Allograft Colonization and Infections With Pseudomonas in Cystic Fibrosis Lung Transplant Recipients

Nunley, David R.; Grgurich, Wayne F.; Iacono, Aldo; Yousem, Samuel A.; Ohori, N. Paul; Dauber, James H.

doi:10.1378/chest.113.5.1235

Cited by 86 publications

(71 citation statements)

References 20 publications

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“…Episodes of acute rejection, aspergillus, and pseudomonas are treated as time-dependent covariates to assess the effects of zero to multiple episodes. For transition hazards l 12 and l 13 In the above formulae, l ij,0 (t) are the baseline hazards from state i to j, Z ij,k (t) are vectors of covariates of interest at time t for the kth patient, b ij are the corresponding vectors of regression coefficients, and T 2 is the time of BOS i; j2f1; 2; 3g.…”

Section: Methodsmentioning

confidence: 99%

“…The gram-negative Pseudomonas aeruginosa is the most frequently isolated bacterium after lung transplantation (5)(6)(7)(9)(10)(11)(12). Moreover, bacterial pulmonary infections have been associated with increased bronchoalveolar lavage fluid (BALF) levels of inflammatory markers, including the glutamic acid-leucine-arginine-positive (ELR 1 ) CXC chemokine IL-8 (CXCL8) (13)(14)(15)(16). Prior studies have suggested that pseudomonas may influence the development of BOS by de novo colonization after lung transplantation (17) or by persistent colonization (18).…”

mentioning

confidence: 99%

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Interaction between Pseudomonas and CXC Chemokines Increases Risk of Bronchiolitis Obliterans Syndrome and Death in Lung Transplantation

Gregson

Wang

Weigt

et al. 2013

Am J Respir Crit Care Med

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Rationale: Pseudomonas aeruginosa is the most commonly isolated gram-negative bacterium after lung transplantation and has been shown to up-regulate glutamic acid-leucine-arginine-positive (ELR 1 ) CXC chemokines associated with bronchiolitis obliterans syndrome (BOS), but the effect of pseudomonas on BOS and death has not been well defined. Objectives: To determine if the influence of pseudomonas isolation and ELR 1 CXC chemokines on the subsequent development of BOS and the occurrence of death is time dependent. Methods: A three-state model was developed to assess the likelihood of transitioning from lung transplant (state 1) to BOS (state 2), from transplant (state 1) to death (state 3), and from BOS (state 2) to death (state 3). This Cox semi-Markovian approach determines state survival rates and cause-specific hazards for movement from one state to another. Measurements and Main Results: The likelihood of transition from transplant to BOS was increased by acute rejection, CXCL5, and the interaction between pseudomonas and CXCL1. The pseudomonas effect in this transition was due to infection rather than colonization. Movement from transplant to death was facilitated by pseudomonas infection and single lung transplant. Transition from BOS to death was affected by the length of time in state 1 and by the interactions between any pseudomonas isolation and CXCL5 and aspergillus, either independently or in combination. Conclusions: Our model demonstrates that common post-transplantation events drive movement from one post-transplantation state to another and influence outcomes differently depending upon when after transplantation they occur. Pseudomonas and the ELR 1 CXC chemokines may interact to negatively influence lung transplant outcomes.Keywords: transplantation; lung; BOS; pseudomonas; chemokine Lung transplantation is a life-saving procedure for end-stage lung disease. Long-term success is limited by the high incidence of chronic lung allograft dysfunction, predominantly due to bronchiolitis obliterans syndrome (BOS). Acute rejection is perhaps the most widely recognized event to increase the risk of chronic lung allograft dysfunction. There is expanding evidence that a variety of infections increase the chances of developing BOS. Fungal pneumonia or colonization (1, 2) and viral pneumonitis (1, 3, 4) are among infectious conditions shown to increase the risk of BOS. However, the most commonly isolated pathogens after lung transplantation are bacteria, broadly separated into gram-negative and gram-positive organisms (5-8). The gram-negative Pseudomonas aeruginosa is the most frequently isolated bacterium after lung transplantation (5-7, 9-12). Moreover, bacterial pulmonary infections have been associated with increased bronchoalveolar lavage fluid (BALF) levels of inflammatory markers, including the glutamic acid-leucine-arginine-positive (ELR 1 ) CXC chemokine IL-8 (CXCL8) (13-16). Prior studies have suggested that pseudomonas may influence the development of BOS by de novo colonization after lung transp...

