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Lung Allograft Injury: Need for Different Police for links image Every Breath They Take

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Aric Gregson, MD
UCLA School of Medicine
Los Angeles, CA, United States

Because the lung allograft is continuously exposed to the external environment, it is uniquely susceptible to insults that do not plague most other solid organ transplants. The upper respiratory and gastrointestinal tracts provide a conduit by which both environmental and commensal microbes can enter the lung allograft. Under non-transplant settings such incursions rarely result in significant sequelae, like pneumonia. The lung transplant recipient is, however, in a disadvantageous position to adequately respond to microbial advance into the allograft due to both reduced mucociliary clearance and impaired immunologic responses. This increases the probability that non-commensal microbes, such as pseudomonas and aspergillus, can establish chronic colonization within the lung allograft. Chronic residence by pseudomonas results in an inflammatory allograft milieu that promotes fibrosis and angiogenesis, hastening the development and progression of chronic lung allograft dysfunction.

Given the fact that the lung allograft is exposed to the external environment, lacks some of the bacterial clearance mechanisms present in normal hosts and is within an immunocompromised host, it is not surprising that pulmonary infections are a frequent complication after lung transplantation. In fact, at our center, aspergillus and pseudomonas isolation occurs in approximately 35% of recipients. Bacterial infections constitute the vast majority of these post-transplant pulmonary infections [1-3]. Gram negative bacteria make up the majority of bacterial infections, with Pseudomonas aeruginosa being the most frequently isolated, occurring between 25% and 58% of the time [4-7]. At our center, like others, Staphylococcus aureus is the most frequent gram positive bacteria isolated in 14 to 30% of cases (15% of our recipients have had isolation of S. aureus) (ibid). It is no wonder that gram positive and negative bacteria have been widely studied and shown to increase the risk for BOS [5,7,8].

What plausible mechanism is there for this? Pseudomonas within the lung allograft is associated with both increased concentrations of interleukin 8 (IL-8), an ELR+ CXC chemokine, and decreased concentrations of IL-10 [9]. As expected, bacterial pneumonia causes BALF neutrophilia, but only gram negative bacterial infections lead to increased BALF IL-8 and subsequent decline in FEV1 [10]. The ELR+ CXC chemokines are critical chemotaxins for neutrophils, but also recruit T cells expressing their receptor CXCR1. These T cells are more frequent in the blood of cystic fibrosis patients colonized with pseudomonas, suggesting that chronic pseudomonal colonization does influence the adaptive immune system [11]. Furthermore, alveolar epithelial cells (AEC) may express both HLA class I and II during epithelial injury, such as occurs during acute cellular rejection [12,13]. Could it be that such inflammation leads to expansion of a pool of alloreactive lymphocytes?

Ps. aeruginosa increases AEC ELR+ CXC chemokine production, resulting in lymphocyte recruitment to the allograft. This potentially drives alloreactivity associated with airway fibrosis, suggesting an important role for pseudomonas in allograft outcomes. Vos [14], Botha [15] and Hachem [16] all showed that pseudomonas was an important risk factor for BOS, but none accounted for the allograft milieu. Clearly the milieu of the allograft must be considered when assessing the effect of pseudomonas on transplant outcomes. We recently investigated lung transplant outcomes and the interaction between pseudomonas and the allograft milieu as determined by BALF concentrations of the ELR+ CXC chemokines [17]. By using a multistate Cox Semi-Markov model we were able to separate the effect of pseudomonas at different stages post-lung transplantation. For example, in patients who had not yet developed BOS, pseudomonas infection, not colonization, increased both the risk of death and of subsequent BOS development. Elevated BALF levels of ELR+ CXC chemokines further increased the risk of developing BOS and of death after BOS. The chemokine CXCL5 was alone sufficient to increase both the risk of BOS and of death after BOS, while CXCL1 acted in conjunction with pseudomonas infection to increase the risk of BOS. Interestingly, pseudomonas colonization pre-transplantation was an insufficient stimulus to drive the development of BOS, but after BOS developed such colonization via an interaction with CXCL5 did elevate the risk of death after BOS, suggesting a heightened inflammatory milieu in the post-BOS allograft.

Single massive insults to the lung allograft appear to be important risks for subsequent CLAD, with community acquired respiratory infections and severe PGD being prime examples [18,19]. Repeated insults may be even more important, as increasing numbers of episodes of either pseudomonas pneumonia or acute cellular rejection carry greater risk than do single or fewer episodes [17]. Much like repeated insults, organisms that are able to create a chronic niche within the allograft may yet have the greatest impact upon the allograft state. Also, although we tend not to see frequent massive insults or infections with aspergillus, it remains a risk for the development of BOS [20]. Alteration of the allograft environment toward an inflammatory state should show a greater effect on allograft outcome if that influence persists over time, which both pseudomonas and aspergillus colonization tend to do. These organisms dwell within the lung to first create and then maintain an inflammatory milieu promoting angiogenesis and fibrosis. Markers for such conditions are likely to include lymphocytic bronchitis, BALF neutrophilia, and the ELR+ CXC chemokines and CXCR3 ligands, but these are markers of ongoing inflammation, acting as messengers, and of dubious importance in their own right. However, the effect of azithromycin in improving outcomes may be, in part, due to attenuation of lung epithelial cell ELR+ CXC chemokine production, arguing that the ELR+ CXC chemokines such as CXCL5 may have important downstream effects of their own [21]. Additional support for an increased inflammatory environment after the development of BOS comes from our finding that minor graft insults are more influential on outcomes post BOS than prior to BOS. Suddenly, events that could not influence graft outcomes before BOS such as pseudomonas colonization rather than infection, are now a viable risk. Efforts to reduce chronic carriage of either aspergillus or pseudomonas, particularly after the development of BOS, may offer one pathway to improve outcomes for selected lung transplant recipients. ■

Disclosure Statement: The author has no conflicts of interest to disclose.


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