Association between early airway damage-associated molecular patterns and subsequent bacterial infection in patients with inhalational and burn injury

Abstract

Bacterial infection is a major cause of morbidity affecting outcome following burn and inhalation injury. While experimental burn and inhalation injury animal models have suggested that mediators of cell damage and inflammation increase the risk of infection, few studies have been done on humans. This is a prospective, observational study of patients admitted to the North Carolina Jaycee Burn Center at the University of North Carolina who were intubated and on mechanical ventilation for treatment of burn and inhalational injury. Subjects were enrolled over a 2-yr period and followed till discharge or death. Serial bronchial washings from clinically indicated bronchoscopies were collected and analyzed for markers of tissue injury and inflammation. These include damage-associated molecular patterns (DAMPs) such as hyaluronic acid (HA), double-stranded DNA (dsDNA), heat-shock protein 70 (HSP-70), and high-mobility group protein B-1 (HMGB-1). The study population was comprised of 72 patients who had bacterial cultures obtained for clinical indications. Elevated HA, dsDNA, and IL-10 levels in bronchial washings obtained early (the first 72 h after injury) were significantly associated with positive bacterial respiratory cultures obtained during the first 14 days postinjury. Independent of initial inhalation injury severity and extent of surface burn, elevated levels of HA dsDNA and IL-10 in the central airways obtained early after injury are associated with subsequent positive bacterial respiratory cultures in patients intubated after acute burn/inhalation injury.

Keywords: acute lung injury; burn injury; inhalational injury; innate immunology; respiratory infection.

Fig. 1.

Serial bronchial samples were collected for analysis over time, with a wide distribution of bacterial infection frequency postinjury. Serial bronchial washings from clinically indicated bronchoscopies were collected. With the use of a multivariate regression model, damage-associated molecular patterns (DAMPs) and cytokines in early washings were tested for association with bacterial respiratory infection during the first 14 days after injury (A), with the percentage of patients in study who had a bronchial washing sent for culture by day postinjury during the first 14 days after injury (B), and the percentage of bronchial washing cultures that were positive for any bacterial pathogen by day postinjury (C).

Fig. 2.

Elevated hyaluronic acid (HA) and double-stranded DNA (dsDNA) were significantly associated with subsequent bacterial infection. Serial bronchial washings from clinically indicated bronchoscopies were collected. Elevated HA (A) and dsDNA (B) were significantly associated with bacterial infection in the model, in all infected patients and in patients with positive bacterial culture within the first 72 h (“infected <72 h”), whereas heat shock protein-70 (HSP-70) and high-mobility group protein B-1 (HMGB-1) were not (not shown). Statistical significance (P) was quantified using t-test.

Fig. 3.

Early levels of HA and dsDNA in bronchial washings were significantly correlated with each other. Serial bronchial washings from clinically indicated bronchoscopies were collected and analyzed for markers of tissue injury and inflammation. Each DAMP in early washings (average concentration over the first 72 h) was tested for association with each other during the first 14 days after injury. Statistical significance (P) and degree of fit (r²) was quantified using linear regression line fitting.

Fig. 4.

The ratio of IL-10/IL-12p70 was significantly higher for infected patients compared with uninfected patients. Early IL-10 and IL-12 levels were measured within serial bronchial mainstem washes from patients with inhalational and burn injury and tested for association with later bacterial respiratory infection in all infected patients and in patients with positive bacterial culture within the first 72 h (“infected <72 h”). Statistical significance (P) was quantified using t-test.