lamy syndromes). Levels of interleukin (IL)-1beta, IL-6, IL-8, tumor necrosis factor alpha, macrophage inflammatory protein 1alpha, and granulocyte colony-stimulating factor in BAL fluid samples obtained before HCT were higher in patients with mucopolysaccharidoses than in patients with leukodystrophies. In addition, levels of IL-1beta, IL-6, IL-8, and granulocyte colony-stimulating factor were increased in the BAL fluid of patients who developed noninfectious pulmonary complications compared with those who did not develop pulmonary complications. It is interesting to note that most noninfectious pulmonary complications occurred in patients with mucopolysaccharidoses, especially diffuse alveolar hemorrhage, which occurred exclusively in patients with mucopolysaccharidoses. Higher levels of bronchial proinflammatory cytokines and chemokines may be predictive of the development of subsequent posttransplantation noninfectious complications in patients with mucopolysaccharidoses, especially those with Hurler syndrome. Larger studies will be required to further elucidate etiologic mechanisms and predictive factors.

Absence of host tumor necrosis factor receptor 1 attenuates manifestations of idiopathic pneumonia syndrome.

The interaction of TNF-alpha with TNF receptor 1 (TNFR1) activates several signal transduction pathways that lead to apoptosis or NF-kappa B-dependent inflammation and immunity. We hypothesized that host TNFR1 expression contributes to noninfectious lung injury and inflammation commonly observed after bone marrow transplantation (BMT), termed idiopathic pneumonia syndrome (IPS). C57BL/6 TNFR1-sufficient (TNFR1(+/+)) and -deficient (TNFR1(-/-)) mice were total body irradiated with or without cyclophosphamide conditioning and were given bone marrow plus IPS-inducing donor spleen T cells from B10.BR wild-type mice. TNFR1(-/-) recipient mice exhibited improved early post-BMT survival associated with decreased permeability edema. In addition, the low lung compliance measured in anesthetized, ventilated TNFR1(+/+) mice on day 7 after BMT was restored to baseline during TNFR1 deficiency. Importantly, bronchoalveolar lavage fluid (BALF) inflammatory cells from TNFR1(-/-) vs. TNFR1(+/+) mice generated less nitric oxide (.NO) and nitrating species and exhibited suppressed programmed cell death as assessed using flow cytometry. However, cellular infiltration and levels of proinflammatory cytokines and chemokines were generally higher in BALF collected on day 7 after BMT from TNFR1(-/-) compared with TNFR1(+/+) recipient mice. Our results support a major role of host TNFR1 in regulation of .NO production and lung dysfunction after allogeneic BMT.

Natural history of pulmonary complications in children after bone marrow transplantation.

We sought, in children after bone marrow transplantation (BMT), (1) to determine the natural history and incidence of pulmonary complications, (2) to evaluate the diagnostic yield of fiberoptic bronchoscopy and bronchoalveolar lavage (BAL); and (3) to determine the effect of bronchoscopy with lavage on patient outcome. The study design was a retrospective review in a tertiary care university hospital of all children undergoing BMT over a 5-year period. Patients were separated into 2 study groups: children with and without pulmonary complications. Pulmonary complications were defined as new or persistent pulmonary infiltrates on chest radiograph or chest computed tomography scan, respiratory symptoms, hypoxemia, or hemoptysis. Three hundred sixty-three pediatric patients underwent BMT between January 1, 1995, and December 31, 1999. Ninety patients (25%) developed pulmonary complications and were evaluated with bronchoscopy and BAL. Patients with pulmonary complications had a higher mortality (65% versus 44%; P < .01). The median posttransplantation survival for children with pulmonary complications was 258 days, compared with 1572 days in patients without pulmonary complications. The incidence of pulmonary complications was increased in patients with allogeneic BMT (P < .01). The time-dependent onset of severe (grade III to IV) graft-versus-host disease increased the relative risk of pulmonary complications by 2.0 (95% confidence interval, 1.1-3.7; P = .02). Pulmonary complications increased the time-dependent relative risk of mortality by 3.5 (95% confidence interval, 2.5-4.8). The diagnostic yield of bronchoscopy with lavage was 46% in patients undergoing BAL. Diagnostic bronchoscopy did not enhance either 30- or 100-day survival. Pathogen identification did not decrease mortality (P = .45). Pulmonary complications occur in 25% of children undergoing BMT and increase the risk of death in the first year after BMT. Although pathogen identification does not confer a survival advantage, rigorous, prospective screening may allow for earlier identification of pathogens and thereby provide a benefit to this uniquely vulnerable population.

Exuberant inflammation in nicotinamide adenine dinucleotide phosphate-oxidase-deficient mice after allogeneic marrow transplantation.

