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Acute and chronic effects of treatment with mesenchymal stromal cells on LPS-induced pulmonary inflammation, emphysema and atherosclerosis development.

Fri, 10/13/2017 - 12:45
Related Articles

Acute and chronic effects of treatment with mesenchymal stromal cells on LPS-induced pulmonary inflammation, emphysema and atherosclerosis development.

PLoS One. 2017;12(9):e0183741

Authors: Khedoe PPSJ, de Kleijn S, van Oeveren-Rietdijk AM, Plomp JJ, de Boer HC, van Pel M, Rensen PCN, Berbée JFP, Hiemstra PS

Abstract
BACKGROUND: COPD is a pulmonary disorder often accompanied by cardiovascular disease (CVD), and current treatment of this comorbidity is suboptimal. Systemic inflammation in COPD triggered by smoke and microbial exposure is suggested to link COPD and CVD. Mesenchymal stromal cells (MSC) possess anti-inflammatory capacities and MSC treatment is considered an attractive treatment option for various chronic inflammatory diseases. Therefore, we investigated the immunomodulatory properties of MSC in an acute and chronic model of lipopolysaccharide (LPS)-induced inflammation, emphysema and atherosclerosis development in APOE*3-Leiden (E3L) mice.
METHODS: Hyperlipidemic E3L mice were intranasally instilled with 10 μg LPS or vehicle twice in an acute 4-day study, or twice weekly during 20 weeks Western-type diet feeding in a chronic study. Mice received 0.5x106 MSC or vehicle intravenously twice after the first LPS instillation (acute study) or in week 14, 16, 18 and 20 (chronic study). Inflammatory parameters were measured in bronchoalveolar lavage (BAL) and lung tissue. Emphysema, pulmonary inflammation and atherosclerosis were assessed in the chronic study.
RESULTS: In the acute study, intranasal LPS administration induced a marked systemic IL-6 response on day 3, which was inhibited after MSC treatment. Furthermore, MSC treatment reduced LPS-induced total cell count in BAL due to reduced neutrophil numbers. In the chronic study, LPS increased emphysema but did not aggravate atherosclerosis. Emphysema and atherosclerosis development were unaffected after MSC treatment.
CONCLUSION: These data show that MSC inhibit LPS-induced pulmonary and systemic inflammation in the acute study, whereas MSC treatment had no effect on inflammation, emphysema and atherosclerosis development in the chronic study.

PMID: 28910300 [PubMed - indexed for MEDLINE]

Change of sleep quality from pre- to 3 years post-solid organ transplantation: The Swiss Transplant Cohort Study.

Thu, 10/12/2017 - 10:01

Change of sleep quality from pre- to 3 years post-solid organ transplantation: The Swiss Transplant Cohort Study.

PLoS One. 2017;12(10):e0185036

Authors: Burkhalter H, Denhaerynck K, Huynh-Do U, Binet I, Hadaya K, De Geest S, Psychosocial Interest Group, Swiss Transplant Cohort Study

Abstract
BACKGROUND: Poor sleep quality (SQ) is common after solid organ transplantation; however, very little is known about its natural history. We assessed the changes in SQ from pre- to 3 years post-transplant in adult heart, kidney, liver and lung recipients included in the prospective nation-wide Swiss Transplant Cohort Study. We explored associations with selected variables in patients suffering persistent poor SQ compared to those with good or variable SQ.
METHODS: Adult single organ transplant recipients enrolled in the Swiss Transplant Cohort Study with pre-transplant and at least 3 post-transplant SQ assessment data were included. SQ was self-reported pre-transplant (at listing), then at 6, 12, 24 and 36 months post-transplant. A single SQ item was used to identify poor (0-5) and good sleepers (6-10). Between organ groups, SQ was compared via logistic regression analysis with generalized estimating equations. Within the group reporting persistently poor SQ, we used logistic regression or Kaplan-Meier analysis as appropriate to check for differences in global quality of life and survival.
RESULTS: In a sample of 1173 transplant patients (age: 52.1±13.2 years; 65% males; 66% kidney, 17% liver, 10% lung, 7% heart) transplanted between 2008 and 2012, pre- transplant poor SQ was highest in liver (50%) and heart (49%) recipients. Overall, poor SQ decreased significantly from pre-transplant (38%) to 24 months post-transplant (26%) and remained stable at 3 years (29%). Patients reporting persistently poor SQ had significantly more depressive symptomatology and lower global quality of life.
CONCLUSION: Because self-reported poor SQ is related to poorer global quality of life, these results emphasize the need for further studies to find suitable treatment options for poor SQ in transplant recipients.

