Maria Crespo

University of Pittsburgh, Pittsburgh, Pennsylvania, United States

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Publications (113)352.83 Total impact

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    ABSTRACT: The development of human leukocyte antigen (HLA) antibody responses has been associated with worse clinical outcomes, such as bronchiolitis obliterans syndrome (BOS) and death, in lung transplant recipients (LTRs). However, the role of donor-specific HLA antibody (DSA) responses as a risk factor for poor outcomes remains controversial. We prospectively screened 445 LTRs for DSA at our institution at the time of surveillance bronchoscopies for the first 2 years after transplantation between 2003 and 2008, and evaluated clinical outcomes. For this purpose, we used the combination of panel-reactive antibodies (PRA) by enzyme-linked immunosorbent assay (ELISA) and the Luminex single-antigen bead (SAB) assay (One Lambda, Canoga Park, CA). We detected de novo DSA (dnDSA) in 58 of 445 (13%) LTRs in our cohort. Freedom from BOS was significantly reduced in LTRs with dnDSA versus those without dnDSA (p < 0.001). Using a Cox proportional hazards model, the development of dnDSA was associated with a significantly increased hazard ratio (HR = 6.59 [4.53 to 9.59]; p < 0.001) for BOS and high-grade BOS (Stage ≥2) (HR = 5.76 [3.48 to 9.52]; p < 0.001). Freedom from death was significantly reduced in LTRs with dnDSA (p < 0.001), including mortality attributable to BOS (HR = 9.86 [4.91 to 19.78]; p < 0.001). Taken together, our findings provide evidence that dnDSA is associated with accelerated BOS kinetics and severity, as well as death due to BOS after lung transplantation. In addition, these data support regular monitoring for the development of dnDSA in LTRs and underscore the need for novel strategies to mitigate the increased risk of poor outcomes associated with dnDSA. Copyright © 2014 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.
    The Journal of Heart and Lung Transplantation 12/2014; 33(12):1288-94. · 5.11 Impact Factor
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    ABSTRACT: The intraoperative use of cardiopulmonary bypass (CPB) in lung transplantation has been associated with increased rates of pulmonary dysfunction and bleeding complications. More recently, extracorporeal membrane oxygenation (ECMO) has emerged as a valid alternative method of support and has been our preferred method of support since March 2012. We compared early and midterm outcomes of these 2 support methods. Between July 2007 and April 2013, 271 consecutive patients underwent lung transplant using CPB (n = 222) or ECMO (n = 49). We retrospectively reviewed the outcomes of these patients requiring CPB or ECMO during lung transplant. The CPB and ECMO groups had comparable demographic and operative characteristics; however, the ECMO group had higher mean lung allocation scores (73 vs 52, p < 0.001). In the CPB group, more patients required reintubation (35.6% vs 20.4%, p = 0.04) or temporary tracheostomy (44.6% vs 28.6%, p = 0.05). Patients in the CPB group had a higher rate of renal failure requiring dialysis than the ECMO group (22.1% vs 8.2 %, p = 0.028). There were no differences in severe PGD requiring postoperative circulatory support (p = 0.83) or the need for perioperative red blood cell transfusions (p = 0.64) between the groups. No differences in 30-day (5% CPB vs 4.1% ECMO) or 6-month mortality (14.4% CPB vs 14.3% ECMO) were noted. The use of ECMO in lung transplant is safe and in our experience was associated with decreased rates of pulmonary and renal complications, as compared with CPB. Extracorporeal membrane oxygenation has become our preferred method of intraoperative support during lung transplantation. Copyright © 2014 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.
    The Annals of thoracic surgery. 12/2014; 98(6):1936-43.
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    ABSTRACT: Human polyomavirus 7 (HPyV7) is one of 11 human polyomaviruses recently discovered through genomic sequencing technologies. Two lung transplant recipients on immunosuppressive therapy developed pruritic, brown plaques on the trunk and extremities showing a distinctive epidermal hyperplasia hyperplasia with virus-laden keratinocytes containing densely-packed 36-45 nm icosahedral capsids. Rolling circle amplification and gradient centrifugation testing were positive for encapsidated human polyomavirus 7 (HPyV7) DNA in skin and peripheral blood from both patients, and HPyV7 early and capsid proteins were abundantly expressed in affected tissues. We describe for the first time that HPyV7 is associated with novel pathogenicity in some immunosuppressed individuals.
