Noninfectious Pulmonary Complication Research Articles

Airway Dilation in Bronchiolitis Obliterans After Allogeneic Hematopoietic Stem Cell Transplantation.

AbstractAbstract 3058 Rationale:Bronchiolitis obliterans syndrome (BOS) is a late, non-infectious pulmonary complication following hematopoietic stem cell transplantation (HSCT). The prevalence is estimated to be between 5–10% after allogeneic HSCT with a significant increase in morbidity and mortality. We were interested in assessing quantitative radiologic characterization of airway remodeling in these subjects. Objectives:To examine quantitative measurements of airway morphology and their correlation with lung function in a cohort of patients who underwent HSCT and developed BOS. Methods:All patients who underwent an allogeneic HSCT at the Dana-Farber Cancer Institute/Brigham and Women's Hospital (n=1854) between January 1st 2000 and June 30th2010 were screened for the development of BOS using modified NIH diagnostic criteria. Clinically acquired high resolution CT (HRCT) scans of the chest were collected. Discrete measures of airway wall area were performed in a total of 16 manually selected airways in the right and left upper and lower lobes using Airway Inspector (www.airwayinspector.org). From these measures, the square root of wall area of a 10-mm luminal perimeter (Pi10) was calculated. Spearman correlation was used to assess the relationship between square root of wall area at Pi10 and pulmonary function measures. Paired t-test was used for within group comparisons. Analyses were performed with SAS v. 9.2. Measurements and Main Results:Within our cohort 89 cases of BOS were identified of which 37 patients had HRCT scans available for analysis. 33 patients had pulmonary function tests within 30 days of the HRCT (Table 1). Ten of the 37 BOS patients had a HRCT scan at or prior to transplantation and a HRCT scan available after the diagnosis of BOS. Square root of wall area at Pi10 correlated significantly with FEV1(r = 0.636, p<0.0001), RV/TLC (r = −0.736, p< 0.0001) (Fig. 1), and when adjusted for age, sex and total lung capacity, the correlations remained significant (p<0.0001). There was a significant decline in square root of wall area at Pi10 in BOS cases compared to pre-transplant CT scans (p<0.001) (Fig 2). Conclusions:On HRCT scan BOS is characterized by central airway dilation, the degree of which is correlated to decrements in lung function. Future studies will examine whether chest CT assessment of central airway dilation can be used as a sensitive and specific tool for diagnosis and staging of BOS.Table 1Correlation coefficients (r Values) of the univariate regression analysis for square root of wall area at Pi10 with pulmonary function tests. FVC indicates forced vital capacity; FEV1, 1-second forced expiratory volume; FEF25–75 %, forced expiratory flow between 25–75%; VC, vital capacity; IC, inspiratory capacity; ERV, end residual volume; TLC, total lung capacity; RV, residual volume; DLCO,carbon monoxide diffusion capacityPFTr value<0.0001FVC %0.5460.001FEV1 %0.636<0.0001FEV1/FVC0.343NSFEF25–75 %0.5780.0004VC %0.5950.002IC %0.6020.002ERV %−0.353NSTLC %0.219NSRV %−0.5610.002RV/TLC %−0.736<0.0001DLCO %–0.175NS [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Low Dose Busulfan Is Associated with Bronchiolitis Obliterans Syndrome Following Allogeneic Hematopoietic Stem Cell Transplantation.