PMID: 29020112 [PubMed - in process]

Venous Thromboembolism After Adult Lung Transplantation: A Frequent Event Associated with Lower Survival.

Thu, 10/12/2017 - 10:01

Venous Thromboembolism After Adult Lung Transplantation: A Frequent Event Associated with Lower Survival.

Transplantation. 2017 Oct 10;:

Authors: Ribeiro Neto ML, Budev M, Culver DA, Lane CR, Gomes M, Wang XF, Rocha PN, Olman MA

Abstract
BACKGROUND: The incidence of venous thromboembolism (VTE) after lung transplantation (LTX) varies significantly across studies. Two studies have suggested that these thrombotic events are associated with a lower posttransplant survival. Herein, we sought to determine the incidence, predictors and impact of VTE on survival after LTX at a quaternary referral center.
METHODS: This was a large cohort study of LTX recipients. Key outcome parameters were time to VTE after transplant and survival. Deep vein thrombosis (DVT) diagnosis required a positive ultrasound. Pulmonary embolism diagnosis required either a positive chest computed tomography angiogram or a high-probability ventilation/perfusion scan.
RESULTS: The overall incidence of VTE among 701 LTX recipients was 43.8%, of which 97.7% were DVT episodes, of which 71.3% were in the upper extremities. Predictors of VTE were prior history of DVT (HR 2.82, 95% CI 1.49 - 5.37), days in intensive care (HR 1.01, 95% CI 1.01 - 1.02), and the use of extracorporeal membrane oxygenation (HR 2.22, 95% CI 1.43 - 3.45). Importantly, VTE predicted a lower posttransplant survival (HR 1.70, 95% CI 1.28 - 2.26), when occurring within or after the first 30 days. The location of the DVT, either upper extremity or below the knee, also predicted a poor survival.
CONCLUSIONS: VTE was frequent in LTX recipients and predicted a poor survival even when located in the upper extremities or below the knee. Post LTX factors were the major predictors of VTE. These data suggest that aggressive VTE screening/treatment protocols be implemented in post LTX population.

PMID: 29019812 [PubMed - as supplied by publisher]

Interstitial Lung Disease in Children Made Easier…Well, Almost.

Thu, 10/12/2017 - 10:01

Interstitial Lung Disease in Children Made Easier…Well, Almost.

Radiographics. 2017 Oct;37(6):1679-1703

Authors: Semple TR, Ashworth MT, Owens CM

Abstract
Interstitial lung disease (ILD) in pediatric patients is different from that in adults, with a vast array of pathologic conditions unique to childhood, varied modes of presentation, and a different range of radiologic appearances. Although rare, childhood ILD (chILD) is associated with significant morbidity and mortality, most notably in conditions of disordered surfactant function, with respiratory failure in 100% of neonates with surfactant protein B dysfunction and 100% mortality without lung transplantation. The authors present a summary of lung development and anatomy, followed by an organized approach, using the structure and nomenclature of the 2013 update to the chILD Research Network classification system, to aid radiologic diagnosis of chILD. Index radiologic cases with contemporaneous histopathologic findings illustrate a summary of recent imaging studies covering the full spectrum of chILD. chILD is best grouped by age at presentation from infancy (diffuse developmental disorders, lung growth abnormalities, specific conditions of unknown origin, surfactant dysfunction mutations) to later childhood (disorders of the normal host, disorders related to systemic disease processes, disorders related to immunocompromise). Appreciation of the temporal division of chILD into infant and later childhood onset, along with a sound understanding of pulmonary organogenesis and surfactant homeostasis, will aid in providing useful insight into this important group of pediatric conditions. Application of secondary lobular anatomy to interpretation of thin-section computed tomographic images is pivotal to understanding patterns of ILD and will aid in selecting and narrowing a differential diagnosis. (©)RSNA, 2017.

PMID: 29019755 [PubMed - in process]

Very Early-Onset Inflammatory Manifestations of X-Linked Chronic Granulomatous Disease.

