Acute Responses to Oxygen Delivery via High Flow Nasal Cannula in Patients with Severe Chronic Obstructive Pulmonary Disease-HFNC and Severe COPD.

Differences in oxygen delivery methods to treat hypoxemia have the potential to worsen CO2 retention in chronic obstructive lung disease (COPD). Oxygen administration using high flow nasal cannula (HFNC) has multiple physiological benefits in treating respiratory failure including reductions in PaCO2 in a flow-dependent manner. We hypothesized that patients with COPD would develop worsening hypercapnia if oxygen fraction was increased without increasing flow rate. We evaluated the acute response to HFNC in subjects with severe COPD when flow remained constant and inspired oxygen was increased. In total, 11 subjects with severe COPD (FEV1 < 50%) on supplemental oxygen with baseline normocapnia (PaCO2 < 45 mm Hg; n = 5) and hypercapnia (PaCO2 ≥ 45 mm Hg; n = 6) were studied. Arterial blood gas responses were studied at three timepoints: Baseline, HFNC at a flow rate of 30 L/min at resting oxygen supplementation for 1 h, and FiO2 30% above baseline with the same flow rate for the next hour. The primary endpoint was the change in PaCO2 from baseline. No significant changes in PaCO2 were noted in response to HFNC applied at baseline FiO2 in the normocapnic and hypercapnic group. At HFNC with FiO2 30% above baseline, the normocapnic group did not show a change in PaCO2 (baseline: 38.9 ± 1.8 mm Hg; HFNC at higher FiO2: 38.8 ± 3.1 mm Hg; p = 0.93), but the hypercapnic group demonstrated significant increase in PaCO2 (baseline: 58.2 ± 9.3 mm Hg; HFNC at higher FiO2: 63.3 ± 10.9 mm Hg; p = 0.025). We observed worsening hypercapnia in severe COPD patients and baseline hypercapnia who received increased oxygen fraction when flow remained constant. These data show the need for careful titration of oxygen therapy in COPD patients, particularly those with baseline hypercapnia when flow rate is unchanged.

Massive hemorrhage after inspection bronchoscopy for carcinoid tumor.

Carcinoid tumor is a neuroendocrine tumor that can arise in the bronchial tree and can be hypervascular. Here we describe a case of bronchial carcinoid tumor in a 34-year-old previously healthy male who presented with hemoptysis and right lung mass. Inspection bronchoscopy revealed bronchus intermedius endobronchial lesion and was complicated by urgent intubation and placement of endobronchial blocker for massive hemorrhage. Subsequent angiography with embolization of the bronchial artery supplying the mass resulted in control of bleeding. While massive hemorrhage has been described with biopsy of bronchial carcinoid tumor, this case suggests that careful planning for inspection bronchoscopy is needed when carcinoid tumor is suspected.

A 42-Year-Old Woman With Abnormal Chest CT Scan and Chylous Ascites.

A 42-year-old white woman presented to the pulmonary clinic for evaluation of abnormal chest imaging. Twenty years prior to presentation, she was noted to have an abnormal chest radiograph during a routine preemployment evaluation. A subsequent bronchoscopy was nondiagnostic. She was followed up with annual imaging, which demonstrated little or no progression of her disease. She remained symptom free throughout this period. A year before her visit to the pulmonary clinic, she developed abdominal discomfort and was found to have ascites. Subsequently, she underwent three paracenteses with analysis revealing chylous fluid. She was a nonsmoker without a history of exposures or travel.

Neuregulin-1-human epidermal receptor-2 signaling is a central regulator of pulmonary epithelial permeability and acute lung injury.

The mechanisms behind the loss of epithelial barrier function leading to alveolar flooding in acute lung injury (ALI) are incompletely understood. We hypothesized that the tyrosine kinase receptor human epidermal growth factor receptor-2 (HER2) would be activated in an inflammatory setting and participate in ALI. Interleukin-1ß (IL-1ß) exposure resulted in HER2 activation in human epithelial cells and markedly increased conductance across a monolayer of airway epithelial cells. Upon HER2 blockade, conductance changes were significantly decreased. Mechanistic studies revealed that HER2 trans-activation by IL-1ß required a disintegrin and metalloprotease 17 (ADAM17)-dependent shedding of the ligand neuregulin-1 (NRG-1). In murine models of ALI, NRG-1-HER2 signaling was activated, and ADAM17 blockade resulted in decreased NRG-1 shedding, HER2 activation, and lung injury in vivo. Finally, NRG-1 was detectable and elevated in pulmonary edema fluid from patients with ALI. These results suggest that the ADAM17-NRG-1-HER2 axis modulates the alveolar epithelial barrier and contributes to the pathophysiology of ALI.

