COPD with elevated sputum group 2 innate lymphoid cells is characterized by severe disease.

Rationale: Pulmonary innate immune cells play a central role in the initiation and perpetuation of chronic obstructive pulmonary disease (COPD), however the precise mechanisms that orchestrate the development and severity of COPD are poorly understood. Objectives: We hypothesized that the recently described family of innate lymphoid cells (ILCs) play an important role in COPD. Methods: Subjects with COPD and healthy controls were clinically evaluated, and their sputum samples were assessed by flow cytometry. A mouse model of spontaneous COPD [genetically deficient in surfactant protein-D (SP-D -/- )] and ozone (O 3 ) exposure were used to examine the mechanism by which lack of functional SP-D may skew ILC2s to produce IL-17A in combination with IL-5 and IL-13, leading to a mixed inflammatory profile and more severe disease. Measurements and Main Results: COPD was characterized by poor spirometry, sputum inflammation, and the emergence of sputum GATA3 + ILCs (ILC2s), but not T-bet + ILCs (ILC1s) nor RORγt + ILCs (ILC3s). COPD subjects with elevated sputum ILC2s (the ILC2 high group) had worse spirometry and sputum neutrophilia and eosinophilia than healthy and ILC2 low subjects. This was associated with the presence of dual-positive IL-5 + IL-17A + and IL-13 + IL-17A + ILCs and nonfunctional SP-D in the sputum in ILC2 high subjects. SP-D -/- mice showed spontaneous airway neutrophilia. Lack of SP-D in the mouse lung licensed ILC2s to produce IL-17A, which was dose-dependently inhibited by recombinant SP-D. SP-D -/- mice showed enhanced susceptibility to O 3 -induced airway neutrophilia, which was associated with the emergence of inflammatory IL-13 + IL-17A + ILCs. Conclusions: We report that the presence of sputum ILC2s predicts the severity of COPD, and unravel a novel pathway of IL-17A plasticity in lung ILC2s, prevented by the immunomodulatory protein SP-D.

Oxylipin concentration shift in exhaled breath condensate (EBC) of SARS-CoV-2 infected patients.

Infection of airway epithelial cells with severe acute respiratory coronavirus 2 (SARS-CoV-2) can lead to severe respiratory tract damage and lung injury with hypoxia. It is challenging to sample the lower airways non-invasively and the capability to identify a highly representative specimen that can be collected in a non-invasive way would provide opportunities to investigate metabolomic consequences of COVID-19 disease. In the present study, we performed a targeted metabolomic approach using liquid chromatography coupled with high resolution chromatography (LC-MS) on exhaled breath condensate (EBC) collected from hospitalized COVID-19 patients (COVID+) and negative controls, both non-hospitalized and hospitalized for other reasons (COVID-). We were able to noninvasively identify and quantify inflammatory oxylipin shifts and dysregulation that may ultimately be used to monitor COVID-19 disease progression or severity and response to therapy. We also expected EBC-based biochemical oxylipin changes associated with COVID-19 host response to infection. The results indicated ten targeted oxylipins showing significative differences between SAR-CoV-2 infected EBC samples and negative control subjects. These compounds were prostaglandins A2 and D2, LXA4, 5-HETE, 12-HETE, 15-HETE, 5-HEPE, 9-HODE, 13-oxoODE and 19(20)-EpDPA, which are associated with specific pathways (i.e. P450, COX, 15-LOX) related to inflammatory and oxidative stress processes. Moreover, all these compounds were up-regulated by COVID+, meaning their concentrations were higher in subjects with SAR-CoV-2 infection. Given that many COVID-19 symptoms are inflammatory in nature, this is interesting insight into the pathophysiology of the disease. Breath monitoring of these and other EBC metabolites presents an interesting opportunity to monitor key indicators of disease progression and severity.

Predominant SARS-CoV-2 variant impacts accuracy when screening for infection using exhaled breath vapor.

