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Perhaps, the most unsettling aspect to clinical lung transplantation is the fact that at all stages of the posttransplant period, lung recipients face the dual threats of infection and alloimmunity. Nearly, all management questions revolve around how to reconcile these two risks, and we endeavor to understand where each patient exists with respect to appropriate immunosuppression and adequate protective immunity. Hence, like most aspects of medicine, we crave information to guide treatment decisions. For the past three decades, the modality that has guided much of the decision making has been the transbronchial biopsy (Tbbx) obtained via bronchoscopy. Similar to renal and cardiac transplantation, the microscopic assessment of the allografted tissue stands as the gold standard to which all other measurements are benchmarked. Tbbx has a solid-track record as a predictive tool. Glanville et al [1] have demonstrated a strong correlation between the lymphocytic bronchiolitis and the development of bronchiolitis obliterans. Nevertheless, it bears noting that it remains unproven whether a program of surveillance bronchoscopy in asymptomatic patients has any impact in overall transplant survival. Given the fact that Tbbx does carry some risk to the patient, some have advocated for only using biopsy when rejection is suspected [2]. In short, this “gold standard” could be better.

An untapped resource in lung transplant monitoring has been the analysis of bronchoalveolar lavage (BAL) fluid. BAL allows for characterization of the cellular constituents of the alveolar space. Analysis of BAL has a proven track record in the diagnosis of several pulmonary diseases such as sarcoidosis and hypersensitivity pneumonitis [3, 4]. Obtaining BAL is relatively safe compared with transbronchial lung biopsy and can be extended to patients who might be at high risk for lung biopsy such as patients on anticoagulation. The cell component of BAL is complex; including alveolar macrophages, which represent the majority population in healthy individuals. Additional cellular populations include neutrophils, CD4 and CD8 lymphocytes, natural killer (NK) cells, eosinophils and basophils. The complex and varied nature of BAL cellularity has led many investigators to probe the utility of cellular analysis of this fluid in lung transplantation. Until now, most studies utilizing BAL phenotyping have existed at the level of proof of concept. In this issue of the journal, Greenland et al [5] report on the most extensive analysis of BAL cellularity to date. In so doing, these investigators have elevated BAL beyond a measure, which correlates with Tbbx to a tool that may ultimately transcend the biopsy.

The study from Greenland et al [5] is a testament to persistence. They collected lung lavages from nearly all patients (317 of 356) transplanted between 1997 and 2011. Flow cytometry was performed by their clinical pathology department on fresh cells. By today's standards, their flow analysis would be considered relatively simple, as they assessed bulk populations of monocytes, NK cells, CD4 and CD8 cells, eosinophils and basophils. With respect to T cell populations, only CD25 was utilized. Based on this simple phenotyping platform, they divided all patient samples (>2900 total) into those having infection, rejection, both infection and rejection and neither infection nor rejection. Utilizing a derivation and validation cohort, they were able to define a scoring system with a modest predictive capacity at detecting present and future rejection. Low levels of monocytes and NK cells combined with high frequency of CD25+ cells and any measurable eosinophils were associated with a significant increased risk of rejection on biopsy. To further highlight the value of BAL cells, these investigators developed a scoring system that distinguished infection from rejection (IR-score). Importantly, they showed that high IR-scores seen in the setting of rejection also strongly correlated with subsequent bronchiolitis obliterans. The findings from this study parallel a growing trend in renal transplantation to use urinary biomarkers as a window into the renal allograft. A recent National Institutes of Health sponsored multi-centered study by Suthanthiran et al [6] has demonstrated the predictive role of urine cell mRNA for acute rejection. Collectively, these studies show that biological materials obtained via less invasive or even noninvasive means can inform management decisions.

There are two major messages from the present study. The first is that we should continue to look at BAL as an untapped resource of information in lung transplantation. The data from the present study come from a single center and should be corroborated by future studies. Fortunately, the scoring systems in this study are within the technical reach of most transplant programs, involving techniques already being employed.

The second message is that BAL cellularity is complex and this complexity should guide future study design. That BAL is complex should not surprise us. There are many dangers that transplanted lungs face including respiratory viruses, aspiration, even air pollution. Therefore, it makes sense that different injury signals would emerge in the setting of different exposures. The study here transformed these complex data into a scoring system that can account for many different attributes leading to an elevated rejection score. Speculating on the future, it is possible that with more integrative technologies such as adding multiplex cytokine and chemokine arrays to the data obtained from flow cytometry, BAL analysis may ultimately supplant Tbbx as the gold standard.

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The author of this manuscript has no conflicts of interest to disclose as defined by the American Journal of Transplantation.

References

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