Bleomycin-induced pulmonary fibrosis is attenuated by a monoclonal antibody targeting HER2.

The importance of HER2/HER3 signaling in decreasing the effects of lung injury was recently demonstrated. Transgenic mice unable to signal through HER2/HER3 had significantly less bleomycin-induced pulmonary fibrosis and showed a survival benefit. Based on these data, we hypothesized that pharmacological blockade of HER2/HER3 in vivo in wild-type mice would have the same beneficial effects. We tested this hypothesis in a bleomycin lung injury model using 2C4, a monoclonal antibody directed against HER2 that blocks HER2/HER3 signaling. The administration of 2C4 before injury decreased the effects of bleomycin at days 15 and 21 after injury. HER2/HER3 blockade resulted in less collagen deposition (362.8 +/- 37.9 compared with 610.5 +/- 27.1 microg/mg; P = 0.03) and less lung morphological changes (injury score of 1.99 +/- 1.55 vs. 3.90 +/- 0.76; P < 0.04). In addition, HER2/HER3 blockade resulted in a significant survival advantage with 50% vs. 25% survival at 30 days (P = 0.04). These results confirm that HER2 signaling can be pharmacologically targeted to reduce lung fibrosis and remodeling after injury.

Expression of mutant human epidermal receptor 3 attenuates lung fibrosis and improves survival in mice.

Neuregulin-1 (NRG-1), binding to the human epidermal growth factor receptor HER2/HER3, plays a role in pulmonary epithelial cell proliferation and recovery from injury in vitro. We hypothesized that activation of HER2/HER3 by NRG-1 would also play a role in recovery from in vivo lung injury. We tested this hypothesis using bleomycin lung injury of transgenic mice incapable of signaling through HER2/HER3 due to lung-specific dominant-negative HER3 (DNHER3) expression. In animals expressing DNHER3, protein leak, cell infiltration, and NRG-1 levels in bronchoalveolar lavage fluid increased after injury, similar to that in nontransgenic littermate control animals. However, HER2/HER3 was not activated, and DNHER3 animals displayed fewer lung morphological changes at 10 and 21 days after injury (P = 0.01). In addition, they contained 51% less collagen in injured lungs (P = 0.04). Transforming growth factor-beta1 did not increase in bronchoalveolar lavage fluid from DNHER3 mice compared with nontransgenic littermate mice (P = 0.001), suggesting that a mechanism for the decreased fibrosis was lack of transforming growth factor-beta1 induction in DNHER3 mice. Severe lung injury (0.08 units bleomycin) resulted in 80% mortality of nontransgenic mice, but only 35% mortality of DNHER3 transgenic mice (P = 0.04). Thus inhibition of HER2/HER3 signaling protects against pulmonary fibrosis and improves survival.

Mycobacterium xenopi pneumonia in the southeastern United States.

Mycobacterium xenopi (M. xenopi) is a slow-growing, nontuberculous mycobacterium (NTM). This organism is found in fresh water and has been isolated in water samples collected from water systems in homes and hospitals. Before the acquired immunodeficiency syndrome epidemic, M. xenopi infection was infrequent and occurred in clusters; however, M. xenopi is now a recognized cause of pulmonary infection in immunocompetent patients with preexisting lung disease. The classic chest x-ray appearance is cavitary apical pulmonary disease, which mimics tuberculosis. M. xenopi is currently one of the most common NTM pathogens in parts of England and Canada and has been reported in parts of the northeastern United States. Whether the isolation of M. xenopi from our patient in Tennessee represents a new geographic distribution of this organism or technologic advancements that now allow for reliable identification is debatable. This case serves as a reminder to clinicians that the incidence of NTM infection is rising in the United States and that unusual NTM are capable of causing disease even in patients who are not immunocompromised.