Publications by authors named "Rade Tomic"

27 Publications

  • Page 1 of 1

Lung donation following SARS-CoV-2 infection.

Am J Transplant 2021 Jul 31. Epub 2021 Jul 31.

Division of Thoracic Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.

There have been over 177 million cases of COVID-19 worldwide, many of whom could be organ donors. Concomitantly, there is an anticipated increase in the need for donor lungs due to expanding indications. Given that the respiratory tract is most commonly affected by COVID-19, there is an urgent need to develop donor assessment criteria while demonstrating safety and "efficacy" of lung donation following COVID-19 infection. Accordingly, we report an intentional transplant using lungs from a donor with recent, microbiologically confirmed, COVID-19 infection into a recipient suffering from COVID-19 induced ARDS and pulmonary fibrosis. In addition to the standard clinical assays, both donor and recipient lungs were analyzed using RNAscope, which confirmed that tissues were negative for SARS-CoV-2. Immunohistochemistry demonstrated colocalized KRT17+ basaloid-like epithelium and COL1A1+ fibroblasts, a marker suggestive of lung fibrosis in COVID-19 associated lung disease, in the explanted recipient lungs but absent in the donor lungs. We demonstrate that following a thorough assessment, lung donation following resolved COVID-19 infection is safe and feasible.
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http://dx.doi.org/10.1111/ajt.16777DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8441925PMC
July 2021

COVID-19 in hospitalized lung and non-lung solid organ transplant recipients: A comparative analysis from a multicenter study.

Am J Transplant 2021 08 24;21(8):2774-2784. Epub 2021 Jul 24.

Division of Infectious Disease, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, New York.

Lung transplant recipients (LTR) with coronavirus disease 2019 (COVID-19) may have higher mortality than non-lung solid organ transplant recipients (SOTR), but direct comparisons are limited. Risk factors for mortality specifically in LTR have not been explored. We performed a multicenter cohort study of adult SOTR with COVID-19 to compare mortality by 28 days between hospitalized LTR and non-lung SOTR. Multivariable logistic regression models were used to assess comorbidity-adjusted mortality among LTR vs. non-lung SOTR and to determine risk factors for death in LTR. Of 1,616 SOTR with COVID-19, 1,081 (66%) were hospitalized including 120/159 (75%) LTR and 961/1457 (66%) non-lung SOTR (p = .02). Mortality was higher among LTR compared to non-lung SOTR (24% vs. 16%, respectively, p = .032), and lung transplant was independently associated with death after adjusting for age and comorbidities (aOR 1.7, 95% CI 1.0-2.6, p = .04). Among LTR, chronic lung allograft dysfunction (aOR 3.3, 95% CI 1.0-11.3, p = .05) was the only independent risk factor for mortality and age >65 years, heart failure and obesity were not independently associated with death. Among SOTR hospitalized for COVID-19, LTR had higher mortality than non-lung SOTR. In LTR, chronic allograft dysfunction was independently associated with mortality.
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http://dx.doi.org/10.1111/ajt.16692DOI Listing
August 2021

Lung transplantation for patients with severe COVID-19.

Sci Transl Med 2020 12 30;12(574). Epub 2020 Nov 30.

Division of Pulmonary and Critical Care Medicine, Northwestern Memorial Hospital, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.

Lung transplantation can potentially be a life-saving treatment for patients with nonresolving COVID-19-associated respiratory failure. Concerns limiting lung transplantation include recurrence of SARS-CoV-2 infection in the allograft, technical challenges imposed by viral-mediated injury to the native lung, and the potential risk for allograft infection by pathogens causing ventilator-associated pneumonia in the native lung. Additionally, the native lung might recover, resulting in long-term outcomes preferable to those of transplant. Here, we report the results of lung transplantation in three patients with nonresolving COVID-19-associated respiratory failure. We performed single-molecule fluorescence in situ hybridization (smFISH) to detect both positive and negative strands of SARS-CoV-2 RNA in explanted lung tissue from the three patients and in additional control lung tissue samples. We conducted extracellular matrix imaging and single-cell RNA sequencing on explanted lung tissue from the three patients who underwent transplantation and on warm postmortem lung biopsies from two patients who had died from COVID-19-associated pneumonia. Lungs from these five patients with prolonged COVID-19 disease were free of SARS-CoV-2 as detected by smFISH, but pathology showed extensive evidence of injury and fibrosis that resembled end-stage pulmonary fibrosis. Using machine learning, we compared single-cell RNA sequencing data from the lungs of patients with late-stage COVID-19 to that from the lungs of patients with pulmonary fibrosis and identified similarities in gene expression across cell lineages. Our findings suggest that some patients with severe COVID-19 develop fibrotic lung disease for which lung transplantation is their only option for survival.
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http://dx.doi.org/10.1126/scitranslmed.abe4282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8050952PMC
December 2020

Lung transplantation for pulmonary fibrosis secondary to severe COVID-19.

medRxiv 2020 Oct 27. Epub 2020 Oct 27.