AbstractAbstract 3128 Rationale:Bronchiolitis obliterans syndrome (BOS) is the most common late non-infectious pulmonary complication following hematopoietic stem cell transplantation (HSCT). The prevalence is estimated to be between 5–10% after allogeneic HSCT with a significant increase in morbidity and mortality. We conducted a retrospective case control study to evaluate the associations between patients with BOS and those who did not develop airflow obstruction or symptoms. Methods:Between January 1st 2000 and June 30th 2010 all patients who underwent an allogeneic HSCT at the Dana-Farber Cancer Institute/Brigham and Women’s Hospital (n=1854) were screened for the development of BOS, using a modified NIH diagnostic criteria. BOS was defined as 1) new onset airflow obstruction, FEV1/FVC ratio ≤0.7 and FEV1 <80% predicted; 2) irreversible obstruction defined as no response to bronchodilator per ATS criteria; 3) if airflow obstruction was noted prior to HSCT, a ≥15% decline in FEV1 from baseline; 4) BO confirmed by pathology irrespective of meeting the spirometric definition of BOS. We matched the BOS cases, based on date of HSCT (±90 days), with 2 groups of control subjects: 1) subjects who developed chronic graft vs. host disease (cGVHD) without BOS and 2) subjects who developed neither cGVHD nor BOS. Comparisons between BOS subjects and controls were conducted using t-test or Fisher’s exact tests. We also performed a multivariate regression analysis predicting the development of BOS; all variables with a p <0.1 on univariate analysis were included in the model. All statistical analyses were performed using R. Results:We identified 89 subjects meeting our diagnostic criteria for BOS with a prevalence of 4.8%. The median time from transplantation to meeting criteria for BOS was 491 days (range: 48–2067). Univariate analysis demonstrated that BOS was significantly associated with previously reported risk factors including age, pre-transplantation PFT’s, high risk disease, source of peripheral blood stem cells, unrelated donor, history of respiratory infection prior to day 100, and busulfan based conditioning regimens. (all p<0.05, table 1). Upon further stratification of regimens, univariate analysis demonstrated that reduced intensity conditioning busulfan was associated with the development of BOS (p<0.001). After analyzing our univariate associations in a multivariate model, busulfan-based conditioning and unrelated donors were independent factors associated with BOS (p <0.001), while, ATG use conferred lower odds of BOS (p<0.001). Conclusion:Our findings extend those from prior reports of risk factors associated with BOS. Our results demonstrate that busulfan, even when used at lower doses in reduced intensity conditioning transplantation, confers an increased risk for BOS. Future studies in prospective cohorts will be important to confirm these findings. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Studying the association of plasma S100A12 and noninfectious pulmonary complication in infants and young children following cardiopulmonary bypass

Objective To examine the kinetics of plasma S100A12 and soluble receptor for advanced glycation end products (sRAGE) in infants and young children undergoing cardiopulmonary bypass ( CPB),and to investigate whether they could protective the occurrence of noninfectious pulmonary complication (NPC) after cardiac surgery.Methods This was a case-control study.The subjects included all children aged ＜3 years old who underwent cardiac surgery with CPB during the period from June 1st to July 31st 2011.The patient who showed pulmonary inflammation or had abnormal liver or renal function before surgery was excluded.The remain patients were divided into 2 groups according to whether they had developed NPC postoperatively.Twenty patients were grouped into NPC because they developed the complications of pleural effusion,chylothorax,partial lung collapse,pulmonary hypertensive crisis,airway disorders,pneumothorax,pneumomediastinum,or phrenic nerve palsy.Forty patients were categorized into the no-NPC group.Plasma concentrations of S100A12 and sRAGE were measured using ELISA at baseline,before CPB,immediately after CPB,1 h,12 h and 24 h after operation.Differences concentrations between two groups were analyzed with t test.A stepwise logistic regression analysis was used to indentify the independent risk factor for NPC.A P value ＜0.05 was considered statistically significant.Results Plasma levels of S100A12 and sRAGE dramatically increased immediately after CPB ( P ＜ 0.01 ).The levels of sRAGE dropped to lower than baseline level (P ＜0.05),while S100A12 was still at high level 24h after operation (P ＜0.01 ).Levels of S100A12 and sRAGE immediately after CPB in NPC group were significantly higher than the no-NPC group (P ＜ 0.05).Twenty-four hours after operation,levels of S100A12 were still higher in NPC group than no-NPC (P ＜ 0.01 ),while levels of sRAGE were similar in the two groups ( P ＞ 0.05 ).In the stepwise logistic regression analysis,plasma S100A12 level immediately after CPB remained as a independently predictor for postoperative NPC (OR =1.042,95％ CI:1.010 ～ 1.076,P =0.011 ).Levels of S100A12 immediately after CPB were positively associated with mechanical ventilation time ( r =0.47,P ＜ 0.01 ),duration of surgical Intensive Care Unit ( r =0.407,P =0.002) and hospital stay ( r =0.421,P =0.01 ).Conclusions Plasma levels of S100A12 and sRAGE were significantly increased immediately after CPB and the elevated plasma S100A12 immediately after CPB served as an early reliable biomarker of the occurrence and the prognosis of NPC after CPB in infants and young children. Key words: S100A12; Soluble advanced glycation end products (sRAGE); Noninfectious pulmonary complication (NPC) ; Cardiopulmonary bypass; cardiac surgery; Congenital heart disease; Infant and young children ; Case-control; Correlation.