Thu, 10/12/2017 - 10:01

Very Early-Onset Inflammatory Manifestations of X-Linked Chronic Granulomatous Disease.

Front Immunol. 2017;8:1167

Authors: Labrosse R, Abou-Diab J, Blincoe A, Cros G, Luu TM, Deslandres C, Dirks M, Fazilleau L, Ovetchkine P, Teira P, LeDeist F, Fernandez I, Touzot F, Decaluwe H, Halac U, Haddad E

Abstract
Chronic granulomatous disease (CGD) is a rare primary immune deficiency caused by mutations in genes coding for components of the nicotinamide adenine dinucleotide phosphate oxidase, characterized by severe and recurrent bacterial and fungal infections, together with inflammatory complications. Dysregulation of inflammatory responses are often present in this disease and may lead to granulomatous lesions, most often affecting the gastrointestinal (GI) and urinary tracts. Treatment of inflammatory complications usually includes corticosteroids, whereas antimicrobial prophylaxis is used for infection prevention. Curative treatment of both infectious susceptibility and inflammatory disease can be achieved by hematopoietic stem cell transplantation. We report herein three patients with the same mutation of the CYBB gene who presented with very early-onset and severe GI manifestations of X-linked CGD. The most severely affected patient had evidence of antenatal inflammatory involvement of the GI and urinary tracts. Extreme hyperleukocytosis with eosinophilia and high inflammatory markers were observed in all three patients. A Mycobacterium avium lung infection and an unidentified fungal lung infection occurred in two patients both during their first year of life, which is indicative of the severity of the disease. All three patients underwent bone marrow transplantation and recovered fully from their initial symptoms. To our knowledge, these are the first reports of patients with such an early-onset and severe inflammatory manifestations of CGD.

PMID: 29018441 [PubMed]

Triggering Receptor Expressed on Myeloid Cells-2 (TREM-2) expression tracks with M2-like macrophage activity and disease severity in COPD.

Thu, 10/12/2017 - 10:01

Triggering Receptor Expressed on Myeloid Cells-2 (TREM-2) expression tracks with M2-like macrophage activity and disease severity in COPD.

Chest. 2017 Oct 07;:

Authors: Byers DE, Wu K, Dang-Vu G, Jin X, Agapov E, Zhang X, Battaile JT, Schechtman K, Yusen R, Pierce RA, Holtzman MJ

Abstract
BACKGROUND: Cell and animal models show a key role for Triggering Receptor Expressed on Myeloid Cells-2 (TREM-2) in chronic airway disease after viral infection but comparable evidence in humans still needs to be established.
METHODS: Lung tissue samples were obtained from lung transplant recipients with GOLD Stage 4 COPD (n=16), non-transplantable donor lung tissues (n=10), and resected lung tissues from at-risk or GOLD Stage 1-4 patients (n=72) and were assessed for TREM-2 and TREM-1 mRNA, protein expression, and other markers of a type 2 immune response.
RESULTS: TREM2 (but not TREM1) mRNA levels were increased in GOLD 4 COPD lung tissues compared to non-COPD lung tissues. TREM2 mRNA was co-expressed with its signaling molecule DAP12 as well as the macrophage marker CD68 and M2-macrophage markers CD206 and Chitinase 1 (CHIT1). TREM-2 protein was also increased in COPD lung tissues and was localized to CD14(+) macrophages by flow cytometry and CD68(+) and CCR2(+) macrophages by tissue immunostaining. In lung samples from at-risk and GOLD Stages 1-4 patients, TREM2 but not TREM1 mRNA levels were also increased, and the ratio of TREM2/TREM1 mRNA levels was associated with increases in CHIT1 mRNA and decreases in FEV1 and FEV1/FVC.
CONCLUSION: TREM-2 expression is increased in lung macrophages in COPD, particularly in comparison to TREM-1. Thus, TREM-2 levels and the ratio of TREM-2/TREM-1 signifies M2 activation in COPD lung tissues and may help to guide therapeutics directed against the type 2 immune response in patients with this disease.

PMID: 29017955 [PubMed - as supplied by publisher]

Update of literature from cystic fibrosis registries 2012-2015. Part 6: Epidemiology, nutrition and complications.

Thu, 10/12/2017 - 10:01
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Update of literature from cystic fibrosis registries 2012-2015. Part 6: Epidemiology, nutrition and complications.

