Publications by authors named "Michael Y Shino"

19 Publications

  • Page 1 of 1

Correlation between BAL CXCR3 Chemokines and Lung Allograft Histopathologies: A Multi-Center Study.

Am J Transplant 2021 Apr 11. Epub 2021 Apr 11.

University of California Los Angeles, Los Angeles, CA, USA.

The histopathologic diagnosis of acute allograft injury is prognostically important in lung transplantation with evidence demonstrating a strong and consistent association between acute rejection (AR)(1-7), acute lung injury (ALI)(8, 9) and the subsequent development of chronic lung allograft dysfunction (CLAD). The pathogenesis of these allograft injuries however, remains poorly understood. CXCL9 and CXCL10 are CXC chemokines induced by interferon-γ and act as potent chemoattractants of mononuclear cells. We hypothesized that these chemokines are involved in the mononuclear cell recruitment associated with AR and ALI. We further hypothesized that the increased activity of these chemokines could be quantified as increased levels in the bronchoalveolar lavage fluid. In this prospective multi-center study, we evaluate the incidence of histopathologic allograft injury development during the first-year post-transplant and measure bronchoalveolar CXCL9 and CXCL10 levels at the time of the biopsy. In multivariable models, CXCL9 levels were 1.7-fold and 2.1-fold higher during AR and ALI compared with "normal" biopsies without histopathology. Similarly, CXCL10 levels were 1.6-fold and 2.2-fold higher during these histopathologies, respectively. These findings support the association of CXCL9 and CXCL10 with episodes of AR and ALI, and provide potential insight into the pathogenesis of these deleterious events.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ajt.16601DOI Listing
April 2021

Risk Factors for Acute Rejection in the First Year after Lung Transplant. A Multicenter Study.

Am J Respir Crit Care Med 2020 08;202(4):576-585

University of California Los Angeles, Los Angeles, California.

Acute rejection, manifesting as lymphocytic inflammation in a perivascular (acute perivascular rejection [AR]) or peribronchiolar (lymphocytic bronchiolitis [LB]) distribution, is common in lung transplant recipients and increases the risk for chronic graft dysfunction. To evaluate clinical factors associated with biopsy-proven acute rejection during the first post-transplant year in a present-day, five-center lung transplant cohort. We analyzed prospective diagnoses of AR and LB from over 2,000 lung biopsies in 400 newly transplanted adult lung recipients. Because LB without simultaneous AR was rare, our analyses focused on risk factors for AR. Multivariable Cox proportional hazards models were used to assess donor and recipient factors associated with the time to the first AR occurrence. During the first post-transplant year, 53.3% of patients experienced at least one AR episode. Multivariable proportional hazards analyses accounting for enrolling center effects identified four or more HLA mismatches (hazard ratio [HR], 2.06;  ≤ 0.01) as associated with increased AR hazards, whereas bilateral transplantation (HR, 0.57;  ≤ 0.01) was associated with protection from AR. In addition, Wilcoxon rank-sum analyses demonstrated bilateral (vs. single) lung recipients, and those with fewer than four (vs. more than four) HLA mismatches demonstrated reduced AR frequency and/or severity during the first post-transplant year. We found a high incidence of AR in a contemporary multicenter lung transplant cohort undergoing consistent biopsy sampling. Although not previously recognized, the finding of reduced AR in bilateral lung recipients is intriguing, warranting replication and mechanistic exploration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1164/rccm.201910-1915OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7427399PMC
August 2020

Mitochondrial DNA Stimulates TLR9-Dependent Neutrophil Extracellular Trap Formation in Primary Graft Dysfunction.

Am J Respir Cell Mol Biol 2020 03;62(3):364-372

Department of Medicine.