Lung transplantation can potentially be a life-saving treatment for patients with non-resolving COVID-19 acute respiratory distress syndrome. Concerns limiting transplant include recurrence of SARS-CoV-2 infection in the allograft, technical challenges imposed by viral-mediated injury to the native lung, and potential risk for allograft infection by pathogens associated with ventilator-induced pneumonia in the native lung. Additionally, the native lung might recover, resulting in long-term outcomes preferable to transplant. Here, we report the results of the first two successful lung transplantation procedures in patients with non-resolving COVID-19 associated acute respiratory distress syndrome in the United States. We performed smFISH to detect both positive and negative strands of SARS-CoV-2 RNA in the explanted lung tissue, extracellular matrix imaging using SHIELD tissue clearance, and single cell RNA-Seq on explant and warm post-mortem lung biopsies from patients who died from severe COVID-19 pneumonia. Lungs from patients with prolonged COVID-19 were free of virus but pathology showed extensive evidence of injury and fibrosis which resembled end-stage pulmonary fibrosis. Single cell RNA-Seq of the explanted native lungs from transplant and paired warm post-mortem autopsies showed similarities between late SARS-CoV-2 acute respiratory distress syndrome and irreversible end-stage pulmonary fibrosis requiring lung transplantation. There was no recurrence of SARS-CoV-2 or pathogens associated with pre-transplant ventilator associated pneumonias following transplantation in either patient. Our findings suggest that some patients with severe COVID-19 develop fibrotic lung disease for which lung transplantation is the only option for survival.

Single Sentence Summary: Some patients with severe COVID-19 develop end-stage pulmonary fibrosis for which lung transplantation may be the only treatment.
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http://dx.doi.org/10.1101/2020.10.26.20218636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605582PMC
October 2020

Impact of Screening and Treatment of Ureaplasma spp on Hyperammonemia Syndrome in Lung Transplant Recipients: A Single Center Experience.

Clin Infect Dis 2020 Oct 17. Epub 2020 Oct 17.

Division of Infectious Diseases, Northwestern University Feinberg School of Medicine, Chicago, Illinois.

Background: Infection with Ureaplasma species (spp) has been linked to fatal hyperammonemia syndrome (HS) in lung transplant recipients. We sought to characterize the epidemiology of Ureaplasma spp in candidates and donors and describe outcomes of antimicrobial therapy in preventing and treating HS.

Methods: Candidate testing for Ureaplasma spp was performed with urine culture and PCR pre-transplant. Positive candidates were treated with levofloxacin. Donor testing was performed with bronchoalveolar lavage culture and PCR intraoperatively. From 7/2014-2/2017 patients were treated according to results; from 2/2017-10/2018 recipients received empiric levofloxacin and azithromycin at transplant until testing returned negative. HS was defined as new onset altered mental status after transplant with ammonia > 200 µmol/L.

Results: 60 patients who underwent lung transplant were included. 80% (n = 48) of patients had negative screening tests in donor and candidate pre-lung transplant, 8.3% (n = 5) of recipients had positive Ureaplasma spp testing in urine pre-transplant, and 13.3% (n = 8) had positive donor BAL testing at the time of lung transplant. 3 patients developed HS a median of 7 days post-transplant; 2 died of HS. Recipients of organs with Ureaplasma spp who received empiric therapy did not develop HS. Donors with Ureaplasma spp were younger and more sexually active.

Conclusion: Donor-derived Ureaplasma spp in lung transplant was associated with HS. Screening lung donors for Ureaplasma spp might allow for targeted therapy to reduce risk for development of HS, but future confirmatory studies are needed.
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http://dx.doi.org/10.1093/cid/ciaa1570DOI Listing
October 2020

Feasibility of Venovenous Extracorporeal Membrane Oxygenation Without Systemic Anticoagulation.

Ann Thorac Surg 2020 10 12;110(4):1209-1215. Epub 2020 Mar 12.

Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois; Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois. Electronic address:

Background: Venovenous extracorporeal membrane oxygenation (ECMO) is increasingly being used for acute respiratory distress syndrome and as a bridge to lung transplantation. After initiation of venovenous ECMO, systemic anticoagulation therapy is traditionally administered and can cause bleeding diathesis. Here, we investigated whether venovenous ECMO can be administered without continuous systemic anticoagulation administration for patients with acute respiratory distress syndrome.

Methods: This is a retrospective review of an institutional ECMO database. We included consecutive patients from January 2015 through February 2019. Overall, 38 patients received low levels of continuous systemic anticoagulation (AC+) whereas the subsequent 36 patients received standard venous thromboprophylaxis (AC-). Published Extracorporeal Life Support Organization guidelines were used for the definition of outcomes and complications.

Results: Overall, survival was not different between the two groups (P = .58). However, patients in the AC+ group had higher rates of gastrointestinal bleeding (28.9%, vs AC- group 5.6%; P < .001). The events per patient-day of gastrointestinal bleeding was 0.00025 in the AC- group and 0.00064 in the AC+ group (P < .001). In addition, oxygenator dysfunction was increased in the AC+ group (28.9% and 0.00067 events per patient-day, vs AC- 11.1% and 0.00062 events per patient-day; P = .02). Furthermore, the AC+ group received more transfusions: packed red blood cells, AC+ group 94.7% vs AC- group 55.5% (P < .001); fresh frozen plasma, AC+ 60.5% vs AC- 16.6% (P = .001); and platelets, AC+ 84.2% vs AC- 27.7% (P < .001). There was no circuit thrombosis in either groups throughout the duration of ECMO support.