Factors Associated With Prolonged Recovery After the Arterial Switch Operation for Transposition of the Great Arteries in Infants

This study aimed specifically to identify the predictors of prolonged recovery after the arterial switch operation for transposition of the great arteries in infants. The clinical records of all infants admitted to the surgical intensive care unit (SICU) between January 2000 and March 2011 after an arterial switch operation were retrospectively reviewed. The cohort was divided into a prolonged recovery group that included all patients who exceeded the 75th percentile for duration of SICU stay and a standard recovery group that included all the remaining patients. Of the 102 patients in the final analysis, 31 experienced prolonged recovery. The median SICU stay was 18 days (range, 14-58 days) for the patients in the prolonged recovery group and only 8 days (range, 5-13 days) for the patients in the standard recovery group. After univariate analysis, a stepwise logistic regression model analysis was used to compare the demographic data as well as the pre-, intra-, and postoperative variables between the two groups. Of all the variables analyzed, high postbypass serum lactate level [odds ratio (OR), 2.610; 95 % confidence interval (CI), 1.464-4.653; p = 0.039], need for larger volume of resuscitation fluid (OR, 3.154; 95 % CI, 1.751-5.682; p = 0.018), and noninfectious pulmonary complication (OR, 2.844; 95 % CI, 1.508-5.363; p = 0.025) were identified as independent risk factors for prolonged recovery among infants undergoing an arterial switch operation for transposition of the great arteries.

Engraftment Syndrome After Hematopoietic Stem Cell Transplantation

Engraftment syndrome is a noninfectious pulmonary complication after hematopoietic stem cell transplantation that represents a form of diffuse capillary leak associated with lung injury and pulmonary edema. The high-resolution computed tomography findings are interstitial edema and pleural effusions. A combination of clinical information and high-resolution computed tomography findings may help to confirm the diagnosis.

A Case of Acute Eosinophilic Pneumonia after Hematopoietic Stem Cell Transplantation

Pulmonary complications occur in 40~60% of patients who receive hematopoietic stem cell transplantation (HSCT) and are a source of substantial morbidity and mortality. Acute eosinophilic pneumonia (AEP) is an uncommon, non-infectious pulmonary complication occurring in HSCT recipients. We now report the case of a 52-year-old man with AEP who was treated with allogenic HSCT due to acute myeloid leukemia. He complained of fever, cough and dyspnea 390 days after allogenic HSCT. He also had skin and hepatic graft versus host disease (GVHD). Hypoxemia, diffuse pulmonary infiltrates on a chest x-ray and eosinophilia in bronchoalveolar lavage fluid were also noted in several tests. His symptoms, pulmonary infiltrates, hepatic dysfunction and skin lesions rapidly improved after treatment with corticosteroid therapy. Our case supports the idea that AEP is a late phase non-infectious pulmonary complication and one of the manifestations of chronic GVHD.

Bronchiolitis Obliterans Following Unrelated-Donor Allogeneic Hematopoietic Stem Cell Transplantation.