Pediatr Pulmonol. 2017 Mar;52(3):390-398

Authors: Salvatore D, Buzzetti R, Mastella G

Abstract
Patient registries provide useful information to afford more knowledge on rare diseases like Cystic Fibrosis (CF). Twenty-two studies originating from national CF registries, focusing on demographics, survival, genetics, nutritional status, and non-pulmonary complications, were published between December 2011 and March 2015. The purpose of this review article is to examine these reports, aiming attention to the clinical characteristics of CF patients included in the registries, current, and estimated future epidemiological data, the role of gender gap, the increasing survival in different countries. Some studies offer insights into pubertal growth and non-pulmonary complications, such as liver disease, nephropathy, and cancer. Pediatr Pulmonol. 2017;52:390-398. © 2016 Wiley Periodicals, Inc.

PMID: 27685428 [PubMed - indexed for MEDLINE]

Investigation of cardiac fibroblasts using myocardial slices.

Wed, 10/11/2017 - 12:45

Investigation of cardiac fibroblasts using myocardial slices.

Cardiovasc Res. 2017 Aug 18;:

Authors: Perbellini F, Watson SA, Scigliano M, Alayoubi S, Tkach S, Bardi I, Quaife N, Kane C, Dufton NP, Simon A, Sikkel MB, Faggian G, Randi AM, Gorelik J, Harding SE, Terracciano CM

Abstract
Aims: Cardiac fibroblasts (CFs) are considered the principal regulators of cardiac fibrosis. Factors that influence CF activity are difficult to determine. When isolated and cultured in vitro , CFs undergo rapid phenotypic changes including increased expression of α-SMA. Here we describe a new model to study CFs and their response to pharmacological and mechanical stimuli using in vitro cultured mouse, dog and human myocardial slices.
Methods and Results: Unloading of myocardial slices induced CF proliferation without α-SMA expression up to 7 days in culture . CFs migrating onto the culture plastic support or cultured on glass expressed αSMA within 3 days. The cells on the slice remained αSMA(-) despite TGF-β (20ng/mL) or angiotensin II (200µM) stimulation. When diastolic load was applied to myocardial slices using A-shaped stretchers, CF proliferation was significantly prevented at day 3 and 7 (P < 0.001).
Conclusions: Myocardial slices allow the study of CFs in a multicellular environment and may be used to effectively study mechanisms of cardiac fibrosis and potential targets.

PMID: 29016704 [PubMed - as supplied by publisher]

Feasibility and reliability of functional muscle tests in lung transplant recipients.

Wed, 10/11/2017 - 12:45

Feasibility and reliability of functional muscle tests in lung transplant recipients.

Am J Phys Med Rehabil. 2017 Oct 10;:

Authors: Kienbacher T, Achim-Gunacker G, Pachner M, Kerschan-Schindl K, Gunacker P, Habenicht R, Klepetko W, Jaksch P, Doblhammer S, Ebenbichler G

Abstract
OBJECTIVE: This study investigates the feasibility, reliability, and correlations of recommended functional tests in lung transplant recipients shortly after surgery.
DESIGN: Observational study METHODS: 50 patients (28 females) performed well standardized maximum isometric back extension in a sitting position, hand grip strength, and Biering-Sørensen endurance tests shortly before discharge from the acute hospital, shortly thereafter, and two months later following subacute rehabilitation.
RESULTS: Back extension testing was well feasible but only two thirds of the patients could perform the Biering-Sørensen test at baseline and they experienced a greater number of minor but no major adverse events. Absolute reliability measures and the intraclass-correlation-coefficients were excellent for the strength [0.97 - 0.98 (0.95 - 0.99)] and good for the endurance tests [0.69 (0.26 - 0.87)]. Hand grip revealed high correlation with back strength (≥0.75) but not with Biering-Sørensen scores.
CONCLUSION: Well controlled maximum back strength testing is feasible, reliable, and the scores are highly correlated with grip strength in lung transplant recipients shortly before hospital discharge. The Biering-Sørensen test should be limited to patients without dominant weakness and/or fear. Future research should investigate if grip instead of back extension strength can safely be used for proper exercise prescription.

PMID: 29016397 [PubMed - as supplied by publisher]

Is Visceral Leishmaniasis Different in Immunocompromised Patients Without Human Immunodeficiency Virus? A Comparative, Multicenter Retrospective Cohort Analysis.