Conclusions: Our results suggest that venovenous ECMO can be safely administered without continuous systemic anticoagulation therapy. This approach may be associated with reduced bleeding diathesis and need for blood transfusions.
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http://dx.doi.org/10.1016/j.athoracsur.2020.02.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7486253PMC
October 2020

Need for tracheostomy after lung transplant predicts decreased mid- and long-term survival.

Clin Transplant 2020 01 31;34(1):e13766. Epub 2019 Dec 31.

Division of Cardiothoracic Transplantation and Circulatory Support, Texas Heart Institute, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX, USA.

Background: Tracheostomy is an important adjunct for lung transplant patients requiring prolonged ventilation. We explored the effects of post-transplant tracheostomy on survival and bronchiolitis obliterans syndrome after lung transplant.

Methods: A retrospective, single center analysis was performed on all lung transplant recipients during the Lung Allocation Score (LAS) era. Risk factors for post-transplant tracheostomy or death within 30 days were assessed. Kaplan-Meier estimates and Cox proportional hazards models were used to examine the association between tracheostomy within 30 days after transplant and survival at 1 and 3 years. A total of 403 patients underwent single or bilateral lung transplant between May 2005 and February 2016 with complete data for 352 cases, and 35 patients (9.9%) underwent tracheostomy or died (N = 10, 2.8%) within 30 days.

Results: In adjusted analyses, primary graft dysfunction grade 3 (PGD3) was associated with a composite end point of tracheostomy or death within 30 days (HR 3.11 (1.69, 5.71), P-value < .001). Tracheostomy within 30 days was associated with decreased survival at 1(HR 4.25 [1.75, 10.35] P-value = .001) and 3 years (HR 2.74 [1.30, 5.76], P-value = .008), as well as decreased bronchiolitis obliterans (BOS)-free survival at 1 (HR 1.87 [1.02, 3.41] P-value = .042) and 3 years (HR 2.15 [1.33, 3.5], P-value = .002).

Conclusion: Post-transplant tracheostomy is a marker for advanced lung allograft dysfunction with significant reduction in long-term overall and BOS-free survival.
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http://dx.doi.org/10.1111/ctr.13766DOI Listing
January 2020

Initial skin cancer screening for solid organ transplant recipients in the United States: Delphi method development of expert consensus guidelines.

Transpl Int 2019 Dec 8;32(12):1268-1276. Epub 2019 Oct 8.

Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Skin cancer is the most common malignancy affecting solid organ transplant recipients (SOTR), and SOTR experience increased skin cancer-associated morbidity and mortality. There are no formal multidisciplinary guidelines for skin cancer screening after transplant, and current practices are widely variable. We conducted three rounds of Delphi method surveys with a panel of 84 U.S. dermatologists and transplant physicians to establish skin cancer screening recommendations for SOTR. The transplant team should risk stratify SOTR for screening, and dermatologists should perform skin cancer screening by full-body skin examination. SOTR with a history of skin cancer should continue regular follow-up with dermatology for skin cancer surveillance. High-risk transplant patients include thoracic organ recipients, SOTR age 50 and above, and male SOTR. High-risk Caucasian patients should be screened within 2 years after transplant, all Caucasian, Asian, Hispanic, and high-risk African American patients should be screened within 5 years after transplant. No consensus was reached regarding screening for low-risk African American SOTR. We propose a standardized approach to skin cancer screening in SOTR based on multidisciplinary expert consensus. These guidelines prioritize and emphasize the need for screening for SOTR at greatest risk for skin cancer.
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http://dx.doi.org/10.1111/tri.13520DOI Listing
December 2019

Clinical relevance of lung-restricted antibodies in lung transplantation.

Hum Immunol 2019 Aug 8;80(8):595-601. Epub 2019 May 8.

Division of Thoracic Surgery, Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. Electronic address:

Lung transplant is a definitive treatment for several end-stage lung diseases. However, the high incidence of allograft rejection limits the overall survival following lung transplantation. Traditionally, alloimmunity directed against human leukocyte antigens (HLA) has been implicated in transplant rejection. Recently, the clinical impact of non-HLA lung-restricted antibodies (LRA) has been recognized and extensive research has demonstrated that they may play a dominant role in the development of lung allograft rejection. The immunogenic lung-restricted antigens that have been identified include amongst others, collagen type I, collagen type V, and k-alpha 1 tubulin. Pre-existing antibodies against these lung-restricted antigens are prevalent in patients undergoing lung transplantation and have emerged as one of the predominant risk factors for primary graft dysfunction which limits short-term survival following lung transplantation. Additionally, LRA have been shown to predispose to chronic lung allograft rejection, the predominant cause of poor long-term survival. This review will discuss ongoing research into the mechanisms of development of LRA as well as the pathogenesis of associated lung allograft injury.
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http://dx.doi.org/10.1016/j.humimm.2019.04.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6844365PMC
August 2019

Acute exacerbation of interstitial lung disease after procedures.