AbstractAbstract 4504Bronchiolitis obliterans (BO), occurring beyond 3 months after allogeneic hematopoietic stem cell transplantation (allo-HSCT), has been recognized as a late-onset noninfectious pulmonary complication associated with substantial morbidity and mortality. Some reports have described this complication with different incidence, associated risk factors, prognoses and therapeutic strategies. However, up to date, there is no unified understanding with respect to BO worldwide. In this study, we retrospectively analyzed the incidence, risk factors, clinical characteristics, management approaches and prognosis of BO among unrelated donor allo-HSCT recipients in our transplant center, aiming to improve cognition, reduce misdiagnose and dicrease motality in the future. Between June 2005 and May 2009, 117 patients underwent unrelated donor allo-HSCT while 98 patients who survived and were free of disease for more than 3 months after engraftment were enrolled. Myeloablative conditioning therapies for HLA-mathced transplant included busulfan-Cyclophosphamide (Bu-Cy) based regimens. In HLA-mismatched transplant, anti-thymocyte globulin (ATG) were added in addition to Bu-Cy based regimen. Patients were offered nonmyeloablative conditioning regimens when they were ineligible for myeloablative preparative regimens with fludarabine-based regimens including fludarabine, ATG and Bu. The diagnosis of BO was based on pulmonary function abnormalities, chest high-resolution CT (HRCT) findings and exclusion from respiratory infections. Management approaches for BO included immunosuppressive agents, azithromycin and symptomatic support. Some patients were further treated with etanercept (anti-tumour necrosis factor). In total 14 of the 98 patients (14.3%) developed BO at a median interval of 307.5 days post engraftment (range, 188–1316 days). Pulmonary function tests showed a decline in FEV1/FVC to a median interval of 0.51 (0.33-0.69) and FEV1 to 32% (17-46.2%) of predicted at BO diagnosis. Chest HRCT of BO patients showed areas of air trapping on expiratory views (71.4%), hyperinflation or bronchial dilatation (64.3%). All the 14 patients (100%) with BO complicated with chronic GVHD versus 41 of the 84 patients(48.6%) without BO (P<0.05). In total 1 of the 14 patients (7.1%) with BO underwent ATG-containing conditioning regimen versus 30 of 84 patients (35.7%) without BO (P<0.05). Multivariate analysis showed that primary disease type, donor and recipient's sex or age, stem cell type, myeloablative or nonmyeloablative conditioning regimen, aGVHD complication and HLA-disparities were not associated with the incidence of BO statistically. The prognoses of most BO patients were poor. In total only 4 of the 14 patients got improved and 3 were stable due to treatment while 2 were progressive and 5 (35.7%) died. Pulmonary failure was the leading cause of death for BO patients. In non-BO group, 23 of the 84 patients (28.6%) died, with a non-relapse mortality of 15.5% and infection became the leading cause of death. The non-relapse mortality in BO patients was higher than that in non-BO patients although there was no statistical significance (P>0.05). In all, our results demonstrated that chronic GVHD and conditioning regimen containing ATG, but not others which had been reported to be related with BO, were two risk factors associated with BO and the prognosis was extremely poor. More clinical trials and basic researches should be carried out to allow prospective identification of patients at greatest risk and early new therapeutic intervention to finally improve the survival of patients in this group. Disclosures:No relevant conflicts of interest to declare.

Life-Threatening Complications Suspected Due to Clinical Pharmacokinetic Interaction Between Cyclosporine A and Triazole Antifungal Agents in Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT) Recipients.

Abstract 4319 BackgroundIt is well documented that the co-medication with the triazole antifungal agents is associated with a flattening of the CSA blood concentration profile via the cytochrome P450 3A4 dependent metabolic pathway in allogeneic hematopoietic stem cell transplantation (allo-HSCT). Then it raises the question if the therapeutic monitoring of CsA trough levels is sufficient enough to reflect the drug exposure and to assess the transplant-related complications such as transplant rejection and drug toxicity. ObjectivesTo evaluate the tolerability, toxicity and clinical outcome of the co-administration of CSA and triazole antifungal agents in allo-HSCT recipients. Patients and methodsA retrospective review of the medical records of 104 consecutive patients undergoing allo-HSCT for hematologic malignancies at our transplant center over past 5 years was conducted. The causality of administration of CSA in combination with triazole in 12 cases with life-threatening complications experiencing supratherapeutic trough levels of CSA were identified and analyzed. ResultsIn all these 12 patients, the CSA trough levels remained highly than therapeutic range even after gradual tapering of CSA dosage. Shortly after the engraftment, 6 patients (50 %) developed acute graft-versus-host disease (aGVHD) and non-infectious pulmonary complication, and 2 patient (16.66 %) acute graft rejection. Which indicates the trough plasma concentration might be inadequately reflect CSA absorption profile. Whereas, 4 (33.33 %) patients were evaluated with neurological complications, 1 (8.33%) patient cardiovascular complication accompanied by acute renal failure and liver dysfunction, that might be ascribed to CSA-related adverse effects. 10 (83.33 %) out of the 12 patients eventually died, 2 (16.66 %) patient are still alive after graft rejecting. The major causes of death were GVHD related pulmonary injury with fungi infection ConclusionAlthough preemptive CSA dosage reduction and the close monitoring of its whole blood trough levels may minimize the drug-toxicity when co-administration with triazole antifungal agents, the different clinical spectrum and different disease evolution post transplant in this group warn that in the set of hematopoietic cell transplantation with CSA as immunosuppression agent the individual variables influence the drug-exposure and drug-toxicity. Thereof, as clinicians we should not be mislead by trough plasma concentrations as a routine therapeutic drug monitoring in terms of CSA exposure related efficacy or toxicity, especially when CSA in combination with triazole. Disclosures:No relevant conflicts of interest to declare.