The immune system is designed to robustly respond to pathogenic stimuli but to be tolerant to endogenous ligands to not trigger autoimmunity. Here, we studied an endogenous damage-associated molecular pattern, mitochondrial DNA (mtDNA), during primary graft dysfunction (PGD) after lung transplantation. We hypothesized that cell-free mtDNA released during lung ischemia-reperfusion triggers neutrophil extracellular trap (NET) formation via TLR9 signaling. We found that mtDNA increases in the BAL fluid of experimental PGD (prolonged cold ischemia followed by orthotopic lung transplantation) and not in control transplants with minimal warm ischemia. The adoptive transfer of mtDNA into the minimal warm ischemia graft immediately before lung anastomosis induces NET formation and lung injury. TLR9 deficiency in neutrophils prevents mtDNA-induced NETs, and TLR9 deficiency in either the lung donor or recipient decreases NET formation and lung injury in the PGD model. Compared with human lung transplant recipients without PGD, severe PGD was associated with high levels of BAL mtDNA and NETs, with evidence of relative deficiency in DNaseI. We conclude that mtDNA released during lung ischemia-reperfusion triggers TLR9-dependent NET formation and drives lung injury. In PGD, DNaseI therapy has a potential dual benefit of neutralizing a major NET trigger (mtDNA) in addition to dismantling pathogenic NETs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1165/rcmb.2019-0140OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7055700PMC
March 2020

Molecular diagnostics for lung transplant rejection: An information pipeline or a pipe dream?

J Heart Lung Transplant 2019 05;38(5):514-515

Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.healun.2019.02.014DOI Listing
May 2019

Pulmonary Allograft Versus Host Disease.

Transplant Direct 2017 Dec 20;3(12):e333. Epub 2017 Nov 20.

Division of Pulmonary and Critical Care Medicine, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/TXD.0000000000000749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5828692PMC
December 2017

The Impact of Allograft CXCL9 during Respiratory Infection on the Risk of Chronic Lung Allograft Dysfunction.

OBM Transplant 2018 30;2(4). Epub 2018 Nov 30.

Division of Pulmonary and Critical Care Medicine, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-1690, USA.

Background: The long term clinical significance of respiratory infections after lung transplantation remains uncertain.

Methods: In this retrospective single-center cohort study of 441 lung transplant recipients, we formally evaluate the association between respiratory infection and chronic lung allograft dysfunction (CLAD). We furthermore hypothesized that bronchoalveolar lavage fluid (BALF) CXCL9 concentrations are augmented during respiratory infections, and that episodes of infection with elevated BALF CXCL9 are associated with greater CLAD risk.

Results: In univariable and multivariable models adjusted for other histopathologic injury patterns, respiratory infection, regardless of the causative organism, was a strong predictor of CLAD development (adjusted HR 1.8 95% CI 1.3-2.6). Elevated BALF CXCL9 concentrations during respiratory infections markedly increased CLAD risk in a dose-response manner. An episode of respiratory infection with CXCL9 concentrations greater than the 25, 50, and 75 percentile had adjusted HRs for CLAD of 1.8 (95% CI 1.1-2.8), 2.4 (95% CI 1.4-4.0) and 4.4 (95% CI 2.4-8.0), respectively.

Conclusions: Thus, we demonstrate that respiratory infections, regardless of the causative organism, are strong predictors of CLAD development. We furthermore demonstrate for the first time, the prognostic importance of BALF CXCL9 concentrations during respiratory infections on the risk of subsequent CLAD development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21926/obm.transplant.1804029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6693350PMC
November 2018

Gene Expression Profiling of Bronchoalveolar Lavage Cells During Aspergillus Colonization of the Lung Allograft.

Transplantation 2018 06;102(6):986-993

Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA.

Background: Aspergillus colonization after lung transplant is associated with an increased risk of chronic lung allograft dysfunction (CLAD). We hypothesized that gene expression during Aspergillus colonization could provide clues to CLAD pathogenesis.

Methods: We examined transcriptional profiles in 3- or 6-month surveillance bronchoalveolar lavage fluid cell pellets from recipients with Aspergillus fumigatus colonization (n = 12) and without colonization (n = 10). Among the Aspergillus colonized, we also explored profiles in those who developed CLAD (n = 6) or remained CLAD-free (n = 6). Transcription profiles were assayed with the HG-U133 Plus 2.0 microarray (Affymetrix). Differential gene expression was based on an absolute fold difference of 2.0 or greater and unadjusted P value less than 0.05. We used NIH Database for Annotation, Visualization and Integrated Discovery for functional analyses, with false discovery rates less than 5% considered significant.