We have shown that NO and superoxide (O-*2)contribute to donor T cell-dependent lung dysfunction after bone marrow transplantation (BMT) in mice. We hypothesized that inhibiting superoxide production during inducible NO synthase induction would suppress oxidative/nitrative stress and result in less severe lung injury. Irradiated mice lacking the phagocytic NADPH-oxidase (phox(-/-)), a contributor to superoxide generation, were conditioned with cyclophosphamide and given donor bone marrow in the presence or absence of inflammation-inducing allogeneic spleen T cells. On day 7 after allogeneic BMT, survival, weight loss, and indices of lung injury between phox(-/-) and wild-type mice were not different. However, the majority of macrophages/monocytes from phox(-/-) mice given donor T cells produced fewer oxidants and contained less nitrotyrosine than cells obtained from T cell-recipient wild-type mice. Importantly, suppressed oxidative stress was associated with marked infiltration of the lungs with inflammatory cells and was accompanied by increased bronchoalveolar lavage fluid levels of the chemoattractants monocyte chemoattractant protein-1 and macrophage-inflammatory protein-1alpha and impaired clearance of recombinant mouse macrophage-inflammatory protein-1beta from the circulation. Furthermore, cultured macrophages/monocytes from NADPH-deficient mice produced 3-fold more TNF-alpha compared with equal number of cells from NADPH-sufficient mice. The high NO production was not modified during NADPH-oxidase deficiency. We conclude that phox(-/-) mice exhibit enhanced pulmonary influx of inflammatory cells after BMT. Although NO may contribute to increased production of TNF-alpha in phox(-/-) mice, the data suggest that NADPH-oxidase-derived oxidants have a role in limiting inflammation and preventing lung cellular infiltration after allogeneic transplantation.

Surfactant protein A is a required mediator of keratinocyte growth factor after experimental marrow transplantation.

We reported an association between the ability of recombinant human keratinocyte growth factor (rHuKGF) to upregulate the expression of surfactant protein A (SP-A) and to downregulate pulmonary inflammation that occurs after allogeneic bone marrow transplantation (BMT). To establish a causal relationship, rHuKGF (5 mg/kg) was administered subcutaneously for three consecutive days before irradiation to SP-A-sufficient and -deficient [SP-A(+/+) and SP-A(-/-), respectively] mice given inflammation-inducing allogeneic spleen T cells at the time of BMT. In contrast with SP-A(+/+) mice, rHuKGF failed to suppress the high levels of TNF-alpha, IFN-gamma, and nitric oxide contained in bronchoalveolar lavage fluids collected on day 7 after BMT from SP-A(-/-) mice. Early post-BMT weight loss was attenuated by rHuKGF in both SP-A(+/+) and SP-A(-/-) recipients. In the absence of supportive respiratory care, however, SP-A deficiency eventually abolished the ability of rHuKGF to prevent weight loss and to improve survival monitored for 1 mo after allogeneic BMT. In further experiments, the addition of cyclophosphamide (which is known to cause severe injury to the alveolar epithelium in donor T cell-recipient mice) to the conditioning regimen prevented rHuKGF-induced upregulation of SP-A and suppression of lung inflammation in both SP-A(+/+) and SP-A(-/-) mice. We conclude that endogenous baseline SP-A levels and optimal upregulation of SP-A are required for the anti-inflammatory protective effects of KGF after allogeneic transplantation.

Surfactant protein A decreases lung injury and mortality after murine marrow transplantation.

Surfactant protein A (SP-A), a collectin associated with surfactant lipids, can have immune modulatory effects. We hypothesized that exogenous and basal endogenous SP-A can function to suppress donor T-cell-dependent inflammation that occurs during the generation of idiopathic pneumonia syndrome after bone marrow transplantation (BMT). Wild-type and SP-A-deficient mice were conditioned with cyclophosphamide and lethal irradiation and then given allogeneic donor bone marrow plus inflammation-inducing spleen T cells. On Day 7 after BMT, bronchoalveolar lavage fluids from SP-A-deficient mice contained increased numbers of inflammatory cells and higher levels of proinflammatory mediators tumor necrosis factor-alpha, interferon-gamma, and nitric oxide than wild-type mice. Exaggerated inflammation in SP-A-deficient mice was associated with decreased dynamic lung compliance and increased donor T-cell-dependent mortality (P = 0.0007, n = 10). Nitrative stress in alveolar macrophages from SP-A(-/-)-conditioned BMT recipients was higher than for SP-A(+/+) mice. Similarly, mice treated with transtracheal human SP-A (50 micro g), instilled on Day 4 after BMT during a time of in vivo donor T cell activation, exhibited decreased inflammation and improved early survival compared with buffer-instilled mice. We concluded that basal endogenous SP-A and enhanced alveolar SP-A level modulate donor T-cell-dependent immune responses and prolong survival after allogeneic BMT.

Myeloperoxidase deficiency enhances inflammation after allogeneic marrow transplantation.

Myeloperoxidase (MPO)-derived oxidants participate in the respiratory antimicrobial defense system but are also implicated in oxidant-mediated acute lung injury. We hypothesized that MPO contributes to lung injury commonly observed after bone marrow transplantation (BMT). MPO-sufficient (MPO+/+) and -deficient (MPO-/-) mice were given cyclophosphamide and lethally irradiated followed by infusion of inflammation-inducing donor spleen T cells at time of BMT. Despite suppressed generation of nitrative stress, MPO-/- recipient mice unexpectedly exhibited accelerated weight loss and increased markers of lung dysfunction compared with MPO+/+ mice. The increased lung injury during MPO deficiency was a result of donor T cell-dependent inflammatory responses because bronchoalveolar lavage fluids (BALF) from MPO-/- mice contained increased numbers of inflammatory cells and higher levels of the proinflammatory cytokine TNF-alpha and the monocyte chemoattractant protein-1 compared with wild-type mice. Enhanced inflammation in MPO-/- mice was associated with suppressed apoptosis of BALF inflammatory cells. The inflammatory process in MPO-/- recipients was also associated with enhanced necrosis of freshly isolated alveolar type II cells, critical for preventing capillary leak. We conclude that suppressed MPO-derived oxidative/nitrative stress is associated with enhanced lung inflammation and persistent alveolar epithelial injury.