Influenza A Virus Infection Causes Chronic Lung Disease Linked to Sites of Active Viral RNA Remnants.

Clinical and experimental observations suggest that chronic lung disease is linked to respiratory viral infection. However, the long-term aspect of this relationship is not yet defined using a virus that replicates at properly high levels in humans and a corresponding animal model. In this study, we show that influenza A virus infection achieves 1 × 106-fold increases in viral load in the lung and dose-dependent severity of acute illness in mice. Moreover, these events are followed by persistence of negative- and positive-strand viral RNA remnants for 15 wk and chronic lung disease for at least 26 wk postinfection. The disease is manifested by focal areas of bronchiolization and mucus production that contain increased levels of viral RNA remnants along with mucin Muc5ac and Il13 mRNA compared with uninvolved areas of the lung. Excess mucus production and associated airway hyperreactivity (but not fibrosis or emphysema) are partially attenuated with loss of IL-13 production or signaling (using mice with IL-13 or STAT6 deficiency). These deficiencies cause reciprocal increases in l17a mRNA and neutrophils in the lung; however, none of these disease endpoints are changed with IL-13/IL-17a compared with IL-13 deficiency or STAT6/IL-17a compared with STAT6 deficiency. The results establish the capacity of a potent human respiratory virus to produce chronic lung disease focally at sites of active viral RNA remnants, likely reflecting locations of viral replication that reprogram the region. Viral dose dependency of disease also implicates high-level viral replication and severity of acute infection as determinants of chronic lung diseases such as asthma and COPD with IL-13-dependent and IL-13/IL-17-independent mechanisms.

Frequent Versus Infrequent Monitoring of Endotracheal Tube Cuff Pressures.

BACKGROUND: Currently there is no accepted standard of practice for the optimal frequency of endotracheal tube cuff pressure monitoring in mechanically ventilated patients. Therefore, we conducted a study to compare infrequent endotracheal tube cuff pressure monitoring (immediately after intubation and when clinically indicated for an observed air leak or due to tube migration) with frequent endotracheal tube cuff pressure monitoring (immediately after intubation, every 8 h, and when clinically indicated). METHODS: We performed a prospective clinical trial with subjects assigned to study groups based on room assignment. The primary outcome was the occurrence of a ventilator-associated event (VAE) and was adjudicated by individuals blinded to the conduct of this study. RESULTS: We enrolled 305 subjects, with 166 (54.4%) assigned to frequent monitoring and 139 (45.6%) assigned to infrequent monitoring. The total number of endotracheal tube cuff pressure monitoring events for both groups was 1,531 versus 336, respectively. The occurrence of VAEs was infrequent and similar for both groups (3.6% vs 5.8%, P = .37). Witnessed aspiration events (0.6% vs 0%, P = .36), ventilator-associated pneumonia (0% vs 0.7%, P = .27), 30-d mortality (31.3% vs 30.2%, P = .83), and hospital length of stay (10 d [6 d, 21 d] vs 11 d [6 d, 21 d], P = .34) were also similar for both study groups. The 30-d hospital readmission rate was statistically lower for the group that received infrequent monitoring (15.1% vs 6.5%, P = .02). CONCLUSIONS: More frequent cuff pressure monitoring was not associated with any identifiable clinical outcome benefit.