    The Journal of infectious diseases. 09/2014;
  • American Journal of Respiratory and Critical Care Medicine 06/2014; 189(12):1564-7. · 11.04 Impact Factor
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    ABSTRACT: Rationale: Biological pathways with significant genetic conservation across human populations have been implicated in the pathogenesis of primary graft dysfunction (PGD). The evaluation of the role of recipient genetic variation in PGD has thus far been limited to single, candidate gene analyses. Objective: We sought to identify genetic variants in lung transplant recipients that are responsible for increased risk of PGD using a two-phase large-scale genotyping approach. Methods: Phase 1 was a large-scale candidate gene association study of the multicenter, prospective Lung Transplant Outcomes Group cohort. Phase 2 included functional evaluation of selected variants and a bioinformatics screening of variants identified in phase 1. Main Result: After genetic data quality control, 680 lung transplant recipients were included in the analysis. In phase 1, seventeen variants were significantly associated with PGD, four of which were in the prostaglandin E2 family of genes. Among these were a coding variant in the gene encoding prostaglandin E2 synthase (PTGES2, p=9.3x10-5) resulting in an arginine to histidine substitution at amino acid position 298, and three variants in a block containing the 5' promoter and first intron of the PTGER4 gene (encoding prostaglandin E2 receptor subtype 4, all p<5x10-5). Functional evaluation in regulatory T-cells identified that rs4434423A in the PTGER4 gene was associated with differential suppressive function of regulatory T cells. Conclusions: Further research aimed at replication and additional functional insight into the role played by genetic variation in prostaglandin E2 synthetic and signaling pathways in PGD is warranted.
    American Journal of Respiratory and Critical Care Medicine 01/2014; · 11.04 Impact Factor
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    ABSTRACT: Inherent recipient factors, including pretransplant diagnosis, obesity and elevated pulmonary pressures, are established primary graft dysfunction (PGD) risks. We evaluated the relationship between preoperative lung injury biomarkers and PGD to gain further mechanistic insight in recipients. We performed a prospective cohort study of recipients in the Lung Transplant Outcomes Group enrolled between 2002 and 2010. Our primary outcome was Grade 3 PGD on Day 2 or 3. We measured preoperative plasma levels of five biomarkers (CC-16, sRAGE, ICAM-1, IL-8 and Protein C) that were previously associated with PGD when measured at the postoperative time point. We used multivariable logistic regression to adjust for potential confounders. Of 714 subjects, 130 (18%) developed PGD. Median CC-16 levels were elevated in subjects with PGD (10.1 vs. 6.0, p < 0.001). CC-16 was associated with PGD in nonidiopathic pulmonary fibrosis (non-IPF) subjects (OR for highest quartile of CC-16: 2.87, 95% CI: 1.37, 6.00, p = 0.005) but not in subjects with IPF (OR 1.38, 95% CI: 0.43, 4.45, p = 0.59). After adjustment, preoperative CC-16 levels remained associated with PGD (OR: 3.03, 95% CI: 1.26, 7.30, p = 0.013) in non-IPF subjects. Our study suggests the importance of preexisting airway epithelial injury in PGD. Markers of airway epithelial injury may be helpful in pretransplant risk stratification in specific recipients.