BACKGROUND: New technologies with novel and ambitious approaches are being developed to diagnose or screen for SARS-CoV-2, including breath tests. The US FDA approved the first breath test for COVID-19 under emergency use authorization in April 2022. Most breath-based assays measure volatile metabolites exhaled by persons to identify a host response to infection. We hypothesized that the breathprint of COVID-19 fluctuated after Omicron became the primary variant of transmission over the Delta variant. METHODS: We collected breath samples from 142 persons with and without a confirmed COVID-19 infection during the Delta and Omicron waves. Breath samples were analyzed by gas chromatography-mass spectrometry. RESULTS: Here we show that based on 63 exhaled compounds, a general COVID-19 model had an accuracy of 0.73 ± 0.06, which improved to 0.82 ± 0.12 when modeling only the Delta wave, and 0.84 ± 0.06 for the Omicron wave. The specificity improved for the Delta and Omicron models (0.79 ± 0.21 and 0.74 ± 0.12, respectively) relative to the general model (0.61 ± 0.13). CONCLUSIONS: We report that the volatile signature of COVID-19 in breath differs between the Delta-predominant and Omicron-predominant variant waves, and accuracies improve when samples from these waves are modeled separately rather than as one universal approach. Our findings have important implications for groups developing breath-based assays for COVID-19 and other respiratory pathogens, as the host response to infection may significantly differ depending on variants or subtypes.

In recent decades, scientists have found we exhale thousands of compounds that reveal much about our health, including whether we are sick with COVID-19. Our team asked whether the breath profile of someone infected with the Delta variant of COVID-19 would match the breath profile caused by the Omicron variant­a version of the virus that is more transmissible. We analyzed breath samples from 142 people, some sick with either the Delta or Omicron variant of COVID-19, and others who were negative for COVID-19. Our results indicate that the Delta variant altered the contents of our breath in a different way than the Omicron variant, and breath-based tests improved when optimized to detect only one of the variants. These findings might impact the design of future breath-based tests for COVID-19.

Real-world impact of vaccination on coronavirus disease 2019 (COVID-19) incidence in healthcare personnel at an academic medical center.

OBJECTIVE: Coronavirus disease 2019 (COVID-19) vaccination effectiveness in healthcare personnel (HCP) has been established. However, questions remain regarding its performance in high-risk healthcare occupations and work locations. We describe the effect of a COVID-19 HCP vaccination campaign on SARS-CoV-2 infection by timing of vaccination, job type, and work location. METHODS: We conducted a retrospective review of COVID-19 vaccination acceptance, incidence of postvaccination COVID-19, hospitalization, and mortality among 16,156 faculty, students, and staff at a large academic medical center. Data were collected 8 weeks prior to the start of phase 1a vaccination of frontline employees and ended 11 weeks after campaign onset. RESULTS: The COVID-19 incidence rate among HCP at our institution decreased from 3.2% during the 8 weeks prior to the start of vaccinations to 0.38% by 4 weeks after campaign initiation. COVID-19 risk was reduced among individuals who received a single vaccination (hazard ratio [HR], 0.52; 95% confidence interval [CI], 0.40-0.68; P < .0001) and was further reduced with 2 doses of vaccine (HR, 0.17; 95% CI, 0.09-0.32; P < .0001). By 2 weeks after the second dose, the observed case positivity rate was 0.04%. Among phase 1a HCP, we observed a lower risk of COVID-19 among physicians and a trend toward higher risk for respiratory therapists independent of vaccination status. Rates of infection were similar in a subgroup of nurses when examined by work location. CONCLUSIONS: Our findings show the real-world effectiveness of COVID-19 vaccination in HCP. Despite these encouraging results, unvaccinated HCP remain at an elevated risk of infection, highlighting the need for targeted outreach to combat vaccine hesitancy.

Autophagy, Apoptosis, the Unfolded Protein Response, and Lung Function in Idiopathic Pulmonary Fibrosis.