Living-donor single lobe lung transplantation for bronchiolitis obliterans from mother to child following previous allogeneic hematopoietic stem cell transplantation from the same donor

Bronchiolitis obliterans (BO) is a late-onset noninfectious pulmonary complication that may occur 3 to 15 months following allogeneic hematopoietic stem cell transplantation (HSCT) [1, 2]. The incidence of BO following allogeneic HSCT is estimated at 1.7–19.4% [1–3] and the mortality rate varies from 14 to 100% [2]. While chronic graft-versus-host disease (GVHD) is thought to play an important role in the development of BO in the recipients, the other nonimmunologic factors, which include the conditioning regimen, viral pneumonitis and the use of immunosuppressive medications, are also potentially involved [1, 4]. Only 16–49% of BO patients showed improvement after administering immunosuppressive agents such as methylprednisolone, prednisolone, cyclosporine (CsA), tacrolimus, antithymocyte globulin and azathioprine [1, 2, 4]. At present, there is no established standard therapy for BO. We report a successful case of living-donor lobar lung transplantation (LDLLT) for therapy-resistant BO after allogeneic HSCT from the same donor. A 4-year-old boy was diagnosed as having B-cell precursor acute lymphoblastic leukemia. He was treated with combination chemotherapy and remained in complete remission after 2 years of chemotherapy. However, he developed a relapse 14 months after the completion of therapy, at age 7 years. He underwent bone marrow transplantation (BMT) from his HLA serotype-matched and blood type-matched mother at age 8 years. Genomic HLA typing was not performed. The conditioning regimen consisted of total body irradiation (12 Gy), etoposide (60 mg/kg), and cyclophosphamide (60 mg/kg 92). GVHD prophylaxis consisted of CsA and short-term methotrexate. Engraftment (absolute neutrophil count [500/ll) occurred on day 17. Acute grade IV GVHD, which affected the skin (stage 4) and liver (stage 1), developed on day 31. Treatment was initiated with prednisolone (1 mg/kg/day) in addition to CsA for 43 days with complete resolution of clinical GVHD. Chronic GVHD of the liver and gastrointestinal involvement evolved around day 180 and was confirmed by biopsy. Those symptoms improved with an increase in the CsA dosage. Around day 300, he began complaining of wheezing and dyspnea, which gradually worsened. Therefore, prednisolone (2 mg/ kg/day) was initiated in addition to CsA again, believing the cause was pulmonary GVHD. Thereafter, cyclosporine was replaced with tacrolimus on day 351 because he developed cyclosporine encephalopathy. He also developed several episodes of severe spontaneous pneumothorax, cutaneous and mediastinal emphysema and asthmatic attack requiring mechanical ventilation. Home oxygen therapy was started 2 years and 10 months after BMT. His respiratory distress continued to deteriorate and he developed hypercapnia resulting in respiratory failure 4 years and 7 months after BMT. A request for lung transplantation was raised by the family and the ethical problems were fully discussed. The patient (13 years old, height: 125 cm, weight: 16.4 kg) was considered a candidate for LDLLT, because he could not wait for a cadaveric lung graft, due to K. Oshima (&) A. Kikuchi S. Mochizuki R. Hanada Division of Hematology/Oncology, Saitama Children’s Medical Center, 2100 Magome, Iwatsuki-ku, Saitama 339-8551, Japan e-mail: oshima-k@umin.ac.jp

Infliximab Induced Lung Disease

Purpose: To discuss a non infectious pulmonary complication of infliximab therapy. Methods: A 51 year old woman with a 10 year history of ulcerative colitis previously treated with oral and rectal mesalamine, 6-mercaptopurine, and tapering courses of oral steroids presented with dyspnea on exertion. Because of steroid induced diabetes and intolerance to 6-mercaptopurine she was begun on a scheduled regimen of infliximab. She had a negative PPD and chest x-ray prior to initiating treatment. Her colitis improved, but after receiving a total of 5 doses she developed pleuritic chest pain and exertional dyspnea. Her previous unlimited exercise tolerance had decreased to 1 block. She denied cough, fever, chills, hemoptysis, or night sweats. Results: Physical examination was significant for an oxygen saturation of 98% on room air and bibasilar crackles. A CT of the chest demonstrated bibasilar consolidative appearance with multifocal patchy airspace opacities. Laboratory evaluation included a white blood cell count of 10 K/uL. Urine specimen was negative for Legionella pneumophila. Bronchoscopy with bronchoalveolar-lavage (BAL) was performed. Specimens were negative for malignant cells, mycobacterium, fungal organisms and pneumocystis pneumonia. Transbronchial biopsy demonstrated a mixed interstitial inflammatory cell infiltrate without significant supervening chronic changes in concert with striking depositis of IgM, IgA, and components of complement activation within the subsegmental bronchus. This was felt to be compatible with an underlying lupus like autoimmune diathesis. Staining of inflammatory cells and bronchial epithelial cells for all classes of immunoglobulin were indicative of a positive antinuclear antibody. The patient's serum was negative for antinuclear antibodies and double stranded DNA antibody. It was thought that the lung disease was secondary to drug induced obliterative bronchiolitis. Infliximab therapy was stopped but mesalamine was continued. The patient had gradual resolution of dyspnea and radiographic improvement. Conclusion: Infliximab is a chimeric monoclonal antibody to tumor necrosis factor alpha that is used in gastroenterology for the induction and maintenance of remission in inflammatory bowel disease. Because of its immunosuppressive effects, the Food and Drug Administration has placed a black-box warning regarding the risk of serious and potentially fatal infections. A transbronchial biopsy and BAL ruled out infectious agents as the cause of her pulmonary dysfunction. The subacute presentation along with the radiographic picture and histology are typical of drug induced lung disease. This case demonstrates a non-infectious pulmonary complication infliximab therapy.