    American Journal of Transplantation 01/2014; · 6.19 Impact Factor
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    ABSTRACT: PURPOSE 1. Review patient demographics and surgical procedures. 2. Assess CT-pathologic features of fibrosis, ground glass opacity (GGO), lung nodules, consolidation, lymphadenopathy, +/- thoracic malignancy. METHOD AND MATERIALS Patient age, gender, history of smoking & malignancy, etiology of UIP, surgical procedures, pathologic & MDCT techniques, & intervals between MDCT & LTx were recorded. MDCTs & explanted lung specimens were reviewed by 2 chest radiologists & a pulmonary pathologist, respectively. We correlated the MDCT pattern & distribution of UIP, emphysema, GGO, lung nodules, consolidation, nodular fibrosis, lymph nodes >12mm, +/- thoracic malignancy, with pathology reports of the explanted lungs. Discordant cases were re-evaluated by our pathologist. Cancers were staged via the revised 2010 American Joint Committee on Cancer Manual. RESULTS 99 patients (63 M:36 F) with UIP underwent LTx over a 2 year period. Mean age was 49.3 years (36.0-77.6 years). 58 (58%) had been smokers, & 6 (6%) had a history of treated malignancy (lung or breast cancer or lymphoma). DLTx (n=61) or SLTx (n=38) was performed. Mean interval between CT & LTx was 5.0 months (0.25-15.5 mo). Etiology of UIP was idiopathic (n=68, 69%), scleroderma (n=12, 12%), or other (n=19, 19%). CTs revealed classic (n=73, 74%) or atypical patterns of UIP (n=26, 26%); emphysema (n=31, 31%) +/- GGO (n=31, 31%); solitary (n=5, 5%) or multiple nodules (n=10, 10%), +/- consolidation (n=16, 16%); +/- mediastinal / hilar lymphadenopathy (n=68, 69%). Most nodules were not detected on pathologic evaluation. GOO or consolidation typically represented nonspecific interstitial pneumonia (NSIP), acute pneumonia, alveolar injury, smoking-related fibrosis, aspiration or lymphoid infiltration. Malignancy (n=7, 7%) was detected on pathologic assessment & included lung cancer (n=5) & metastases (n=2). Lung cancer was stage 1 or 2 (n=4) and stage 3A (n=1). CONCLUSION Pneumonia, acute lung injury & NSIP may manifest as GGO or consolidation. 7% of UIP patients had cancer in the explanted lung, typically stage 1 or 2 lung cancer that was CT-occult. Inflammatory nodules & mediastinal lymphadenopathy are common & may mimic malignancy. CLINICAL RELEVANCE/APPLICATION 7% of UIP patients had malignancy detected in the explanted lung, typically stage 1 or 2 lung cancer. Inflammatory nodules & lymphadenopathy are common in advanced UIP & may mimic malignancy.
    Radiological Society of North America 2013 Scientific Assembly and Annual Meeting; 12/2013
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    ABSTRACT: Little is known about the use of lung transplantation in the management of sickle cell disease-associated pulmonary arterial hypertension (SCD-PAH). We present clinical and pathological data and report the first successful outcome of bilateral lung transplantation in a patient with severe SCD-PAH and pulmonary veno-occlusive disease (PVOD). We discuss the complexities of multidisciplinary planning and management of lung transplantation in patients with SCD-associated pulmonary vascular complications. This case reports the first documented successful lung transplant and first case of PVOD in a patient with SCD-PAH.
    Pulmonary circulation. 12/2013; 3(4):952-8.
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    ABSTRACT: Ganciclovir-resistant cytomegalovirus (CMV) infections are reported infrequently among lung transplant recipients receiving extended valganciclovir prophylaxis. We performed a single-center, retrospective review of ganciclovir-resistant CMV infections in a program that employed valganciclovir prophylaxis for ≥6 months post-lung transplant. CMV infections were diagnosed in 28% (170/607) of patients. UL97 mutations were detected in 9.4% (16/170) of CMV-infected patients, at median 8.5 months post-transplant (range: 5-21) and despite prophylaxis for median 7 months (range: 4-21). UL97 mutations were canonical; 25% (4/16) of strains carried concurrent UL54 mutations. Ganciclovir-resistant CMV was more likely with breakthrough infections (75% (12/16) vs. 19% (30/154); p=0.00001) and D+/R- serostatus (75% vs. 45% (69/154); p=0.03). Median whole-blood CMV load was 4.13-log10 copies/cm(3) (range: 2.54-5.53), and 93% (14/15) of patients had low-moderate immune responses (Cylex Immunoknow). Antiviral therapy was successful, failed, or eradicated viremia followed by relapse in 12% (2/16), 31% (5/16) and 56% (9/16) of patients, respectively. Eighty-seven percent (14/16) of patients were treated with foscarnet-containing regimens; toxicity developed in 78% (11/14). Median viral load half-life and time to viremia eradication among foscarnet-treated patients were 2.6 and 23 days, respectively, and did not correlate with protection from relapse. Sixty-nine percent (11/16) and 25% (4/16) of patients developed and died due to CMV pneumonitis, respectively. Serum viral load was independently associated with death among foscarnet-treated patients (p=0.04). In conclusion, ganciclovir-resistant CMV infections remained a major cause of morbidity and mortality following lung transplantation. Foscarnet-based regimens often eradicated viremia rapidly, but were ineffective in the long-term and limited by toxicity.