Autophagy, apoptosis, and the unfolded protein response (UPR) are fundamental biological processes essential for manifold cellular functions in health and disease. Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal pulmonary disorder associated with aging that has limited therapies, reflecting our incomplete understanding. We conducted an observational study linking molecular markers of cell stress response pathways (UPR: BiP, XBP1; apoptosis: cleaved caspase-3; autophagy: LC3ß) in lung tissues from IPF patients and correlated the expression of these protein markers to each subject's lung function measures. We hypothesized that changes in lung tissue expression of apoptosis, autophagy, and UPR markers correlate with lung function deficits in IPF. The cell stress markers BiP, XBP1, LC3ß puncta, and cleaved caspase-3 were found to be elevated in IPF lungs compared to non-IPF lungs, and, further, BiP and cleaved caspase-3 co-localized in IPF lungs. Considering lung function independently, we observed that increased XBP1, BiP, and cleaved caspase-3 were each associated with reduced lung function (FEV1, FVC, TLC, RV). However, increased lung tissue expression of LC3ß puncta was significantly associated with increased diffusion capacity (DLCO), an indicator of alveolar-capillary membrane function. Similarly, the co-localization of UPR (XBP1, BiP) and autophagy (LC3ß puncta) markers was positively correlated with increased lung function (FEV1, FVC, TLC, DLCO). However, the presence of LC3ß puncta can indicate either autophagy flux inhibition or activation. While the nature of our observational cross-sectional study design does not allow conclusions regarding causal links between increased expression of these cell stress markers, lung fibrosis, and lung function decline, it does provide some insights that are hypothesis-generating and suggests that within the milieu of active UPR, changes in autophagy flux may play an important role in determining lung function. Further research is necessary to investigate the mechanisms linking UPR and autophagy in IPF and how an imbalance in these cell stress pathways can lead to progressive fibrosis and loss of lung function. We conclude by presenting five testable hypotheses that build on the research presented here. Such an understanding could eventually lead to the development of much-needed therapies for IPF.

SARS-CoV-2 detection and genomic sequencing from hospital surface samples collected at UC Davis.

RATIONALE: There is little doubt that aerosols play a major role in the transmission of SARS-CoV-2. The significance of the presence and infectivity of this virus on environmental surfaces, especially in a hospital setting, remains less clear. OBJECTIVES: We aimed to analyze surface swabs for SARS-CoV-2 RNA and infectivity, and to determine their suitability for sequence analysis. METHODS: Samples were collected during two waves of COVID-19 at the University of California, Davis Medical Center, in COVID-19 patient serving and staff congregation areas. qRT-PCR positive samples were investigated in Vero cell cultures for cytopathic effects and phylogenetically assessed by whole genome sequencing. MEASUREMENTS AND MAIN RESULTS: Improved cleaning and patient management practices between April and August 2020 were associated with a substantial reduction of SARS-CoV-2 qRT-PCR positivity (from 11% to 2%) in hospital surface samples. Even though we recovered near-complete genome sequences in some, none of the positive samples (11 of 224 total) caused cytopathic effects in cultured cells suggesting this nucleic acid was either not associated with intact virions, or they were present in insufficient numbers for infectivity. Phylogenetic analysis suggested that the SARS-CoV-2 genomes of the positive samples were derived from hospitalized patients. Genomic sequences isolated from qRT-PCR negative samples indicate a superior sensitivity of viral detection by sequencing. CONCLUSIONS: This study confirms the low likelihood that SARS-CoV-2 contamination on hospital surfaces contains infectious virus, disputing the importance of fomites in COVID-19 transmission. Ours is the first report on recovering near-complete SARS-CoV-2 genome sequences directly from environmental surface swabs.

Interstitial lung abnormality is prevalent and associated with worse outcome in patients undergoing transcatheter aortic valve replacement.