Respir Med 2019 04 12;150:30-37. Epub 2019 Feb 12.

Department of Medicine, Division of Pulmonary, Allergy, Critical Care, and Sleep, University of Minnesota, Minneapolis, MN, United States. Electronic address:

Interstitial lung disease (ILD) is a category of diffuse parenchymal lung diseases characterized by inflammation and/or fibrosis. The best characterized ILD is idiopathic pulmonary fibrosis (IPF). Acute exacerbation of IPF is a dreaded occurrence with grim prognosis and suboptimal treatment options. There have been recent reports that acute exacerbation can occur in other ILDs (AE-ILD). Of note, some of these acute exacerbations follow lung procedures. This review summarizes the available information on AE-ILD and discusses the procedures reported to cause AE-ILD. We also discuss proposed mechanisms, risk factors, treatment and prognosis. This review should help to inform decision-making about risks versus benefits of procedures that are commonly recommended to diagnose ILD.
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http://dx.doi.org/10.1016/j.rmed.2019.02.012DOI Listing
April 2019

Patients' perceptions and patient-reported outcomes in progressive-fibrosing interstitial lung diseases.

Eur Respir Rev 2018 Dec 21;27(150). Epub 2018 Dec 21.

Clinical Research Center, National Hospital Organization Kinki-Chuo Chest Medical Center, Osaka, Japan.

The effects of interstitial lung disease (ILD) create a significant burden on patients, unsettling almost every domain of their lives, disrupting their physical and emotional well-being and impairing their quality of life (QoL). Because many ILDs are incurable, and there are limited reliably-effective, life-prolonging treatment options available, the focus of many therapeutic interventions has been on improving or maintaining how patients with ILD feel and function, and by extension, their QoL. Such patient-centred outcomes are best assessed by patients themselves through tools that capture their perceptions, which inherently incorporate their values and judgements. These patient-reported outcome measures (PROs) can be used to assess an array of constructs affected by a disease or the interventions implemented to treat it. Here, we review the impact of ILD that may present with a progressive-fibrosing phenotype on patients' lives and examine how PROs have been used to measure that impact and the effectiveness of therapeutic interventions.
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http://dx.doi.org/10.1183/16000617.0075-2018DOI Listing
December 2018

Single Versus Bilateral Lung Transplantation for Idiopathic Pulmonary Fibrosis in the Lung Allocation Score Era.

J Surg Res 2019 02 5;234:84-95. Epub 2018 Oct 5.

Division of Cardiothoracic Surgery, Department of Surgery, University of Minnesota, Minneapolis, Minnesota.

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease. Lung transplantation is the only therapy associated with prolonged survival. The ideal transplant procedure for IPF is unclear. Outcomes after single transplantation (SLTx) versus bilateral lung transplantation (BLTx) in IPF patients after introduction of the Lung Allocation Score were examined.

Methods: Records of patients undergoing lung transplantation for IPF at our institution between May 2005 and March 2017 were reviewed to examine the effect of transplant laterality. Primary outcomes were overall, rejection-free, and bronchiolitis obliterans (BOS)-free survival at 1 and 5 years post-transplant.

Results: Lung transplantation was performed in 151 IPF patients post-Lung Allocation Score. Most recipients were male with average age 59 ± 8 years. SLTx was performed in 94 patients (62%). In the overall cohort, comparative survival between SLTx and BLTx was similar at 1 and 5 years before and after adjusting for age and pulmonary hypertension (PH). SLTx was associated with shorter ventilator time and intensive care unit stay and trended toward improved survival over BLTx in patients without PH.

Conclusions: The use of SLTx versus BLTx in IPF did not correspond to significantly different survival adjusting for age and PH. BLTx was associated with prolonged postoperative ventilation and length of stay compared with SLTx. Patients without PH, all older patients, and patients with PH and advanced disease should be considered for SLTx for IPF.
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http://dx.doi.org/10.1016/j.jss.2018.08.054DOI Listing
February 2019

Secondary pulmonary arterial hypertension: to treat or not to treat?

Curr Opin Organ Transplant 2018 06;23(3):324-329

Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA.

Purpose Of Review: The purpose of this review is to review recent literature related to mechanisms and treatment options for 'secondary' (i.e., WHO Groups 3 and 5) pulmonary arterial hypertension (PAH).

Recent Findings: Published randomized controlled trials, in general, do not support the use of approved therapies for 'primary' (i.e., WHO Group 1) PAH patients in patients with Group 3 PAH because of the small numbers of patients and inconsistent benefit. Therefore, we currently recommend against the use of these medications for Group 3 PAH. Similarly, there is limited evidence supporting the use of Group 1 PAH medications in Group 5 patients. In most patients with Group 5 PAH, treatment should be directed to the underlying disease.