    Antimicrobial Agents and Chemotherapy 10/2013; · 4.57 Impact Factor
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    ABSTRACT: Lung Transplantation PostersSESSION TYPE: Original Investigation PosterPRESENTED ON: Wednesday, October 30, 2013 at 01:30 PM - 02:30 PMPURPOSE: Airway complications such as bronchial stenosis can be a significant cause of morbidity and mortality after lung transplantation. These patients often require multiple interventional bronchoscopic procedures. Since sirolimus has well recognized antiproliferative and immunosuppressive properties, we hypothesized that adding rapamycin to the immunosuppressant regimen of lung transplant recipients who required multiple bronchoscopic intervention for bronchial stenosis would facilitate achieving and maintaining airway patency.METHODS: We retrospectively reviewed the charts of all lung transplant patients who were started on rapamycin after development of severe bronchial stenosis that required multiple consecutive interventions including balloon bronchoplasty, laser photoresection, endobronchial brachytherapy, and bronchial stents placement.RESULTS: A total of 10 patients who underwent single or double lung transplantation from 2000 to 2012 were included. All patient had severe airway occlusion (80-100% reduction in cross sectional area) requiring multiple interventional bronchoscopic procedures prior to initiating rapamycin. After adding rapamycin, 8 of 10 patients achieved airway patency within 3 months and 7 of 10 had a significant response in the first month. Additionally, 5 of 7 patients who continued Rapa as part of their immunosuppressive regiment for more than 6 month did not require other subsequent interventional bronchoscopic procedures.CONCLUSIONS: Airway complications have been mainly attributed to ischemia of the donor bronchus during the immediate post-transplant period. Primary graft dysfunction and especially grade 3-4 ischemia-reperfusion injury( Herrera clasification) is the main risk factors for airway complications. Rapamycin represents a promising option for lung transplant patients with severe airway stenosis.CLINICAL IMPLICATIONS: The presence of severe persistent IRI should prompt starting Rapamycin early in the first 4-6 month after transplant.DISCLOSURE: The following authors have nothing to disclose: Irina Timofte, Maria Crespo, Christian Bermudez, Jonathan D'Cunha, Jay Bhama, Norihisa Shigemura, Bruce JohnsonNo Product/Research Disclosure Information.
    Chest 10/2013; 144(4_MeetingAbstracts):1014A. · 7.13 Impact Factor
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    ABSTRACT: Lung Transplantation PostersSESSION TYPE: Original Investigation PosterPRESENTED ON: Wednesday, October 30, 2013 at 01:30 PM - 02:30 PMPURPOSE: Diaphragm dysfunction after lung transplantation is considered to represent a major source of morbidity for patients and compromise their quality of life; however, the underlying mechanisms appear to be complex/multi-factorial and their impact on outcomes in lung transplantation remains largely unknown.METHODS: Patients who received lung transplants at our institution between January 2007 and December 2012 were identified (n=702). Data on complications including occurrence, timing, management and outcome were extracted from our transplant database and medical record review. Diaphragm dysfunction following lung transplantation was defined based on positive results for sniff test performed under fluoroscope.RESULTS: Thirty two patients (4.5%) experienced diaphragm dysfunction within 1 month after lung transplantation. Six patients (19%) had pre-existing unilateral diaphragm dysfunction and others (81%) had new onset of diaphragm dysfunction after the surgery. There were 2 in-hospital deaths. The 90-day, 1- and 5-year survivals were 89%, 78% and 52%, respectively. All patients with pre-existing diaphragm dysfunction underwent double lung transplantation and survived longer than 3 years with acceptable pulmonary function. Patient major comorbidities included severe primary graft dysfunction requiring postoperative extracorporeal membrane oxygenation (ECMO; 3 patients), acute renal insufficiency (5 patients), and prolonged mechanical ventilator support (15 patients). Their average posttransplant peak FEV1.0 was 70%. In multivariate analysis, prolonged cardiopulmonary bypass use (>4 hours), prior cardiothoracic surgery, and prior ECMO increased the risk of severe diaphragm dysfunction followed by mortality (p<0.05).CONCLUSIONS: Diaphragm dysfunction is a well-documented complication after lung transplantation; however, despite increasing number of patients with prior cardiothoracic surgery being referred to our institution to consider for lung transplantation, the incidence was 4%. In addition, in most of the cases with diaphragm dysfunction, it was transient and not associated with significantly adverse posttransplant outcomes.CLINICAL IMPLICATIONS: The impact of diaphragm dysfunction after lung transplantation on short- and long-term outcomes has been defined. This report presents the largest series of patients with diaphragm dysfunction who underwent lung transplantation to date.DISCLOSURE: The following authors have nothing to disclose: Norihisa Shigemura, Jonathan D'Cunha, Jay Bhama, Cynthia Gries, Maria Crespo, Joseph Pilewski, Christian BermudezNo Product/Research Disclosure Information.