BACKGROUND: Interstitial lung abnormality (ILA) is found in 5-10% of the general population and is associated with increased mortality risk. Risk factors for ILA, including advanced age and smoking history also increase the risk for aortic stenosis (AS). Transcatheter aortic valve replacement (TAVR) has become an increasingly utilized intervention for patients with severe AS, and requires a high-resolution computed tomography (HRCT) of the chest to assess aortic valve dimensions. OBJECTIVES: To determine the prevalence and clinical significance of ILA on HRCT performed in patients referred for TAVR. METHODS: Consecutive pre-TAVR HRCTs performed over a 5-year period were reviewed. ILA was defined as bilateral, nondependent reticular opacities. All-cause mortality among TAVR recipients was compared between ILA cases and non-ILA controls matched 2:1 by age and gender using Cox proportional hazards regression and the Kaplan Meier estimator. RESULTS: Of 623 HRCTs screened, ILA was detected in 92 (14.7%), including 62 patients that underwent TAVR. Among ILA cases, 17 (27.4%) had a typical or probable usual interstitial pneumonia pattern, suggesting a diagnosis of idiopathic pulmonary fibrosis. Survival was worse in ILA cases compared to non-ILA controls (p = 0.008) and ILA was an independent predictor of mortality after multivariable adjustment (HR 3.29, 95% CI 1.34-8.08; p = 0.009). CONCLUSIONS: ILA is a common finding among patients with severe AS and is associated with increased mortality in those undergoing TAVR. Further research is needed to elucidate the biology underpinning this observation and determine whether ILA evaluation and risk stratification modulates this mortality risk.

Acute exacerbation of idiopathic pulmonary fibrosis-a review of current and novel pharmacotherapies.

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive form of lung disease of unknown etiology for which a paucity of therapies suggest benefit, and for which none have demonstrated improved survival. Acute exacerbation of IPF (AE-IPF) is defined as a sudden acceleration of the disease or an idiopathic acute injury superimposed on diseased lung that leads to a significant decline in lung function. An AE-IPF is associated with a mortality rate as high as 85% with mean survival periods of between 3 to 13 days. Under these circumstances, mechanical ventilation (MV) is controversial, unless used a as a bridge to lung transplantation. Judicious fluid management may be helpful. Pharmaceutical treatment regimens for AE-IPF include the use of high dose corticosteroids with or without immunosuppressive agents such as cyclosporine A (CsA), and broad spectrum antibiotics, despite the lack of convincing evidence demonstrating benefit. Newer research focuses on abnormal wound healing as a cause of fibrosis and preventing fibrosis itself through blocking growth factors and their downstream intra-cellular signaling pathways. Several novel pharmaceutical approaches are discussed.

Management of critical asthma syndrome during pregnancy.

One-third of pregnant asthmatics experience a worsening of their asthma that may progress to a critical asthma syndrome (CAS) that includes status asthmaticus (SA) and near-fatal asthma (NFA). Patients with severe asthma before pregnancy may experience more exacerbations, especially during late pregnancy. Prevention of the CAS includes excellent asthma control involving targeted early and regular medical care of the pregnant asthmatic, together with medication compliance. Spontaneous abortion risk is higher in pregnant women with uncontrolled asthma than in non-asthmatics. Should CAS occur during pregnancy, aggressive bronchodilator therapy, montelukast, and systemic corticosteroids can be used in the context of respiratory monitoring, preferably in an Intensive Care Unit (ICU). Systemic epinephrine should be avoided due to potential teratogenic side-effects and placental/uterine vasoconstriction. Non-invasive ventilation has been used in some cases. Intratracheal intubation can be hazardous and rapid-sequence intubation by an experienced physician is recommended. Mechanical ventilation parameters are adjusted based on changes to respiratory mechanics in the pregnant patient. An inhaled helium-oxygen gas admixture may promote laminar airflow and improve gas exchange. Permissive hypercapnea is controversial, but may be unavoidable. Sedation with propofol which itself has bronchodilating properties is preferred to benzodiazepines. Case reports delineating good outcomes for both mother and fetus despite intubation for SA suggest that multidisciplinary ICU care of the pregnant asthmatic with critical asthma are feasible especially if hypoxemia is avoided.

A review of current and novel therapies for idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressively fibrotic interstitial lung disease that is associated with a median survival of 2-3 years from initial diagnosis. To date, there is no treatment approved for IPF in the United States, and only one pharmacological agent has been approved outside of the United States. Nevertheless, research over the past 10 years has provided us with a wealth of information on its histopathology, diagnostic work-up, and a greater understanding of its pathophysiology. Specifically, IPF is no longer thought to be a predominantly pro-inflammatory disorder. Rather, the fibrosis in IPF is increasingly understood to be the result of a fibroproliferative and aberrant wound healing cascade. The development of therapeutic targets has shifted in accord with this paradigm change. This review highlights the current understanding of IPF, and the recent as well as novel therapeutics being explored in clinical trials for the treatment of this devastating disease.