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Interaction between Pseudomonas and CXC Chemokines Increases Risk of Bronchiolitis Obliterans Syndrome and Death in Lung Transplantation

Gregson

Wang

Weigt

et al. 2013

Am J Respir Crit Care Med

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“…First, a link between Pseudomonas colonisation, airway neutrophilia and BOS has been hypothesised [12,13], and it was assumed that Pseudomonas colonisation is a prerequisite for azithromycin responsiveness. GERHARDT et al [2] demonstrated that four out of six patients had Pseudomonas colonisation in the airways or sinuses.…”

Section: Anti-inflammatory Effect Of Azithromycin In Bosmentioning

confidence: 99%

A dichotomy in bronchiolitis obliterans syndrome after lung transplantation revealed by azithromycin therapy

Vanaudenaerde

Meyts²,

Vos³

et al. 2008

European Respiratory Journal

149

110

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Bronchiolitis obliterans syndrome (BOS) is the most important cause of late mortality following lung transplantation, resulting in major morbidity and a huge burden on healthcare resources. Treatment options are limited, resulting in a mere stabilisation of the lung function decline. Recent introduction of the macrolide antibiotic azithromycin raised new hope after demonstrating lung function improvement in subsets of patients.The present study aimed to provide an overview of the clinical effects on azithromycin in the setting of BOS after lung transplantation, with special emphasis on the anti-inflammatory actions. Moreover, the authors proposed a new frame of thinking centred on a dichotomy in the pathogenesis and clinical phenotype of BOS. Subsets of BOS patients were identified who do or do not respond to azithromycin (regarding forced expiratory volume in one second (FEV1), bronchoalveolar lavage (BAL) neutrophilia/interleukin-8). These observations have shed new light on the current belief that BOS represents a homogenous clinical entity in which the neutrophil is the main culprit.Recent clinical observations, supported by research findings, have revealed a dichotomy in the clinical spectrum of BOS with neutrophilic (partially) reversible allograft dysfunction (responding to azithromycin) and fibroproliferative BOS (not responding to azithromycin). This concept is reinforced by unique data obtained in BOS patients, consisting of histology specimens, physical and radiological examination, FEV1 and BAL examination.The acceptance of this dichotomy can improve understanding of the heterogeneous pathological condition that constitutes bronchiolitis obliterans syndrome, thus encouraging a more accurate diagnosis and, ultimately, better tailored treatment for each bronchiolitis obliterans syndrome patient.

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“…Former Pseudomonas species have recently been reclassified and belong to other genera, such as Burkholderia (B. cepacia, Alcaligenes xylosoxidans), Xanthomonas (Stenothrophomonas), Aeromonas, etc., which are generally referred to as Pseudomonads [1]. Airway colonisation with Pseudomonads, especially P. aeruginosa, is common in patients with altered pulmonary defences [2][3][4][5][6], but also in immunocompromised lung transplant (LTx) recipients [7][8][9]. Colonisation with mucoid or multiple-antibiotic resistant P. aeruginosa or B. cepacia is associated with a worse prognosis, particularly in cystic fibrosis (CF) patients [10][11][12].…”

mentioning

confidence: 99%

“…It has been extensively shown that colonisation triggers expression of diverse cytokines by structural airway cells, inducing neutrophil recruitment and thereby perpetuating a cycle of airway inflammation and destruction [13][14][15][16][17][18]. However, whether pseudomonal airway colonisation after LTx occurs secondary to the airway remodelling in bronchiolitis obliterans syndrome (BOS), the major cause of late graft failure and death in long-term survivors after LTx [19], or similarly plays a primordial role in its aetiology and progression remains elusive [7,[20][21][22]. The aim of the present retrospective study, therefore, was to assess the importance of pseudomonal airway colonisation for the development of BOS after LTx.…”

mentioning

confidence: 99%

Pseudomonal airway colonisation: risk factor for bronchiolitis obliterans syndrome after lung transplantation?

Vos¹,

Vanaudenaerde²,

Geudens³

et al. 2008

European Respiratory Journal

157

134

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Airway colonisation with Pseudomonads, especially Pseudomonas aeruginosa, is common in lung transplant (LTx) recipients. The current authors investigated whether pseudomonal colonisation affects the prevalence of bronchiolitis obliterans syndrome (BOS) after lung transplantation.In the present retrospective study, 92 double (SS)LTx recipients (26 cystic fibrosis (CF) and 66 non-CF patients), with at least two consecutive post-operative bronchoalveolar lavage or sputum cultures evaluated for Pseudomonads, were included. Freedom of BOS was investigated in postoperatively colonised and noncolonised patients.The current study has shown post-operative airway colonisation to be an independent risk factor for BOS stage o1 and to be associated with a worse BOS stage o1-free survival in univariate analysis, especially in CF SSLTx recipients. Multivariate analysis demonstrated a trend for colonisation only as an independent risk factor for BOS; however, this pointed to a possible role in the development of BOS.In conclusion, pseudomonal airway colonisation after lung transplantation may be associated with an increased prevalence of bronchiolitis obliterans syndrome, especially in cystic fibrosis patients. Possible pathophysiological mechanisms in the development of bronchiolitis obliterans syndrome need further investigation, although the induction of neutrophilic airway inflammation seems to be its main characteristic.

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Allograft Colonization and Infections With Pseudomonas in Cystic Fibrosis Lung Transplant Recipients

Cited by 86 publications

References 20 publications

Interaction between Pseudomonas and CXC Chemokines Increases Risk of Bronchiolitis Obliterans Syndrome and Death in Lung Transplantation

Interaction between Pseudomonas and CXC Chemokines Increases Risk of Bronchiolitis Obliterans Syndrome and Death in Lung Transplantation

A dichotomy in bronchiolitis obliterans syndrome after lung transplantation revealed by azithromycin therapy

Pseudomonal airway colonisation: risk factor for bronchiolitis obliterans syndrome after lung transplantation?

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