    Chest 10/2013; 144(4_MeetingAbstracts):1009A. · 7.13 Impact Factor
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    ABSTRACT: CXCL10 (IP-10) is a potent chemoattractant for T cells that has been postulated to play a role in infection and acute cellular rejection (ACR) in animal models. We measured CXCL10 (IP-10) (and other cytokines previously implicated in the pathogenesis of ACR) in the bronchoalveolar lavage (BAL) of lung transplant recipients (LTRs) to determine the association between CXCL10 (IP-10) and ACR in LTRs. In a prospective study of 85 LTRs, expression of cytokines (tumor necrosis factor, interferon-γ, interleukin [IL]-6, IL-8, IL-15, IL-16, IL-17, CXCL10 [IP-10], and MCP-1 [CCL2]) in BAL samples (n=233) from patients with episodes of ACR (n=44), infection ("Infect"; n=25), concomitant "Infect+ACR" (n=10), and "No Infect and No ACR" (n=154) were analyzed. The levels of both CXCL10 (IP-10) and IL-16 were significantly increased in histologically proven ACR compared with the "No Infect and No ACR" group (CXCL10 [IP-10]: 107.0 vs. 31.9 pg/mL [P=0.001] and IL-16: 472.1 vs. 283.01 pg/mL [P=0.01]). However, in a linear mixed-effects model, significant association was found only between CXCL10 (IP-10) and ACR. A one-log increase of CXCL10 (IP-10) was associated with a 40% higher risk of ACR (odds ratio, 1.4; 95% confidence interval, 1.12-1.84). Higher values of CXCL10 (IP-10) in BAL fluid are associated with ACR in LTRs, suggesting a potential mechanistic role in the pathogenesis of ACR in LTRs. These results suggest that therapeutic strategies to inhibit CXCL10 (IP-10) and or its cognate receptor, CXCR3, warrant investigation to prevent and/or treat ACR in clinical lung transplantation.
    Transplantation 09/2013; · 3.78 Impact Factor
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    ABSTRACT: OBJECTIVE. The purpose of this study was to assess the CT-pathologic features of cancer incidentally detected at lung transplantation. MATERIALS AND METHODS. Our lung transplant registry was reviewed over 7 years for incidental malignancy. Patient demographics, diffuse lung disease, surgical procedure, histopathology, and chest CT were recorded. We correlated lesion size, morphology, multiplicity, and location with surgical and pathology reports and histopathology. Cancers were pathologically staged. RESULTS. Of 759 lung transplant recipients, cancer was incidentally detected in 22 (2.9%). Half (11 of 258) or 4.3% were detected within the past 2 years. Four patients had a history of treated malignancy, and three had recurrence. Patients had emphysema (chronic obstructive pulmonary disease [COPD]) (n = 10), fibrosis (n = 10), or combined COPD and fibrosis (n = 2). Histopathology revealed 13 solitary lung carcinomas, four multifocal adenocarcinomas, three metastases, and two lymphoproliferative diseases. Lung cancer (n = 17) stages were I or II (n = 13), IIIA (n = 2), or IV (n = 2). Metastases (n = 3) and lymphoproliferative disease (n = 2) represented advanced disease. The interval between CT and surgery was a mean of 4 months. CT-positive cases (n = 10) represented lung cancer (n = 9) and posttrans-plantation lymphoproliferative disease (n = 1). Cases with no CT findings of malignancy (n = 12) included lung cancer (n = 8), metastases (n = 3), and lymphoma (n = 1). Ten cases (45%) had other histologically benign CT abnormalities that mimicked cancer. CONCLUSION. Detection of incidental malignancy at lung transplantation has increased over the past 2 years. Malignancies were typically stage I or II lung cancers that were occult or indeterminate on CT. Diffuse lung disease, multiple CT abnormalities, and a delay between CT and transplantation compromise the preoperative diagnosis of cancer.