Summary: The utility of PAH-specific therapy in WHO Group 3 PAH is unclear because of the small numbers of patients evaluated and inconsistent beneficial effects observed. There is limited evidence supporting the use of PAH medications in Group 5 patients, and they may be harmful in some cases.
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http://dx.doi.org/10.1097/MOT.0000000000000529DOI Listing
June 2018

Acute Exacerbation of Interstitial Lung Disease After Cryobiopsy.

J Bronchology Interv Pulmonol 2017 Oct;24(4):319-322

*Division of Pulmonary, Allergy, Critical Care and Sleep Medicine †Department of Internal Medicine ‡Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN.

Cryotherapy has been used in treatment of lung cancer for decades. The utility of cryotechnology in diagnosis of lung diseases is emerging and gaining popularity. Cryobiopsy (CB) of the lung, when compared with conventional transbronchial forceps lung biopsy, has proposed to have a higher diagnostic yield in interstitial lung disease by providing larger biopsy specimen and less crush artifact. Acute exacerbation of interstitial lung disease (AEILD) has been well described with surgical lung biopsies and, rarely, with conventional transbronchial forceps biopsy. The incidence of AEILD after CB is not known. Here we are presenting a case of AEILD after CB.
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http://dx.doi.org/10.1097/LBR.0000000000000369DOI Listing
October 2017

Air in the Left Ventricle. An Unusual Case of Endocarditis.

Am J Respir Crit Care Med 2016 05;193(10):1176-7

1 Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, and.

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http://dx.doi.org/10.1164/rccm.201506-1156IMDOI Listing
May 2016

Novel mechanisms and treatment of idiopathic pulmonary fibrosis.

Discov Med 2015 Sep;20(109):145-53

Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA.

Idiopathic pulmonary fibrosis (IPF) is a devastating progressive disease of unknown etiology that carries a grim prognosis. Over the last few decades there have been significant advances in our understanding of the mechanisms that drive the fibrotic process. In this review, we discuss the natural history of IPF, recent discoveries of the genetic factors, and environmental and infectious exposures that influence the development and progression of the disease, and highlight some of the novel discoveries in our understanding of the mechanisms that govern lung fibrosis. Finally, we discuss the new and exciting therapies that are now available to manage this illness.
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September 2015

Cognitive function in idiopathic pulmonary fibrosis.

Chron Respir Dis 2015 Nov 15;12(4):365-72. Epub 2015 Sep 15.

Division of Pulmonary, Allergy, Critical Care, and Sleep, Medical University of South Carolina, Charleston, SC, USA.

The purpose of this study was to investigate whether there is evidence that individuals with severe idiopathic pulmonary fibrosis (IPF) have cognitive deficits when compared to individuals with healthy lungs. Participants completed five neuropsychological tests: Trail Making Test (TMT) A and B, Stroop Color Word Test (1, 2, 3), Hopkins Verbal Learning Test, Boston Naming Test, and Grooved Pegboard Test, additionally, the short form-36 and Beck Depression Index. Twelve participants (7 male, mean age 69.3, 9.4 years) comprised the severe IPF group defined by a diffusion capacity for carbon monoxide (DLCO) <30%. Thirty-four patients (22 male, mean age 63.2, 9.6 years) comprised the mild-to-moderate group with a DLCO >30%. Participating spouses (n = 15, 4 male) served as the control group and had a mean age of 66.0, 10.8 years. Controlling for gender and age, the severe group had a significantly longer mean TMT B time (69.4, 135.9 seconds) than the mild group and the control group (86.7 seconds vs 83.2 seconds; p = 0.004 and 0.008 respectively), suggesting inferior performance on tasks requiring speed divided attention. In addition, the severe group had a significantly lower number of correctly identified colors in the Stroop 3 test (22.4 vs 30.6 vs 38.6; p < 0.001), suggesting slower processing speeds when requiring suppression of a familiar response. Participants with severe IPF had worse cognitive function than mild IPF or control subjects. Further research is needed to explain these findings and to develop interventions tailored to address these deficits.
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http://dx.doi.org/10.1177/1479972315603552DOI Listing
November 2015

Significance of granulomatous inflammation in usual interstitial pneumonia.

Sarcoidosis Vasc Diffuse Lung Dis 2015 Jul 22;32(2):160-6. Epub 2015 Jul 22.

University of Minnesota Medical School.

Sarcoidosis is a systemic granulomatous disease of unclear etiology with characteristic pulmonary lesions. We describe 2 unique cases of sarcoidosis where after approximately 20 years of clinical quiescence, patients developed interstitial opacities on chest CT scan and an increase in shortness of breath. With lack of therapeutic response to a course of prednisone, both patients underwent a surgical lung biopsy that revealed a pattern consistent with Usual Interstitial Pneumonia (UIP) with honeycombing and fibroblastic foci. Postoperatively, the course of the disease was consistent with what would be expected in Idiopathic Pulmonary Fibrosis. Ultimately the disease progressed with one patient needed lung transplantation and the other requiring high-flow oxygen supplementation. In conclusion, we present two patients in whom a diagnosis of sarcoidosis preceded the diagnosis of UIP by 20 years or more. The subsequent course of disease in both patients was consistent with Idiopathic Pulmonary Fibrosis.
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July 2015

Natural history of idiopathic pulmonary fibrosis.