Wed, 10/11/2017 - 12:45

Is Visceral Leishmaniasis Different in Immunocompromised Patients Without Human Immunodeficiency Virus? A Comparative, Multicenter Retrospective Cohort Analysis.

Am J Trop Med Hyg. 2017 Sep 05;:

Authors: Ramos JM, León R, Merino E, Montero M, Aljibe A, Blanes M, Reus S, Boix V, Salavert M, Portilla J

Abstract
Although visceral leishmaniasis (VL) can affect immunocompromised patients, data from the human immunodeficiency virus (HIV) infection context are limited, and the characteristics of VL in other immunosuppression scenarios are not well defined. A retrospective review of all cases of VL in immunocompromised patients from January 1997 to December 2014 in two Spanish hospitals on the Mediterranean coast was performed. We included 18 transplant recipients (kidney: 7, liver: 4, lung: 3, heart: 2, and blood marrow: 2), 12 patients with other causes of immunosuppression (myasthenia gravis: 3 and rheumatoid arthritis: 2), and 73 VL HIV-positive patients. Fever was more common in transplant patients (94.4%) and patients with other types of immunosuppression (100%) than in HIV-positive individuals (73.3%). Hepatomegaly was less common in transplant recipients (27.8%) and patients with other types of immunosuppression (41.7%) compared with HIV-positive patients (69.9%) (P = 0.01; P = 0.001, respectively). Patients with other types of immunosuppression had a median leukocyte count of 1.5 × 10(9)/L, significantly lower than HIV-positive patients (2.5 × 10(9)/L) (P = 0.04). Serology was more commonly positive in nontransplant immunosuppressed individuals (75%) and transplant recipients (78.6%) than in HIV-patients (13.8%) (P < 0.001). Antimonial therapy was rarely used in transplant recipients (1.9%) and never in patients with other immunosuppressive conditions, whereas 34.2% of HIV-positive patients received it (P = 0.05 and P = 0.01, respectively). Mortality was 16.7% in both transplant recipients and patients with other immunosuppressive conditions and 15.1% in HIV-positive patients. The features of VL may be different in immunosuppressed patients, with more fever and less hepatomegaly and leukopenia than in HIV-infected patients.

PMID: 29016284 [PubMed - as supplied by publisher]

Brain abscesses caused by Cladophialophora bantiana in a lung transplant patient: A case report and review of the literature.

Wed, 10/11/2017 - 12:45

Brain abscesses caused by Cladophialophora bantiana in a lung transplant patient: A case report and review of the literature.

Transpl Infect Dis. 2017 Oct 09;:

Authors: Gschwend A, Dégot T, Denis J, Sabou AM, Jeung MY, Zapata E, Porzio M, Renaud-Picard B, Herbrecht R, Kessler R

Abstract
Cladophialophora bantiana brain abscesses are rare, but are frequently and quickly lethal in transplanted patients. We report the case of a 63-year-old man who had undergone lung transplantation for chronic obstructive pulmonary disease and presented with headaches and a neurological deficit. Magnetic resonance imaging revealed multiple brain abscesses. C. bantiana was identified by DNA sequencing performed directly on cerebral tissue obtained by surgical biopsy. After 6 months of antifungal treatment, the brain abscesses were replaced by ischemic sequelae. The patient died suddenly 2 months later from a pulmonary bacterial infection. This is the second reported case of C. bantiana brain abscesses in a lung transplant recipient, to our knowledge, who experienced a long survival period with medical antifungal treatment alone. We review the literature and discuss our treatment. This article is protected by copyright. All rights reserved.

PMID: 28994171 [PubMed - as supplied by publisher]

Localization of Exogenous Mesenchymal Stem Cells in a Pig Model of Lung Transplantation.

Wed, 10/11/2017 - 12:45

Localization of Exogenous Mesenchymal Stem Cells in a Pig Model of Lung Transplantation.

Thorac Cardiovasc Surg. 2017 Oct 09;:

Authors: Piatkowski T, Brandenberger C, Rahmanian P, Choi YH, Zeriouh M, Sabashnikov A, Wittwer T, Wahlers TCW, Ochs M, Mühlfeld C

PMID: 28992651 [PubMed - as supplied by publisher]

Outcomes of Organ Transplants When the Donor Is a Prior Recipient.