Non-Infectious Pulmonary Complication after Stem Cell Transplantation and Genetic Background

Non-infectious pulmonary dysfunction (NIPD) represents a common and often fatal complication of hematopoietic stem cell transplantation (HSCT). We have investigated genetic polymorphisms of some candidate genes and compared the frequency of developing NIPD with the allele frequency. Especially, we have reported ACE gene polymorphism was associated with NIPD. Recently, one report among Caucasian revealed that bactericidal/permeability-increasing (BPI) haplotypes were associated with increased risk of developing pulmonary dysfunction after HSCT. In order to certify the relationship between BPI and pulmonary dysfunction in the above ethnic group, we performed Japanese cohort study. We retrospectively analyzed the incidence of NIPD and genotype and allele frequency of BPI polymorphism in 124 Japanese patients who underwent HSCT from HLA-identical sibling donors at Japanese Red Cross Nagoya first Hospital. These patients received T cell replete transplantation with short-term methotrexate and cyclosporine as a GVHD prophylaxis. Informed consent was obtained from all patients and donors, and this study was approved by the ethics committees at Tokai University School of Medicine and Japanese Red Cross Nagoya First Hospital. We investigated TNFa (−308G/A), IL-8 (−251A/T), IL10 (−592C/A, −819C/T, −1082A/G), MMP9 (−1562C/T), insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) and BPI single nucleotide polymorphisms (rs5741798, rs1934917, rs5743530, rs2275954), by using RFLP and/or the TaqMan® method. Because there are many difference in allele frequency between Caucasian and Japanese, we selected two BPI SNPs which were not investigated in the last report (rs1934917, rs5743530). According to the International HapMap Project data, we could consider these new SNPs as tagSNPs among Japanese population. NIPD occurred in 21 patients (19.3%). In the patient group, the allele frequencies of rs1934917 and rs5743530 were significantly different in the patients with and without NIPD (allele T 83.3% vs 67.8%; P=0.04; 95% CI, 0.3–1.0 and allele C 70.0% vs 51,4%; P=0.03; 95% CI, 1.1–1.7, respectively). In the donors, the C allele of rs5743530 was more frequent in the NIPD group with NIPD than in the group without NIPD (67.5% vs 49.0%; P=0.03; 95% CI, 1.1–1.8). On the other hand, patients who had ACE DD genotype were significantly high frequency of NIPD group (genotype DD 42.9% vs 11.8%; P=0.0006; 95% CI, 1.8–7.5). No significant relationships were noted between the other genes polymorphisms and the development of NIPD. Although the SNPs in BPI associated with NIPD in Caucasian population did not reach statistical significance in this Japanese cohort study, the other two SNPs did. These findings suggest that the BPI may be associated with the development of NIPD in both the two ethnic groups. But in Japanese population study, ACE gene polymorphism may have more strong impact for developing NIPD.

Non-Infectious Bronchiolitis as an Early Pulmonary Complication of Hematopoietic Stem Cell Transplantation

Pulmonary complications occur in up to 60% of patients after hematopoietic stem cell transplantation (HSCT), causing significant morbidity and mortality. Among them, non-infectious bronchiolitis is considered a late complication in the form of bronchiolitis obliterans. We report a patient who developed non-infectious bronchiolitis within four weeks after undergoing HSCT for biphenotypic leukemia. Chest CT revealed centrilobular nodules that were reminiscent of diffuse panbronchiolitis, and lymphocytic bronchiolitis was confirmed by biopsy. Infection and bronchiolitis obliterans were ruled out, and the bronchiolitis resolved when leukemia relapsed. This case suggests that bronchiolitis may be another early, non-infectious pulmonary complication of HSCT.