    American Journal of Roentgenology 07/2013; 201(1):108-16. · 2.90 Impact Factor
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    ABSTRACT: BACKGROUND: Lung volume reduction surgery (LVRS) as a bridge to lung transplantation was first advocated in 1995 and published studies have supported the concept but with limited data. The risk-benefit tradeoffs of the combined procedure have not been thoroughly examined, although substantial information regarding LVRS has emerged. METHODS: Of 177 patients who underwent lung transplantation for end-stage emphysema between 2002 and 2009 at our center, 25 had prior LVRS (22 bilateral and 3 unilateral). Lung transplantation was performed 22.9±15.9 months after LVRS. We compared in-hospital morbidity, functional capacity, and long-term outcomes of patients who underwent LVRS before lung transplantation with a matched cohort of patients without prior LVRS to assess the influence of LVRS on posttransplantation morbidity and mortality. RESULTS: The incidence of postoperative bleeding requiring reexploration and the incidence of renal dysfunction requiring dialysis were higher in patients with LVRS before lung transplantation. Posttransplantation peak forced expiratory volume in 1 s was worse in patients with LVRS before lung transplantation (56.7% vs. 78.8%; P<0.05). Five-year survival was not significantly different (59.7% in patients with LVRS before lung transplantation vs. 66.2% in patients with lung transplantation alone). In multivariate analysis, age more than 65 years, prolonged cardiopulmonary bypass time, and severe pulmonary hypertension were significant predictors for mortality (P<0.05). CONCLUSIONS: Although LVRS remains a viable option as a bridge to lung transplantation in appropriately selected patients, LVRS before lung transplantation can impart substantial morbidity and compromised functional capacity after lung transplantation. LVRS should not be easily considered as a bridge to transplantation for all lung transplant candidates.
    Transplantation 06/2013; · 3.78 Impact Factor
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    ABSTRACT: We conducted a retrospective study of deep surgical site infections (SSIs) among consecutive patients who underwent lung transplantation (LTx) at a single center from 2006 through 2010. Thirty-one patients (5%) developed SSIs at median 25 days after LTx. Empyema was most common (42%), followed by surgical wound infections (29%), mediastinitis (16%), sternal osteomyelitis (6%), and pericarditis (6%). Pathogens included Gram-positive bacteria (41%), Gram-negative bacteria (41%), fungi (10%) and Mycobacterium abscessus, Mycoplasma hominis and Lactobacillus sp. (one each). Twenty-three percent of SSIs were due to pathogens colonizing recipients' native lungs at time of LTx, suggesting surgical seeding as a source. Patient-related independent risk factors for SSIs were diabetes and prior cardiothoracic surgery; procedure-related independent risk factors were LTx from a female donor, prolonged ischemic time and number of perioperative red blood cell transfusions. Mediastinitis and sternal infections were not observed among patients undergoing minimally invasive LTx. SSIs were associated with 35% mortality at 1 year post-LTx. Lengths of stay and mortality in-hospital and at 6 months and 1 year were significantly greater for patients with SSIs other than empyema. In conclusion, deep SSIs were uncommon, but important complications in LTx recipients because of their diverse microbiology and association with increased mortality.
    American Journal of Transplantation 05/2013; · 6.19 Impact Factor
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    ABSTRACT: Intravenous immunoglobulin (IVIG) replacement has been shown to decrease the risk of post-transplant infections secondary to hypogammaglobulinemia, however the use of subcutaneous immunoglobulin (SCIG) in this population has not been reported. A retrospective analysis of the efficacy and tolerability of subcutaneous immunoglobulin replacement on 10 lung-transplant recipients was performed. All 10 patients demonstrated an increase in IgG levels at three months that was sustained at 6-12months with SCIG replacement therapy, with the majority (70%) tolerating infusion without complications. The results of this study suggest that subcutaneous IgG replacement therapy is a well tolerated alternative to IVIG.
    International immunopharmacology 03/2013; · 2.21 Impact Factor
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    ABSTRACT: ABSTRACT BACKGROUND: There is significant heterogeneity within the primary graft dysfunction (PGD) syndrome. We aimed to identify distinct grade 3 PGD phenotypes based on severity of lung dysfunction and patterns of resolution. METHODS: Subjects from the Lung Transplant Outcomes Group (LTOG) cohort study with grade 3 PGD within 72 hours after transplantation were included. Latent Class Analysis (LCA) was used to statistically identify classes based on changes in PGD ISHLT grade over time. Construct validity of the classes was assessed by testing for divergence of recipient, donor, and operative characteristics between classes. Predictive validity was assessed using time to death. RESULTS: 361 of 1255 subjects had grade 3 PGD within the first 72 hours after transplantation. LCA identified 3 distinct phenotypes: 1) severe persistent dysfunction (class 1); 2) complete resolution of dysfunction within 72 hours (class 2); and 3) attenuation, without complete resolution within 72 hours (class 3). Increased use of cardiopulmonary bypass, greater red blood cell transfusion and higher mean pulmonary artery pressure were associated with persistent PGD (class 1). Subjects in class 1 also had the greatest risk of death (HR 2.39, 95% CI: 1.57, 3.63, p<0.001). CONCLUSIONS: There are distinct phenotypes of resolution of dysfunction within the severe PGD syndrome. Subjects with early resolution may represent a different mechanism of lung pathology, such as resolving pulmonary edema, whereas classes with persistent PGD may represent a more severe phenotype. Future studies aimed at PGD mechanism or treatment may focus on phenotypes based on resolution of graft dysfunction.
