Lymphocytic Airway Inflammation in Lung Allografts

Abstract

Lung transplant remains a key therapeutic option for patients with end stage lung disease but short- and long-term survival lag other solid organ transplants. Early ischemia-reperfusion injury in the form of primary graft dysfunction (PGD) and acute cellular rejection are risk factors for chronic lung allograft dysfunction (CLAD), a syndrome of airway and parenchymal fibrosis that is the major barrier to long term survival. An increasing body of research suggests lymphocytic airway inflammation plays a significant role in these important clinical syndromes. Cytotoxic T cells are observed in airway rejection, and transcriptional analysis of airways reveal common cytotoxic gene patterns across solid organ transplant rejection. Natural killer (NK) cells have also been implicated in the early allograft damage response to PGD, acute rejection, cytomegalovirus, and CLAD. This review will examine the roles of lymphocytic airway inflammation across the lifespan of the allograft, including: 1) The contribution of innate lymphocytes to PGD and the impact of PGD on the adaptive immune response. 2) Acute cellular rejection pathologies and the limitations in identifying airway inflammation by transbronchial biopsy. 3) Potentiators of airway inflammation and heterologous immunity, such as respiratory infections, aspiration, and the airway microbiome. 4) Airway contributions to CLAD pathogenesis, including epithelial to mesenchymal transition (EMT), club cell loss, and the evolution from constrictive bronchiolitis to parenchymal fibrosis. 5) Protective mechanisms of fibrosis involving regulatory T cells. In summary, this review will examine our current understanding of the complex interplay between the transplanted airway epithelium, lymphocytic airway infiltration, and rejection pathologies.

Ventilatory capacity in CLAD is driven by dysfunctional airway structure

“… 17 As described earlier, Lymphocytic airway inflammation was indeed previously proposed as a major driver of CLAD. 18 Mucus plugs were often found, mostly in the vicinity of CB lesions, and were filled with neutrophils and some eosinophils, also being related to neutrophils in the airway wall. Interestingly, BOS is predominantly characterized by neutrophilic airway inflammation, mainly shown on BAL, possibly being related to infectious episodes.…”

Impact of air pollution on postoperative outcomes following organ transplantation: Evidence from clinical investigations

“…Risks factor associated with development of CLAD are lymphocytic airway disease (LAD), B-grade (lymphocytic bronchitis) and E-grade of acute cellular injection (ACR). 23 Macrolides is a class of antibiotics, including azithromycin and clarithromycin. These have often been used for treatment in post-lung transplant patients who developed CLAD.…”

“…Clinical syndrome of CLAD can be described as: 1) bronchiolitis obliterans (BOS) (obstructive pattern) or 2) restrictive allograft syndrome (RAS). Risks factor associated with development of CLAD are lymphocytic airway disease (LAD), B‐grade (lymphocytic bronchitis) and E‐grade of acute cellular injection (ACR) 23 . Macrolides is a class of antibiotics, including azithromycin and clarithromycin.…”

Decreased Lymphocytic Bronchitis Severity in the Era of Azithromycin Prophylaxis

“…An analogous syndrome of lymphocytic bronchitis has been identified as a precursor and risk factor for CLAD, associated with BAL neutrophils, and reversal following AZI treatment. [7][8][9] A CLAD prevention study of 83 LTx recipients randomized to AZI or placebo at hospital discharge found decreased BAL neutrophils, improved FEV 1 , and better CLAD-free survival in Background. Large-airway lymphocytic inflammation (LB), assessed on endobronchial biopsies, has been associated with acute cellular rejection and chronic lung allograft dysfunction (CLAD).…”

“…An analogous syndrome of lymphocytic bronchitis has been identified as a precursor and risk factor for CLAD, associated with BAL neutrophils, and reversal following AZI treatment. 7-9…”