Diffuse Alveolar Hemorrhage and Infection-Associated Alveolar Hemorrhage following Hematopoietic Stem Cell Transplantation: Related and High-Risk Clinical Syndromes

Diffuse alveolar hemorrhage (DAH) is a noninfectious pulmonary complication of hematopoietic stem cell transplantation (HSCT) with unclear pathogenesis and treatment. We reviewed prospectively collected data on 1919 consecutive transplants performed between 1995 and 2004 and compared patients with DAH and infection-associated alveolar hemorrhage (IAH) who presented with similar symptoms of hypoxemia, pulmonary infiltrates, and progressively bloody alveolar lavage but also had microorganisms isolated from blood, bronchoalveolar lavage, or tracheal aspirate within 1 week of alveolar hemorrhage. Overall, 116 patients had alveolar hemorrhage (45 with DAH, 71 with IAH). Older age, allogeneic donor source, myeloablative conditioning regimen, and acute severe graft-versus-host disease (GVHD) were independently predictive of an increased risk of post-HSCT alveolar hemorrhage. The DAH and IAH groups were comparable except for a higher proportion of patients receiving umbilical cord blood as a donor source and total-body irradiation–containing conditioning in the IAH group. The probability of 60-day survival from onset of hemorrhage was 16% (95% CI, 6%–26%) for the DAH and 32% (95% CI, 21%–43%) for the IAH group ( P = .08). All except 20 patients were treated with a standard regimen of high-dose corticosteroids. Patients who received corticosteroids had 60-day survival of 26% (95% CI, 18%–34%), compared with 25% (95% CI, 6%–44%) for those who did not ( P = .28). The pathogenesis of alveolar hemorrhage after HSCT is multifactorial, and we propose that IAH and DAH in HSCT recipients are related clinical syndromes with similar clinical presentation, risks, and associated high mortality.

Etanercept Therapy for Late-Onset Idiopathic Pneumonia Syndrome After Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation

Idiopathic pneumonia syndrome (IPS) is a noninfectious pulmonary complication of allogeneic hematopoietic stem cell transplantation (AHSCT), which usually develops within the first 100 days after transplantation. Donor T-cell-derived tumor necrosis factor-α (TNF-α) may play a crucial role in the pathogenesis of IPS, and inhibition of TNF-α has been used as a therapeutic option. We report two patients who had late-onset IPS about day 150 after nonmyeloablative AHSCT (NMA-AHSCT). They responded well to etanercept in combination with standard immunosuppressive drugs. Both patients had relapses and responded to retreatment with etanercept-based therapy. One patient was alive at 30 months after the initial diagnosis on long-term maintenance therapy with etanercept. The second patient was lost to follow-up at our institution but died 13 months after the onset of IPS. Our two cases showed that IPS could develop late after NMA-AHSCT and inhibition of TNF-α activity can be therapeutically effective.

Azithromycin in bronchiolitis obliterans complicating bone marrow transplantation: a preliminary study

Bronchiolitis obliterans (BO) is a serious noninfectious pulmonary complication following allogeneic bone marrow transplantation (BMT). Azithromycin, a macrolide antibiotic, may have a beneficial effect in BO through its anti-inflammatory effect. The aim of the current study was to investigate the potential effect of azithromycin on pulmonary function tests (PFTs) in BO complicating BMT. PFTs of 153 post-BMT patients were followed; eight patients out of 153 (12%) developed obstructive airway disease on their PFTs, along with characteristic findings of BO on high-resolution computed tomography of the chest. These patients were given azithromycin 500 mg q.d. for 3 days, followed by 250 mg three times a week for 12 weeks. Clinically significant improvements were achieved both in forced vital capacity, where the mean (95% confidence interval) increase reported was 410 mL (0.16-0.65), which was an average improvement of 21.57%, and in the forced expiratory volume in one second, where the mean increase noticed was 280 mL (0.10-0.44), which was an average improvement of 20.58%. In conclusion, the potential role of azithromycin in the treatment of bronchiolitis obliterans is intriguing and it warrants further testing.

Endogenous nitric oxide protects against T cell-dependent lethality during graft-versus-host disease and idiopathic pneumonia syndrome.