    Chest 02/2013; · 7.13 Impact Factor
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    ABSTRACT: BACKGROUND: Early major neurologic complications after lung transplantation represent a major source of morbidity for patients and compromise their quality of life; however, the mechanisms underlying neurologic complications and their impact on outcomes in lung transplantation remain largely unknown. METHODS: Patients who received lung transplants at our institution between January 2004 and December 2010 were identified (n=759). Data on complications including occurrence, timing, management, and outcome were extracted from our transplant database and medical record review. Major neurologic complications were defined as those that were potentially life threatening, required urgent treatment/intubation, or required admission to the intensive care unit. RESULTS: Seventy (9.2%) patients experienced major neurologic complications within 2 weeks after lung transplantation. Most common complications were stroke (41%) and severe toxic/metabolic encephalopathy (37%). Multivariate analysis demonstrated that advanced age, history of coronary artery disease, prolonged use of cardiopulmonary bypass, and severe primary graft dysfunction increased the risk for death in patients with early major neurologic complications (P<0.05). There was a significant difference in survival between patients with neurologic complications and without (90-day mortality: 15% of patients who developed neurologic complications versus 4% of patients who did not; P=0.03; 5-year survival: 51.1% in patients who developed neurologic complication versus 62.1% in patients who did not; P<0.05). CONCLUSIONS: Early major neurologic complications after lung transplantation are common and carry substantial morbidity and mortality. Given the risk factors identified in this study, additional pretransplantation workup and intraoperative and postoperative monitoring for high-risk patients may help reduce the incidence of neurologic complications.
    Transplantation 01/2013; · 3.78 Impact Factor
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    ABSTRACT: BACKGROUND: Preoperative extracorporeal membrane oxygenation (ECMO) is a risk factor for poor outcome and currently considered a contraindication to lung transplantation. The lung allocation score system was introduced in May 2005 and prioritizes lung allocation to those with the greatest respiratory impairment. The purpose of this study is to determine whether ECMO as a bridge to lung transplantation is an acceptable option to support those in respiratory failure until donor lungs become available in the lung allocation score era. METHOD: A retrospective review of 715 consecutive lung transplants performed between May 2005 and September 2011 was conducted using a prospectively collected institutional registry database. Twenty-four lung transplants (3.4%) were performed in the 31 patients with attempted pretransplant ECMO; 7 patients who received ECMO patients did not survive or were deemed unfit for transplantation. These patients were compared with a control group of 691 patients who did not receive pretransplant ECMO. RESULTS: The duration of pretransplant ECMO was 171 ± 242 hours (median, 91 hours). Venovenous ECMO was used for respiratory failure in 15 patients, whereas venoarterial ECMO was used for circulatory collapse due to pulmonary hypertension in 9 patients. Patients in the retransplant ECMO group were younger (46 ± 15 years vs 57 ± 14 years, P < .01) compared with the control group, with no difference in recipient gender (male/female: 10/14 vs 380/311), donor age (33 ± 14 years vs 36 ± 15 years), or donor gender (male/female: 10/14 vs 352/339). Emphysema was less common (1, 4% vs 260, 38%, P < .01), and cystic fibrosis (5, 21% vs 72, 10%, P = .09), redo lung transplant (3, 13% vs 28, 4%, P = .08), and bronchiectasis (2, 8% vs 6, 1%, P = .03) were more common in the pretransplant ECMO group. Patients in the pretransplant ECMO group had a significantly higher lung allocation score (87 ± 9 vs 44 ± 15, P < .01). All patients in the pretransplant ECMO group underwent double lung transplants on pump (cardiopulmonary bypass/ECMO), and single lung transplants were performed in 171 patients (25%) and pump was used in 243 patients (35%) in the control group. The cardiopulmonary bypass time was longer in the pretransplant ECMO group (277 ± 69 minutes vs 225 ± 89 minutes, P = .02), with no difference in ischemic time (343 ± 93 minutes vs 330 ± 98 minutes, P = .54). Cadaveric lobar lung transplants were performed because of the urgency to overcome size mismatch with an oversized donor more frequently in 25% (n = 6, no mortality with the longest follow-up at 6 years) of patients in the pretransplant ECMO group versus 0.3% (n = 2) of patients in the control group (P < .01). Post-transplant ECMO was used for primary graft dysfunction in 13 patients (54%) in the pretransplant ECMO group and 41 patients (6%) in the control group (P < .01). The median hospital stay was 46 days in the pretransplant ECMO group versus 27 days in the control group (P = .16). The actuarial survivals after lung transplants at 1, 3, 6, 12, and 24 months were 96%, 88%, 83%, 74%, and 74%, respectively, in the pretransplant ECMO group, and 97%, 94%, 90%, 83%, and 74%, respectively, in the control group (P = .787). CONCLUSIONS: Although the incidence of primary graft dysfunction requiring post-transplant ECMO is higher and the hospital stay is longer in patients receiving pretransplant ECMO, the graft survival is good (2-year survival, 74%). ECMO is efficacious as a bridge to lung transplantation with good post-lung transplant outcomes.