Results: Aspergillus colonization was associated with differential expression of 489 probe sets, representing 404 unique genes. "Defense response" genes and genes in the "cytokine-cytokine receptor" Kyoto Encyclopedia of Genes and Genomes pathway were notably enriched in this list. Among Aspergillus colonized patients, CLAD development was associated with differential expression of 69 probe sets, representing 64 unique genes. This list was enriched for genes involved in "immune response" and "response to wounding", among others. Notably, both chitinase 3-like-1 and chitotriosidase were associated with progression to CLAD.

Conclusions: Aspergillus colonization is associated with gene expression profiles related to defense responses including cytokine signaling. Epithelial wounding, as well as the innate immune response to chitin that is present in the fungal cell wall, may be key in the link between Aspergillus colonization and CLAD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/TP.0000000000002058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5962368PMC
June 2018

The prognostic importance of CXCR3 chemokine during organizing pneumonia on the risk of chronic lung allograft dysfunction after lung transplantation.

PLoS One 2017 7;12(7):e0180281. Epub 2017 Jul 7.

Division of Pulmonary and Critical Care Medicine, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America.

Rationale: Since the pathogenesis of chronic lung allograft dysfunction (CLAD) remains poorly defined with no known effective therapies, the identification and study of key events which increase CLAD risk is a critical step towards improving outcomes. We hypothesized that bronchoalveolar lavage fluid (BALF) CXCR3 ligand concentrations would be augmented during organizing pneumonia (OP) and that episodes of OP with marked chemokine elevations would be associated with significantly higher CLAD risk.

Methods: All transbronchial biopsies (TBBX) from patients who received lung transplantation between 2000 to 2010 were reviewed. BALF concentrations of the CXCR3 ligands (CXCL9, CXCL10 and CXCL11) were compared between episodes of OP and "healthy" biopsies using linear mixed-effects models. The association between CXCR3 ligand concentrations during OP and CLAD risk was evaluated using proportional hazards models with time-dependent covariates.

Results: There were 1894 bronchoscopies with TBBX evaluated from 441 lung transplant recipients with 169 (9%) episodes of OP and 907 (49%) non-OP histopathologic injuries. 62 (37%) episodes of OP were observed during routine surveillance bronchoscopy. Eight hundred thirty-eight (44%) TBBXs had no histopathology and were classified as "healthy" biopsies. There were marked elevations in BALF CXCR3 ligand concentrations during OP compared with "healthy" biopsies. In multivariable models adjusted for other injury patterns, OP did not significantly increase the risk of CLAD when BAL CXCR3 chemokine concentrations were not taken into account. However, OP with elevated CXCR3 ligands markedly increased CLAD risk in a dose-response manner. An episode of OP with CXCR3 concentrations greater than the 25th, 50th and 75th percentiles had HRs for CLAD of 1.5 (95% CI 1.0-2.3), 1.9 (95% CI 1.2-2.8) and 2.2 (95% CI 1.4-3.4), respectively.

Conclusions: This study identifies OP, a relatively uncommon histopathologic finding after lung transplantation, as a major risk factor for CLAD development when considered in the context of increased allograft expression of interferon-γ inducible ELR- CXC chemokines. We further demonstrate for the first time, the prognostic importance of BALF CXCR3 ligand concentrations during OP on subsequent CLAD risk.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0180281PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5501470PMC
September 2017

Gene Expression Profiling of Bronchoalveolar Lavage Cells Preceding a Clinical Diagnosis of Chronic Lung Allograft Dysfunction.

PLoS One 2017 19;12(1):e0169894. Epub 2017 Jan 19.

Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California, United States of America.