Wed, 10/11/2017 - 12:45

Outcomes of Organ Transplants When the Donor Is a Prior Recipient.

Am J Transplant. 2017 Oct 09;:

Authors: Lee GS, Goldberg DS, Levine MH, Abt PL

Abstract
Organ shortage continues to challenge the field of transplantation. One potential group of donors are those who have been transplant recipients themselves, or Organ Donor After Transplant (ODAT). We conducted a retrospective cohort study to describe ODAT donors and to compare outcomes of ODAT grafts versus conventional grafts. From 10/1/87 to 6/30/15, 517 former recipients successfully donated 803 organs for transplant. Former kidney recipients generally survived a median of approximately four years before becoming an ODAT donor whereas liver, lung, and heart recipients generally survived less than a month prior to donation. In the period 1/1/05 to 12/31/14, liver grafts from ODAT donors had a significantly higher risk of graft failure compared to non-ODAT liver transplants (p = 0.008). Kidney grafts donated by ODAT donors whose initial transplant occurred >1 year prior were associated with significantly increased graft failure (p = 0.012). Despite increased risk of graft failure amongst certain ODAT grafts, five year survival was still high. ODAT donors should be considered another form of expanded criteria donor under these circumstances. This article is protected by copyright. All rights reserved.

PMID: 28992380 [PubMed - as supplied by publisher]

The Role of C4d Deposition in the Diagnosis of Antibody-Mediated Rejection after Lung Transplantation.

Wed, 10/11/2017 - 12:45

The Role of C4d Deposition in the Diagnosis of Antibody-Mediated Rejection after Lung Transplantation.

Am J Transplant. 2017 Oct 09;:

Authors: Aguilar PR, Carpenter D, Ritter J, Yusen RD, Witt CA, Byers DE, Mohanakumar T, Kreisel D, Trulock EP, Hachem RR

Abstract
Antibody-mediated rejection (AMR) is an increasingly recognized form of lung rejection. C4d deposition has been an inconsistent finding in previous reports and its role in the diagnosis has been controversial. We conducted a retrospective single-center study to characterize cases of C4d-negative probable AMR and to compare these to cases of definite (C4d-positive) AMR. We identified 73 cases of AMR: 28 (38%) were C4d-positive and 45 (62%) were C4d-negative. The two groups had a similar clinical presentation, and although more patients in the C4d-positive group had neutrophilic capillaritis (54% vs. 29%, p = 0.035), there was no significant difference in the presence of other histologic findings. In spite of aggressive antibody-depleting therapy, 19 of 73 (26%) patients in the overall cohort died within 30 days, but there was no significant difference in freedom from chronic lung allograft dysfunction (CLAD) or survival between the two groups. We conclude that AMR may cause allograft failure, but the diagnosis requires a multidisciplinary approach and a high index of suspicion. C4d deposition does not appear to be a necessary criterion for the diagnosis, and although some cases may initially respond to therapy, there is a high incidence of CLAD and poor survival after AMR. This article is protected by copyright. All rights reserved.

PMID: 28992372 [PubMed - as supplied by publisher]

Mycoplasma hominis Empyema in an 18-Year-old Stem Cell and Lung Transplant Recipient: Case Report and Review of the Literature.

Wed, 10/11/2017 - 12:45

Mycoplasma hominis Empyema in an 18-Year-old Stem Cell and Lung Transplant Recipient: Case Report and Review of the Literature.

J Pediatric Infect Dis Soc. 2017 Jun 24;:

Authors: Dixit A, Alexandrescu S, Boyer D, Graf EH, Vargas SO, Silverman M

Abstract
Mycoplasma hominis has been identified as a rare cause of respiratory infections in immunocompromised adults. Here, we describe a case of Mycoplasma hominis empyema in an 18-year-old immunocompromised patient with a review of the literature highlighting diagnostic challenges associated with this infection.

PMID: 28992317 [PubMed - as supplied by publisher]

Invasive Fungal Disease in Pediatric Solid Organ Transplant Recipients.

Wed, 10/11/2017 - 12:45

Invasive Fungal Disease in Pediatric Solid Organ Transplant Recipients.