Respir Med 2015 Jun 14;109(6):661-70. Epub 2015 Feb 14.

Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, University of Minnesota, 420 Delaware Street, MMC 276, Minneapolis, MN 55455, USA.

Idiopathic pulmonary fibrosis (IPF) is a parenchymal lung disease characterized by progressive interstitial fibrosis. IPF has a poor prognosis, with a median survival time of 2-3 years from diagnosis, but varying from a few months to a decade. The natural history of IPF is highly variable and the course of disease in an individual patient is difficult to predict. Some patients with IPF experience rapid decline, others progress much more slowly, and some patients show periods of relative stability interspersed with acute deteriorations in respiratory function. Many clinical, radiographic, serologic, and histopathologic variables have been shown to predict mortality in IPF. However, the accuracy of these predictors varies due to the retrospective nature of some of the studies and variations in study design. The ability to identify clinical characteristics that predict disease progression and survival would be useful for counseling patients, treatment decision-making, and prompt consideration for lung transplantation. A number of indices for predicting mortality in patients with IPF are available, but they require further validation. As high-resolution computed tomography scans become more widely available and patients with IPF are diagnosed earlier, survival times following diagnosis will improve. Early referral to interstitial lung disease specialty centers is important for accurate diagnosis and may be associated with improved outcomes. The goal of this review is to examine the natural history of IPF, discuss predictors of mortality, and highlight the importance of prompt diagnosis and referral for patients with IPF.
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http://dx.doi.org/10.1016/j.rmed.2015.02.002DOI Listing
June 2015

Cryotechnology in diagnosing and treating lung diseases.

J Bronchology Interv Pulmonol 2015 Jan;22(1):76-84

*Division of Pulmonary, Allergy, Critical Care and Sleep Medicine †Division of Cardiothoracic Surgery, Section of Thoracic and Foregut Surgery, University of Minnesota, Minneapolis, MN.

Cryotechnology has been used in treating lung cancer for many years, now it is emerging to have a new indication in diagnosing lung diseases. Cryoprobe transbronchial lung biopsy has been introduced into clinical practice as a new technique, providing a larger biopsy specimen, potentially improving the diagnostic yield of transbronchial biopsies in parenchymal lung diseases. Although recent small pilot studies suggest that cryotransbronchial lung biopsies are comparable to conventional transbronchial biopsies in terms of diagnostic yield and safety profile in lung transplant patients, cryoprobe transbronchial lung biopsy is still being evaluated and its role in clinical practice is not well defined. Cryotherapy has been proven as a safe and effective method to debulk endobronchial lesions, providing palliation for advanced central obstructive tumors. Its use and efficacy is also studied in direct cryosurgery and percutaneous application in lung cancer. Cryoprobes can also be used to extract foreign bodies from the airways by causing cryoadhesion. We aim to summarize the therapeutic and diagnostic application of cryotechnology in pulmonary diseases.
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http://dx.doi.org/10.1097/LBR.0000000000000103DOI Listing
January 2015

Chyloptysis causing plastic bronchitis.

Respir Med Case Rep 2014 8;13:4-6. Epub 2014 Jun 8.

Pulmonary, Allergy, Critical Care and Sleep Medicine, University of Minnesota, MMC 276, 420 Delaware St SE, Minneapolis, MN 55455, United States.

Chyloptysis is a rare clinical problem that is associated with conditions affecting lymphatic channels in the thorax. Diagnosis is usually made when the patients present with expectoration of milky-white sputum or of thick tenacious mucus in the shape of smaller bronchi (bronchial cast). Typically the symptoms resolve after coughing up of the bronchial casts. Pleural, mediastinal, pulmonary or lymphatic abnormalities result in chyloptysis. Lymphangiography and detection of lipids (cholesterol or triglycerides) in sputum help to establish the diagnosis. However, lymphangiography may not be positive in all patients. We report 2 patients with chyloptysis and bronchial casts with different etiologies. Abnormal lymphatics were demonstrated in one of our cases, but the second patients lymphangiogram was normal. In this patient we suspect that high venous filling pressures due to congestive heart failure had a causative effect in the setting of compromised lymphatic drainage in the thorax due to a prior history of radiation therapy to the chest for lymphoma.
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http://dx.doi.org/10.1016/j.rmcr.2013.12.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4246250PMC
June 2015

Decreased risk of radiation pneumonitis with incidental concurrent use of angiotensin-converting enzyme inhibitors and thoracic radiation therapy.

Int J Radiat Oncol Biol Phys 2012 Sep 31;84(1):238-43. Epub 2012 Jan 31.

Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, WI, USA.

Purpose: Angiotensin-converting enzyme (ACE) inhibitors have been shown to mitigate radiation-induced lung injury in preclinical models. The aim of this study was to evaluate whether ACE inhibitors decrease the risk of radiation pneumonitis in lung cancer patients receiving thoracic irradiation.