Background: Chronic Lung Allograft Dysfunction (CLAD) is the main limitation to long-term survival after lung transplantation. Although CLAD is usually not responsive to treatment, earlier identification may improve treatment prospects.

Methods: In a nested case control study, 1-year post transplant surveillance bronchoalveolar lavage (BAL) fluid samples were obtained from incipient CLAD (n = 9) and CLAD free (n = 8) lung transplant recipients. Incipient CLAD cases were diagnosed with CLAD within 2 years, while controls were free from CLAD for at least 4 years following bronchoscopy. Transcription profiles in the BAL cell pellets were assayed with the HG-U133 Plus 2.0 microarray (Affymetrix). Differential gene expression analysis, based on an absolute fold change (incipient CLAD vs no CLAD) >2.0 and an unadjusted p-value ≤0.05, generated a candidate list containing 55 differentially expressed probe sets (51 up-regulated, 4 down-regulated).

Results: The cell pellets in incipient CLAD cases were skewed toward immune response pathways, dominated by genes related to recruitment, retention, activation and proliferation of cytotoxic lymphocytes (CD8+ T-cells and natural killer cells). Both hierarchical clustering and a supervised machine learning tool were able to correctly categorize most samples (82.3% and 94.1% respectively) into incipient CLAD and CLAD-free categories.

Conclusions: These findings suggest that a pathobiology, similar to AR, precedes a clinical diagnosis of CLAD. A larger prospective investigation of the BAL cell pellet transcriptome as a biomarker for CLAD risk stratification is warranted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0169894PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5245825PMC
August 2017

Voriconazole increases the risk for cutaneous squamous cell carcinoma after lung transplantation.

Transpl Int 2017 Jan 24;30(1):41-48. Epub 2016 Oct 24.

Department of Medicine, University of California, Los Angeles, CA, USA.

Lung transplant recipients (LTR) are at high risk of cutaneous squamous cell carcinoma (SCC). Voriconazole exposure after lung transplant has recently been reported as a risk factor for SCC. We sought to study the relationship between fungal prophylaxis with voriconazole and the risk of SCC in sequential cohorts from a single center. We evaluated 400 adult LTR at UCLA between 7/1/2005 and 12/22/2012. On 7/1/2009, our center instituted a protocol switch from targeted to universal antifungal prophylaxis for at least 6 months post-transplant. Using Cox proportional hazards models, time to SCC was compared between targeted (N = 199) and universal (N = 201) prophylaxis cohorts. Cox models were also used to assess SCC risk as a function of time-dependent cumulative exposure to voriconazole and other antifungal agents. The risk of SCC was greater in the universal prophylaxis cohort (HR 2.02, P < 0.01). Voriconazole exposure was greater in the universal prophylaxis cohort, and the cumulative exposure to voriconazole was associated with SCC (HR 1.75, P < 0.01), even after adjustment for other important SCC risk factors. Voriconazole did not increase the risk of advanced tumors. Exposure to other antifungal agents was not associated with SCC. Voriconazole should be used cautiously in this population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/tri.12865DOI Listing
January 2017

Graft Loss and CLAD-Onset Is Hastened by Viral Pneumonia After Lung Transplantation.

Transplantation 2016 Nov;100(11):2424-2431

1 Division of Infectious Diseases, Department of Medicine, University of California Los Angeles, Los Angeles, CA. 2 Department of Medicine Statistics Core, University of California Los Angeles, Los Angeles, CA. 3 Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, CA. 4 Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California Los Angeles, Los Angeles, CA. 5 Division of Cardiothoracic Surgery, Department of Surgery, University of California Los Angeles.

Background: Community-acquired respiratory virus (CARV) infections occur frequently after lung transplantation and may adversely impact outcomes. We hypothesized that while asymptomatic carriage would not increase the risk of chronic lung allograft dysfunction (CLAD) and graft loss, severe infection would.

Methods: All lung transplant cases between January 2000 and July 2013 performed at our center were reviewed for respiratory viral samples. Each isolation of virus was classified according to clinical level of severity: asymptomatic, symptomatic without pneumonia, and viral pneumonia. Multivariate Cox modeling was used to assess the impact of CARV isolation on progression to CLAD and graft loss.

