Interaction between Pseudomonas and CXC chemokines increases risk of bronchiolitis obliterans syndrome and death in lung transplantation

Abstract

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(+)) 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(+) 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(+) CXC chemokines may interact to negatively influence lung transplant outcomes.

Figure 1.

Markovian model diagram. The three states of the models are shown as individual balls. Transition is denoted by λ (e.g., transition from state 1 to state 2 is represented by λ₁₂).

Figure 2.

The overall outcomes for study subjects. The number of individuals reaching each state is shown within each state ball. Ninety-three of the subjects had an isolation of pseudomonas; 167 had no isolation of pseudomonas.

Figure 3.

Immunohistochemistry sections from patients with recent pseudomonas infections stained for CXCL1 and CXCL5. (a) CXCL1 expression on type 2 pneumocytes. (b) Alveolar macrophages positive for CXCL1. (c) Type II pneumocytes positive for CXCL5. (d) Alveolar macrophages positive for CXCL5.

Figure 4.

Immunohistochemistry sections from patients with recent pseudomonas infections stained for CXC receptors. (a) Negative control for CXC receptors. (b) Mononuclear and endothelial cells positive for CXCR2. (c) Negative control for CXC receptors with macrophages. (d) Macrophages positive for CXCR2. (e) Predominantly alveolar macrophages are positive for CXCR1. (f) Detail of macrophages positive for CXCR1.

Figure 5.

Markovian model results as a diagram. The three states of the models are shown. Covariates that in our models increase the hazard of moving from one state to the other are shown. ∨ refers to an inclusive disjunction.