Methods And Materials: Patients with Stage I through III small-cell and non-small-cell lung cancer treated definitively with radiation from 2004-2009 at the Clement J. Zablocki Veterans Affairs Medical Center were retrospectively reviewed. Acute pulmonary toxicity was quantified within 6 months of completion of treatment according to the Common Terminology Criteria for Adverse Events version 4. The use of ACE inhibitors, nonsteroidal anti-inflammatory drugs, inhaled glucocorticosteroids, statins, and angiotensin receptor blockers; dose-volume histogram parameters; and patient factors were assessed for association with Grade 2 or higher pneumonitis.

Results: A total of 162 patients met the criteria for inclusion. The majority of patients had Stage III disease (64%) and received concurrent chemotherapy (61%). Sixty-two patients were identified as ACE inhibitor users (38%). All patients had acceptable radiation plans based on dose-volume histogram constraints (V20 [volume of lung receiving at least 20 Gy] ≤37% and mean lung dose ≤20 Gy) with the exception of 2 patients who did not meet both criteria. Grade 2 or higher pulmonary toxicity occurred in 12 patients (7.4%). The rate of Grade 2 or higher pneumonitis was lower in ACE inhibitor users vs. nonusers (2% vs. 11%, p = 0.032). Rates of Grade 2 or higher pneumonitis were significantly increased in patients aged greater than 70 years (16% vs. 2%, p = 0.005) or in whom V5 (volume of lung receiving at least 5 Gy) was 50% or greater (13% vs. 4%, p = 0.04). V10 (volume of lung receiving at least 10 Gy), V20, V30 (volume of lung receiving at least 30 Gy), and mean lung dose were not independently associated with Grade 2 or higher pneumonitis.

Conclusion: ACE inhibitors may decrease the incidence of radiation pneumonitis in patients receiving thoracic radiation for lung cancer. These findings are consistent with preclinical evidence and should be prospectively evaluated.
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http://dx.doi.org/10.1016/j.ijrobp.2011.11.013DOI Listing
September 2012

Mitigation of late renal and pulmonary injury after hematopoietic stem cell transplantation.

Int J Radiat Oncol Biol Phys 2012 May 19;83(1):292-6. Epub 2011 Nov 19.

Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.

Purpose: To update the results of a clinical trial that assessed whether the angiotensin-converting enzyme inhibitor captopril was effective in mitigating chronic renal failure and pulmonary-related mortality in subjects undergoing total body irradiation (TBI) in preparation for hematopoietic stem cell transplantation (HSCT).

Methods And Materials: Updated records of the 55 subjects who were enrolled in this randomized controlled trial were analyzed. Twenty-eight patients received captopril, and 27 patients received placebo. Definitions of TBI-HSCT-related chronic renal failure (and relapse) were the same as those in the 2007 analysis. Pulmonary-related mortality was based on clinical or autopsy findings of pulmonary failure or infection as the primary cause of death. Follow-up data for overall and pulmonary-related mortality were supplemented by use of the National Death Index.

Results: The risk of TBI-HSCT-related chronic renal failure was lower in the captopril group (11% at 4 years) than in the placebo group (17% at 4 years), but this was not statistically significant (p > 0.2). Analysis of mortality was greatly extended by use of the National Death Index, and no patients were lost to follow-up for reasons other than death prior to 67 months. Patient survival was higher in the captopril group than in the placebo group, but this was not statistically significant (p > 0.2). The improvement in survival was influenced more by a decrease in pulmonary mortality (11% risk at 4 years in the captopril group vs. 26% in the placebo group, p = 0.15) than by a decrease in chronic renal failure. There was no adverse effect on relapse risk (p = 0.4).

Conclusions: Captopril therapy produces no detectable adverse effects when given after TBI. Captopril therapy reduces overall and pulmonary-related mortality after radiation-based HSCT, and there is a trend toward mitigation of chronic renal failure.
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http://dx.doi.org/10.1016/j.ijrobp.2011.05.081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3299939PMC
May 2012

Nontuberculous mycobacterial hypersensitivity pneumonitis related to a home shower: treatment and secondary prevention.

BMJ Case Rep 2011 Jul 28;2011. Epub 2011 Jul 28.

Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.

A 57-year-old physician with increasing dyspnoea and hypoxaemia had a high-resolution CT scan of the chest, which disclosed diffuse pulmonary ground glass opacities, more pronounced in the upper lobes with minimal mediastinal lymphadenopathy. Transbronchial biopsy of the right middle and lower lobes was performed, demonstrating varying degrees of well circumscribed organising granulomatous pneumonitis thought to be most consistent with hypersensitivity to nontuberculous mycobacteria. Cultures of water obtained from the patient's home shower were positive for Mycobacterium avium complex. The patient began substituting baths for showers, experiencing some gradual improvement of his symptoms. Subsequently, he installed point-of-use 0.2 micron membrane filters on his shower, and resumed regular showering after installation with continued symptomatic improvement. CT scans at 3 and 18 months revealed improvement and resolution, respectively. Four years later, he continues to shower in filtered home shower water and remains clinically well.
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http://dx.doi.org/10.1136/bcr.06.2011.4360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3149474PMC
July 2011

Cellular inflammatory infiltrate in pneumonitis induced by a single moderate dose of thoracic x radiation in rats.