Results: Four thousand four hundred eight specimens were collected from 563 total patients, with 139 patients producing 324 virus-positive specimens in 245 episodes of CARV infection. Overall, the risk of CLAD was elevated by viral infection (hazard ratio [HR], 1.64; P < 0.01). This risk, however, was due to viral pneumonia alone (HR, 3.94; P < 0.01), without significant impact from symptomatic viral infection (HR, 0.97; P = 0.94) nor from asymptomatic viral infection (HR, 0.99; P = 0.98). The risk of graft loss was not increased by asymptomatic CARV infection (HR, 0.74; P = 0.37) nor symptomatic CARV infection (HR, 1.39; P = 0.41). Viral pneumonia did, however, significantly increase the risk of graft loss (HR, 2.78; P < 0.01).

Conclusions: With respect to CARV, only viral pneumonia increased the risk of both CLAD and graft loss after lung transplantation. In the absence of pneumonia, respiratory viruses had no impact on measured outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5077663PMC
http://dx.doi.org/10.1097/TP.0000000000001346DOI Listing
November 2016

Altered Exosomal RNA Profiles in Bronchoalveolar Lavage from Lung Transplants with Acute Rejection.

Am J Respir Crit Care Med 2015 Dec;192(12):1490-503

3 Division of Pulmonary, Critical Care, Allergy, and Immunology, Department of Medicine, and.

Rationale: The mechanism by which acute allograft rejection leads to chronic rejection remains poorly understood despite its common occurrence. Exosomes, membrane vesicles released from cells within the lung allograft, contain a diverse array of biomolecules that closely reflect the biologic state of the cell and tissue from which they are released. Exosome transcriptomes may provide a better understanding of the rejection process. Furthermore, biomarkers originating from this transcriptome could provide timely and sensitive detection of acute cellular rejection (AR), reducing the incidence of severe AR and chronic lung allograft dysfunction and improving outcomes.

Objectives: To provide an in-depth analysis of the bronchoalveolar lavage fluid exosomal shuttle RNA population after lung transplantation and evaluate for differential expression between acute AR and quiescence.

Methods: Serial bronchoalveolar lavage specimens were ultracentrifuged to obtain the exosomal pellet for RNA extraction, on which RNA-Seq was performed.

Measurements And Main Results: AR demonstrates an intense inflammatory environment, skewed toward both innate and adaptive immune responses. Novel, potential upstream regulators identified offer potential therapeutic targets.

Conclusions: Our findings validate bronchoalveolar lavage fluid exosomal shuttle RNA as a source for understanding the pathophysiology of AR and for biomarker discovery in lung transplantation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1164/rccm.201503-0558OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4731719PMC
December 2015

Sarcoidosis-associated pulmonary hypertension and lung transplantation for sarcoidosis.

Semin Respir Crit Care Med 2014 Jun 9;35(3):362-71. Epub 2014 Jul 9.

Division of Pulmonary and Critical Care Medicine, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California.

Pulmonary hypertension (PH) is a significant complication of sarcoidosis, occurring in approximately 6 to > 20% of cases, and markedly increases mortality among these patients. The clinician should exercise a high index of suspicion for sarcoidosis-associated PH (SAPH) given the nonspecific symptomatology and the limitations of echocardiography in this patient population. The pathophysiology of PH in sarcoidosis is complex and multifactorial. Importantly, there are inherent differences in the pathogenesis of SAPH compared with idiopathic pulmonary arterial hypertension, making the optimal management of SAPH controversial. In this article, we review the epidemiology, diagnosis, prognosis, and treatment considerations for SAPH. Lung transplantation (LT) is a viable therapeutic option for sarcoid patients with severe pulmonary fibrocystic sarcoidosis or SAPH refractory to medical therapy. We discuss the role for LT in patients with sarcoidosis, review the global experience with LT in this population, and discuss indications and contraindications to LT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/s-0034-1376863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6507426PMC
June 2014

CXCR3 ligands are associated with the continuum of diffuse alveolar damage to chronic lung allograft dysfunction.