The pathogenesis of idiopathic pneumonia syndrome (IPS), a noninfectious pulmonary complication of allogeneic bone marrow transplantation (BMT), has not been fully elucidated. However, several contributing factors have been proposed, including lung injury caused by reactive oxygen and nitrogen intermediates during preconditioning and development of graft-vs-host disease (GVHD). Studies on the role of reactive oxygen and nitrogen intermediates in IPS have yielded conflicting results. We have described a murine model of IPS, in which the onset of lung inflammation was delayed by several weeks relative to GVHD. This study evaluated whether the delay in onset of IPS was due to slow turnover of NO-producing, immunosuppressive alveolar macrophages (AM) following BMT. The results indicated that AM were immunosuppressive due to synthesis of NO. However, NO production and immunosuppressive activity by AM did not decline after BMT, but rather remained elevated throughout the 12-wk development of GVHD and IPS. In a 14-day model of IPS, continuous inhibition of NO with aminoguanidine (AG) reduced signs of IPS/GVHD, but also led to higher mortality. When AG treatment was initiated after onset of IPS/GVHD, rapid mortality occurred that depended on the severity of IPS/GVHD. AG-enhanced mortality was not due to inhibition of marrow engraftment, elevated serum TNF-alpha, liver injury, or hypertensive responses. In contrast, T cells were involved, because depletion of CD4(+) lymphocytes 24 h before AG treatment prevented mortality. Thus, NO production following allogeneic BMT affords a protective effect that helps down-regulate injury caused by T cells during GVHD and IPS.

Increasing incidence of diffuse alveolar hemorrhage following allogeneic bone marrow transplantation: cryptic etiology and uncertain therapy.

Diffuse alveolar hemorrhage (DAH) is a non-infectious pulmonary complication of bone marrow transplantation (BMT) with resultant high mortality. It reportedly occurs primarily in autologous recipients. We examined the incidence of DAH in our center in order to assess potential risk factors and develop preventive strategies. Between 1991 and 1997, 23 cases of DAH occurred in 922 adult patients (2.5%) receiving BMT for hematological malignancy. Strikingly, 12 cases occurred in 1997 with the majority in recipients of allogeneic matched sibling donor stem cells. Treatment with high-dose steroids, 250 mg to 2 g/day, in 15 patients led to transient improvement in 10 patients, but 21 of the 23 patients required mechanical ventilation. Mortality was high with 17 patients (74%) dying a median of 39 days (range 22-47) post transplant; a median of 17 days post onset of DAH (range 5-34). Six patients are alive with a median follow-up of 18 months (range 12-60). No recognizable alteration in supportive care, conditioning regimen, GVHD prophylaxis or cytokine usage was associated with this striking increase in the frequency of DAH after allografting. Further follow-up is required to establish whether this increase in the incidence of DAH in allogeneic transplantation is an isolated occurrence or an ongoing problem. If indeed there is a real increase in the incidence of this complication, then efforts need to be directed towards elucidating a possible cause or risk factors. We offer the possibility that a new unidentified infection, undetected by current microbiological tests might contribute to this striking increase in DAH. These data, while not establishing a cause, suggest a markedly augmented risk of DAH in allogeneic BMT. In addition, high-dose corticosteroids have only limited efficacy as therapy for DAH after allotransplantation. Further investigation into the pathogenesis of this syndrome is essential as is prompt and immediate consideration of DAH in all patients with respiratory compromise early after BMT.

Pulmonary Cytolytic Thrombi

Lung injury is a frequent and severe complication of bone marrow transplantation (BMT). Over the past 5 years we have recognized a new noninfectious pulmonary complication of allogeneic BMT in 12 patients, presenting with fever, pulmonary nodules on chest computed tomography, and distinctive histopathologic appearance descriptively termed "pulmonary cytolytic thrombi" (PCT). All but one patient were children transplanted for malignant (9) and nonmalignant (3) conditions. Ten of the patients had active graft-versus-host disease (GVHD) of skin, bowel, or both at the time of diagnosis of the PCT. In all cases occlusive vascular lesions were present, most of them associated with hemorrhagic infarcts. The endothelial cell layer was discontinuous in all cases stained with antibody to CD31. The thrombi had entrapped recognizable leukocytes and CD45-positive cell fragments embedded in a tenacious basophilic material. The symptoms and radiologic findings resolved in weeks to months. PCT may represent a previously unrecognized form of pulmonary acute GVHD.