J Pediatric Infect Dis Soc. 2017 Jun 15;:

Authors: Saxena S, Gee J, Klieger S, Kajon A, Petersen H, Zaoutis T, Fisher B

Abstract
Background: Solid organ transplant (SOT) recipients are at risk for invasive fungal disease (IFD). Data on IFD burden in pediatric patients are limited. We aimed to determine the incidence and outcome of IFD in a large cohort of pediatric patients who underwent SOT.
Methods: A single-center cohort of pediatric patients who underwent SOT between 2000 and 2013 was assembled retrospectively. The patients were followed for 180 days after transplant or until death to determine the presence or absence of IFD. The 2008 European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group Consensus Group criteria were used to define IFD as proven or probable. The incidence of IFD, all-cause mortality rate, and case-fatality rate at 180 days were calculated.
Results: Among 584 pediatric patients who underwent SOT, 13 patients sustained 14 episodes of IFD (candidiasis, aspergillosis, and mucormycosis). The overall incidence was 2.2% (14.3 IFD events per 100000 patient-days). The IFD rates according to transplant type were 12.5% (1 of 8) (heart/lung), 11.4% (4 of 35) (lung), 4.7% (8 of 172) (liver), 0% (0 of 234) (kidney), and 0% (0 of 135) (heart). Three patients with IFD (2 lung and 1 heart/lung) died, and all these deaths were deemed likely attributable to the IFD; the case-fatality rate was 21.4% (3 of 14).
Conclusions: The overall incidence of IFD in these pediatric SOT recipients was low but varied across transplant type, with heart/lung and lung recipients having the highest IFD rate. Given the attributable case-fatality rate, the risk of death resulting from IFD is potentially high. More data on groups at higher risk, such as lung transplant recipients, are needed to guide targeted antifungal prophylaxis.

PMID: 28992290 [PubMed - as supplied by publisher]

Caspase-11-mediated endothelial pyroptosis underlies endotoxemia-induced lung injury.

Wed, 10/11/2017 - 12:45

Caspase-11-mediated endothelial pyroptosis underlies endotoxemia-induced lung injury.

J Clin Invest. 2017 Oct 09;:

Authors: Cheng KT, Xiong S, Ye Z, Hong Z, Di A, Tsang KM, Gao X, An S, Mittal M, Vogel SM, Miao EA, Rehman J, Malik AB

Abstract
Acute lung injury is a leading cause of death in bacterial sepsis due to the wholesale destruction of the lung endothelial barrier, which results in protein-rich lung edema, influx of proinflammatory leukocytes, and intractable hypoxemia. Pyroptosis is a form of programmed lytic cell death that is triggered by inflammatory caspases, but little is known about its role in EC death and acute lung injury. Here, we show that systemic exposure to the bacterial endotoxin lipopolysaccharide (LPS) causes severe endothelial pyroptosis that is mediated by the inflammatory caspases, human caspases 4/5 in human ECs, or the murine homolog caspase-11 in mice in vivo. In caspase-11-deficient mice, BM transplantation with WT hematopoietic cells did not abrogate endotoxemia-induced acute lung injury, indicating a central role for nonhematopoietic caspase-11 in endotoxemia. Additionally, conditional deletion of caspase-11 in ECs reduced endotoxemia-induced lung edema, neutrophil accumulation, and death. These results establish the requisite role of endothelial pyroptosis in endotoxemic tissue injury and suggest that endothelial inflammatory caspases are an important therapeutic target for acute lung injury.

PMID: 28990935 [PubMed - as supplied by publisher]

Bronchiectasis and deteriorating lung function in agammaglobulinemia despite immunoglobulin replacement therapy.

Wed, 10/11/2017 - 12:45

Bronchiectasis and deteriorating lung function in agammaglobulinemia despite immunoglobulin replacement therapy.