    The Journal of thoracic and cardiovascular surgery 01/2013; · 3.41 Impact Factor
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    ABSTRACT: RATIONALE: Primary graft dysfunction (PGD) is the main cause of early morbidity and mortality after lung transplantation. Previous studies have yielded conflicting results for PGD risk factors. OBJECTIVE: We sought to identify donor, recipient, and peri-operative risk factors for PGD. METHODS: We performed a 10 center prospective cohort study enrolled between March 2002 and December 2010 (the Lung Transplant Outcomes Group). The primary outcome was ISHLT grade 3 PGD at 48 or 72 hours post transplant. The association of potential risk factors with PGD was analyzed using multivariable conditional logistic regression. MEASUREMENTS AND MAIN RESULTS: 1255 patients from 10 centers were enrolled, 211 subjects (16.8%) developed grade 3 PGD. In multivariable models, independent risk factors for PGD were any history of donor smoking (OR=1.8, 95%CI 1.2, 2.6, p=0.002), FiO2 during allograft reperfusion (OR=1.1 per 10% increase in FiO2, 95%CI 1.0, 1.2; p=0.01), single lung transplant (OR=2.0, 95%CI 1.2, 3.3; p=0.008), use of cardiopulmonary bypass (OR=3.4, 95%CI 2.2, 5.3; p<0.001), overweight (OR=1.8, 95%CI 1.2, 2.7; p=0.01) and obese (OR=2.3, 95%CI 1.3, 3.9; p=0.004) recipient BMI, pre-operative sarcoidosis (OR=2.5, 95%CI 1.1, 5.6; p=0.03) or pulmonary arterial hypertension (OR=3.5, 95%CI 1.6, 7.7; p=0.002), and mean pulmonary artery pressure (OR=1.3 per 10mmHg increase, 95%CI 1.1, 1.5; p<0.001). PGD was significantly associated with 90 day (relative risk (RR)=4.8, absolute risk increase (ARI)=18%, p<0.001) and 1 year (RR=3.0, ARI=23%, p<0.001) mortality. Interpretation: We identified grade 3 PGD risk factors, several of which are potentially modifiable and should be prioritized for future research aimed at preventative strategies.
    American Journal of Respiratory and Critical Care Medicine 01/2013; · 11.04 Impact Factor

Publication Stats

759 Citations
352.83 Total Impact Points


  • 2009–2014
    • University of Pittsburgh
      • • Department of Medicine
      • • School of Medicine
      • • Division of Cardiothoracic Surgery
      Pittsburgh, Pennsylvania, United States
    • Osaka University
      Suika, Ōsaka, Japan
  • 2013
    • Temple University
      Philadelphia, Pennsylvania, United States
  • 2012–2013
    • University of Pennsylvania
      • Division of Pulmonary, Allergy and Critical Care
      Philadelphia, PA, United States
  • 2008–2012
    • Hospital of the University of Pennsylvania
      • • Division of Pulmonary Allergy and Critical Care
      • • Department of Medicine
      Philadelphia, Pennsylvania, United States
  • 2011
    • Columbia University
      • Department of Medicine
      New York City, NY, United States
    • Montefiore Medical Center
      New York City, New York, United States