Am J Respir Crit Care Med 2013 Nov;188(9):1117-25

1 Division of Pulmonary and Critical Care Medicine, Department of Medicine.

Rationale: After lung transplantation, insults to the allograft generally result in one of four histopathologic patterns of injury: (1) acute rejection, (2) lymphocytic bronchiolitis, (3) organizing pneumonia, and (4) diffuse alveolar damage (DAD). We hypothesized that DAD, the most severe form of acute lung injury, would lead to the highest risk of chronic lung allograft dysfunction (CLAD) and that a type I immune response would mediate this process.

Objectives: Determine whether DAD is associated with CLAD and explore the potential role of CXCR3/ligand biology.

Methods: Transbronchial biopsies from all lung transplant recipients were reviewed. The association between the four injury patterns and subsequent outcomes were evaluated using proportional hazards models with time-dependent covariates. Bronchoalveolar lavage (BAL) concentrations of the CXCR3 ligands (CXCL9/MIG, CXCL10/IP10, and CXCL11/ITAC) were compared between allograft injury patterns and "healthy" biopsies using linear mixed-effects models. The effect of these chemokine alterations on CLAD risk was assessed using Cox models with serial BAL measurements as time-dependent covariates.

Measurements And Main Results: There were 1,585 biopsies from 441 recipients with 62 episodes of DAD. An episode of DAD was associated with increased risk of CLAD (hazard ratio, 3.0; 95% confidence interval, 1.9-4.7) and death (hazard ratio, 2.3; 95% confidence interval, 1.7-3.0). There were marked elevations in BAL CXCR3 ligand concentrations during DAD. Furthermore, prolonged elevation of these chemokines in serial BAL fluid measurements predicted the development of CLAD.

Conclusions: DAD is associated with marked increases in the risk of CLAD and death after lung transplantation. This association may be mediated in part by an aberrant type I immune response involving CXCR3/ligands.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1164/rccm.201305-0861OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3863740PMC
November 2013

Pulmonary hypertension complicating interstitial lung disease and COPD.

Semin Respir Crit Care Med 2013 Oct 13;34(5):600-19. Epub 2013 Sep 13.

Division of Pulmonary and Critical Care Medicine, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California.

Pulmonary hypertension (PH) may complicate parenchymal lung disease, specifically interstitial lung diseases and chronic obstructive pulmonary disease, and uniformly increases the mortality risk. The epidemiology and degree of PH is variable and unique to the underlying lung disease. The clinician should exercise a high index of suspicion for PH complicating parenchymal lung disease especially given the nonspecific symptomatology and the limitations of echocardiography in this patient population. In general, PH-specific therapies in this setting have been poorly studied, with concern for increased shunting and/or ventilation/perfusion (V/Q) mismatch and resultant hypoxemia. A better understanding of the mechanisms underlying PH related to parenchymal lung disease may lead to novel pharmacological targets to prevent or treat this serious complication.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/s-0033-1356548DOI Listing
October 2013

Neurofibromatosis-associated diffuse lung disease: case report.

Semin Respir Crit Care Med 2012 Oct 21;33(5):572-5. Epub 2012 Sep 21.

Division of Pulmonary and Critical Care Medicine, Department of Medicine, The David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-1690, USA.

Since the initial report in 1963 several small case series described an association between neurofibromatosis (NF) and interstitial lung disease. To date, more than 60 cases of interstitial lung disease associated with NF have been reported, but relatively few reports included high-resolution computed tomographic (HRCT) scans. Typical findings on HRCT include upper lobe predominant cystic and bullous disease, ground-glass opacification, and basilar reticular abnormalities. We present the case of a 34-year-old male smoker with NF and HRCT findings of diffuse lung disease including bullous emphysema, thin-walled cysts, and diffuse ground glass. Although NF-associated diffuse lung disease (NF-DLD) is disputed as a clinical entity by some, the case presented here adds to the accumulating evidence that NF-DLD is a distinct manifestation of neurofibromatosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/s-0032-1325165DOI Listing
October 2012

Usefulness of immune monitoring in lung transplantation using adenosine triphosphate production in activated lymphocytes.