Clin Exp Immunol. 2017 Oct 09;:

Authors: Stubbs A, Bangs C, Shillitoe B, Edgar JD, Burns SO, Thomas M, Alachkar H, Buckland M, McDermott E, Arumugakani G, Jolles MS, Herriot R, Arkwright PD

Abstract
Immunoglobulin replacement therapy enhances survival and reduces infection risk in patients with agammaglobulinemia. We hypothesized that despite regular immunoglobulin therapy some patients will experience ongoing respiratory infections and develop progressive bronchiectasis with deteriorating lung function. 139 (70%) of 199 patients aged 1 to 80 years from nine cities in the UK with agammaglobulinemia currently listed on the UKPID registry were recruited to this retrospective case study and their clinical and laboratory features analyzed. 94% were male of whom 78% had BTK gene mutations. All patients were on immunoglobulin replacement therapy and 52% had commenced therapy by the time they were two years old. 60% were also taking prophylactic oral antibiotics. 56% of patients had radiological evidence of bronchiectasis, which developed between the ages of 7 to 45 years. Multi-variate analysis showed that three factors were significantly associated with bronchiectasis: reaching 18 years old (relative risk (95% CI) 14.2 (2.7 - 74.6)), history of pneumonia (3.9 (1.1 - 13.8)) and IVIG rather than SCIG (3.5 (1.2 - 10.1)), while starting immunoglobulin replacement after reaching two years old, gender and recent serum IgG concentration were not significantly associated. Independent of age, patients with bronchiectasis had significantly poorer lung function (predicted FEV1 74% (50 - 91)) than those without this complication (92% (84 - 101)) (p < 0.001). We conclude that despite immunoglobulin replacement therapy, many patients with agammaglobulinemia can develop chronic lung disease and progressive impairment of lung function. This article is protected by copyright. All rights reserved.

PMID: 28990652 [PubMed - as supplied by publisher]

Feasibility of Diaphragm Pacing in Patients after Bilateral Lung Transplantation.

Wed, 10/11/2017 - 12:45

Feasibility of Diaphragm Pacing in Patients after Bilateral Lung Transplantation.

Clin Transplant. 2017 Oct 09;:

Authors: Testelmans D, Nafteux P, Van Cromphaut S, Vrijsen B, Vos R, De Leyn P, Decaluwé H, Van Raemdonck D, Verleden GM, Buyse B

Abstract
Recent animal studies and intra-operative studies in humans suggested that phrenic nerve stimulation could attenuate ventilator-induced diaphragm dysfunction. The purpose of the present study is to examine the safety and feasibility of diaphragm pacing during the weaning process after bilateral lung transplantation. Four patients, suffering from chronic pulmonary disease, were included, and diaphragm pacing was evaluated after lung transplantation. Implantation of electrodes at the end of the lung transplant procedure was possible in three of the four patients. In all implanted patients, stimulation of the diaphragm could trigger the ventilator. Implanted electrodes were completely removed by percutaneous retraction after up to 7 days of pacing. Adverse events related to pacing included occurrence of pain. Diaphragm pacing with temporary electrodes, inserted during surgery, is feasible and is able to trigger the ventilator in patients after bilateral lung transplantation. The use of intra-diaphragmatic electrodes creates the additional opportunity to monitor the evolution of diaphragm electromyography during the postoperative weaning process. This article is protected by copyright. All rights reserved.

PMID: 28990225 [PubMed - as supplied by publisher]

Mycobacterium abscessus and massiliense lung infection during macrolide treatment for bronchiolitis obliterans after allogeneic hematopoietic stem cell transplantation.

Wed, 10/11/2017 - 12:45

Mycobacterium abscessus and massiliense lung infection during macrolide treatment for bronchiolitis obliterans after allogeneic hematopoietic stem cell transplantation.

J Infect Chemother. 2017 Oct 05;:

Authors: Miyake N, Chong Y, Nishida R, Takenaka K, Kato K, Miyamoto T, Aono A, Takaki A, Mitarai S, Shimoda S, Shimono N, Akashi K

Abstract
In patients undergoing allogeneic hematopoietic stem cell transplantation (allo-SCT), post-transplant lung infection is critical for their prognosis. Mycobacterium abscessus complex is not fully recognized as a nontuberculous mycobacteria (NTM) pathogen of post-SCT lung infection. Here, we present three post-allogeneic SCT patients who developed pulmonary infection caused by M. abscessus complex including M. abscessus and M. massiliense. In all three cases, macrolide antibiotics had been administered for bronchiolitis obliterans syndrome (BOS) before the confirmation of their infection, and macrolide resistance was noted in the M. abscessus isolates, one of which resulted in an unfavorable treatment outcome. It is important to consider M. abscessus lung infection as well as other NTM in patients receiving allo-SCT, particularly those receiving macrolide therapy for BOS.

PMID: 28988958 [PubMed - as supplied by publisher]

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