Radiat Res 2010 Apr;173(4):545-56

Department of Pathology, Children's Hospital, Milwaukee, Wisconsin 53226, USA.

The goal of these studies was to characterize the infiltrating inflammatory cells during pneumonitis caused by moderate doses of radiation. Two groups of male rats (WAG/RijCmcr, 8 weeks old) were treated with single 10- or 15-Gy doses of thoracic X radiation; a third group of age-matched animals served as controls. Only 25% rats survived the 15-Gy dose. Bronchoalveolar lavage fluid and whole lung mounts were subjected to cytological and histological evaluation after 8 weeks for distribution of resident macrophages, neutrophils, lymphocytes and mast cells. There was a modest increase in airway and airspace-associated neutrophils in lungs from rats receiving 15 Gy. Mast cells (detected by immunohistochemistry for tryptase) increased over 70% with 10 Gy and over 13-fold after 15 Gy, with considerable leakage of tryptase into blood vessels and airways. Circulating levels of eight inflammatory cytokines were not altered after 10 Gy but appeared to decrease after 15 Gy. In summary, there were only modest increases in cellular inflammatory infiltrate during pneumonitis after a non-lethal dose of 10 Gy, but there was a dramatic rise in mast cell infiltration after 15 Gy, suggesting that circulating levels of mast cell products may be useful markers of severe pneumonitis.
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http://dx.doi.org/10.1667/RR1753.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2904484PMC
April 2010

C-reactive protein and copeptin: prognostic predictors in chronic obstructive pulmonary disease exacerbations.

Curr Opin Pulm Med 2009 Mar;15(2):120-5

Pulmonary Department, Medical College of Wisconsin, 9200 W Wisconsin Ave, Milwaukee, WI 53226, USA.

Purpose Of Review: Acute exacerbation of chronic obstructive pulmonary disease (COPD) is a natural event in the course of COPD and remains a major cause of morbidity and mortality associated with this disease. Clinical criteria that define an acute exacerbation are subjective and open for debate. Identifying biomarkers that would be easily measured and followed in patients with acute exacerbation of COPD seems to be highly attractive. The aim of this review is to assess the role of biomarkers, C-reactive protein (CRP) and copeptin, as prognostic predictors in COPD exacerbations.

Recent Findings: Many pulmonary biomarkers have been extensively studied in the recent years. CRP and copeptin have gained particular interest. Recent data suggest that CRP is elevated during an acute exacerbation of COPD but CRP alone is neither sensitive nor specific in predicting clinical severity or outcome. Copeptin increases during acute exacerbation of COPD and may correlate with disease severity.

Summary: Further studies are needed to determine the role of CRP and copeptin as biomarkers that aid in diagnosis and clinical outcome in acute exacerbation of COPD.
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http://dx.doi.org/10.1097/MCP.0b013e3283218603DOI Listing
March 2009

Anti-tissue remodeling effects of corticosteroids: fluticasone propionate inhibits fibronectin expression in fibroblasts.

Chest 2005 Jan;127(1):257-65

Department of Medicine, Atlanta VA Medical Center and Emory University School of Medicine, Atlanta, GA 30322, USA.

Objectives: Tissue remodeling often accompanies diseases such as COPD that are caused by or aggravated by tobacco exposure. Inhaled or systemic corticosteroids are frequently used for the treatment of these illnesses, and their beneficial effects are often ascribed to their anti-inflammatory properties. However, their role in tissue remodeling remains unclear. This study was designed to evaluate the role of corticosteroids in matrix expression in vitro.

Design: We investigated the effects of the corticosteroid fluticasone propionate (FP) on the production of fibronectin by fibroblasts before and after stimulation by nicotine, a plant alkaloid found in tobacco. Fibronectin is an extracellular matrix glycoprotein found elevated in the alveolar lining fluid and airway walls of subjects with obstructive lung disease, and is considered a marker of tissue remodeling after injury.

Results: FP, 1 micromol/L, inhibited the expression of fibronectin messenger RNA and protein in unstimulated NIH-3T3 cells and primary lung fibroblasts, as well as in fibroblasts stimulated with nicotine. The inhibitory effect of FP occurred at the level of gene transcription as demonstrated in lung fibroblasts expressing a construct containing the human fibronectin promoter connected to a luciferase reporter gene, but posttranscriptional effects also appeared involved. Electrophoresis mobility gel shift assays revealed that FP inhibited phosphorylation and DNA binding by the cyclic adenosine monophosphate response element binding protein, a transcription factor required for constitutive and nicotine-induced fibronectin expression.

Conclusions: Together, these data suggest that FP could diminish lung tissue remodeling by inhibiting the production of fibronectin in lung fibroblasts.
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http://dx.doi.org/10.1378/chest.127.1.257DOI Listing
January 2005
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