J Heart Lung Transplant 2012 Sep;31(9):996-1002

Division of Pulmonary and Critical Care Medicine, Department of Medicine, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, CA 90095-1690, USA.

Background: The ImmuKnow (Cylex Inc, Columbia, MD) assay measures the amount of adenosine triphosphate (ATP) produced by helper CD4(+) cells after stimulation with a T-cell mitogen. We hypothesized that this assay can be used to assess the immune function of lung transplant recipients and identify those at risk of developing acute cellular rejection and respiratory infection.

Methods: Lung transplant recipients at University of California Los Angeles between January 1, 2006 and December 31, 2009 received a bronchoscopy with broncheoalveolar lavage, transbronchial biopsy and ImmuKnow values drawn at regular intervals as well as during episodes of clinical deterioration. The recipient's clinical condition at each time-point was classified as healthy, acute cellular rejection, or respiratory infection. Mixed-effects models were used to compare the ATP levels among these groups, and odds ratios for rejection and infection were calculated.

Results: The mean ATP level was 431 ± 189 ng/ml for the rejection group vs 377 ± 187 ng/ml for the healthy group (p = 0.10). A recipient with an ATP level > 525 ng/ml was 2.1 times more likely to have acute cellular rejection (95% confidence interval [CI] 1.1-3.8). Similarly, the mean ATP level was 323 ± 169 ng/ml for the infection group vs 377 ± 187 ng/ml for the healthy group (p = 0.03). A recipient with an ATP level < 225 ng/ml was 1.9 times more likely to have respiratory infection (95% CI, 1.1-3.3). However, the test was associated with poor performance characteristics. It had low sensitivity, specificity with an area under the receiver operating characteristic curve of only 0.61 to diagnose rejection and 0.59 to diagnose infection.

Conclusions: The ImmuKnow assay appears to have some ability to assess the overall immune function of lung transplant recipients. However, this study does not support its use as a reliable predictor of episodes of acute cellular rejection or respiratory infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.healun.2012.05.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4204735PMC
September 2012

Familial aggregation of Parkinson's disease in a multiethnic community-based case-control study.

Mov Disord 2010 Nov;25(15):2587-94

Department of Health Research and Policy, Division of Epidemiology, Stanford University School of Medicine, Stanford, California, USA.

To assess the familial aggregation of Parkinson's disease (PD), we compared the cumulative incidence of PD among first-degree relatives of PD cases and controls. We identified newly diagnosed patients with PD (n = 573) during 1994 to 1995 within Kaiser Permanente Medical Care Program of Northern California and recruited 496 cases (87%) for the case-control study. Of 720 eligible controls matched by birth year and sex to cases, 541 (75%) agreed to participate. Information on family history of PD and other neurodegenerative diseases was obtained by in-person structured interview. We used the reconstructed cohort approach that provides a better estimate of the risk. The cumulative incidence of PD was significantly higher among relatives of PD patients compared with relatives of controls (2.0 vs. 0.7%; relative risk (RR) = 3.4, 95% confidence interval (CI) 1.9-5.9; P = 0.0001). The degree of familial aggregation was higher among first-degree relatives of Hispanic PD cases compared with Hispanic controls (3.7% vs. 0.4%; RR = 8.5, 95% CI 1.0-68.9) than it was among non-Hispanic Caucasian cases and controls (2.0% vs. 0.8%; RR = 2.7, 95% CI 1.5-5.1; P = 0.02). The familial aggregation of PD was stronger among the siblings of PD cases (RR = 5.4, 95% CI 1.8-16.0) than among parents (RR = 2.7, 95% CI 1.3-5.2). The incidence and familial aggregation of PD is highest among Hispanics, warranting further studies of genetic and environmental risk factors in the Hispanic population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mds.23361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2978761PMC
November 2010