Bird fancier's lung: a state-of-the-art review.

Bird fancier's lung (BFL) resulting from avian antigen exposure is a very common form of hypersensitivity pneumonitis. Its pathogenesis is modified by genetic polymorphisms located within the major histocompatibility complex, and also by smoking, which may decrease serum antibody response to inhaled antigen. Acute, subacute, and chronic presentations of BFL are recognized, but often overlap clinically. Continued antigen exposure in the chronic phase portends a worse prognosis. Chronic bronchitis symptoms may be part of the BFL clinical spectrum, and rhinitis may suggest an allergic component. The diagnosis of BFL is enhanced by a high index of suspicion of exposure to avian antigen, recurrent symptomatic episodes occurring 4-8 h after exposure, inspiratory "velcro" crackles on auscultation, weight loss, and positive IgG precipitins to the antigen. Characteristic findings on high-resolution computed tomography of the chest include centrilobular nodules, ground-glass opacification, and mosaicism due to air trapping. Bronchoalveolar lavage will classically show >25% lymphocytosis, a CD4/CD8 ratio of <1.0 and >1% mast cells in the acute phase. Lung biopsies, if obtained in the subacute phase of the disease, typically show loosely formed granulomas, giant cells, a lymphoplasmacytic interstitial infiltrate, and possibly some degree of fibrosis. In some patients, usual interstitial pneumonia or fibrotic non-specific interstitial pneumonia patterns may be seen on surgical biopsy. Skin testing, serological testing, and bronchial provocation tests for BFL frequently suffer from a lack of standardization. Effective treatment for BFL consists mainly of antigen avoidance, as corticosteroids likely do not alter long-term prognosis. Lung transplantation can be considered for progressive chronic disease refractory to medical measures.

Novel computed tomographic chest metrics to detect pulmonary hypertension.

BACKGROUND: Early diagnosis of pulmonary hypertension (PH) can potentially improve survival and quality of life. Detecting PH using echocardiography is often insensitive in subjects with lung fibrosis or hyperinflation. Right heart catheterization (RHC) for the diagnosis of PH adds risk and expense due to its invasive nature. Pre-defined measurements utilizing computed tomography (CT) of the chest may be an alternative non-invasive method of detecting PH. METHODS: This study retrospectively reviewed 101 acutely hospitalized inpatients with heterogeneous diagnoses, who consecutively underwent CT chest and RHC during the same admission. Two separate teams, each consisting of a radiologist and pulmonologist, blinded to clinical and RHC data, individually reviewed the chest CT's. RESULTS: Multiple regression analyses controlling for age, sex, ascending aortic diameter, body surface area, thoracic diameter and pulmonary wedge pressure showed that a main pulmonary artery (PA) diameter ≥29 mm (odds ratio (OR)=4.8), right descending PA diameter ≥19 mm (OR=7.0), true right descending PA diameter ≥16 mm (OR=4.1), true left descending PA diameter ≥21 mm (OR=15.5), right ventricular (RV) free wall ≥6 mm (OR=30.5), RV wall/left ventricular (LV) wall ratio ≥0.32 (OR=8.8), RV/LV lumen ratio ≥1.28 (OR=28.8), main PA/ascending aorta ratio ≥0.84 (OR=6.0) and main PA/descending aorta ratio ≥1.29 (OR=5.7) were significant predictors of PH in this population of hospitalized patients. CONCLUSION: This combination of easily measured CT-based metrics may, upon confirmatory studies, aid in the non-invasive detection of PH and hence in the determination of RHC candidacy in acutely hospitalized patients.

Cutting edge issues in Goodpasture's disease.

Goodpasture's disease, or anti-glomerular basement membrane (anti-GBM) disease, is a systemic autoimmune disorder defined by anti-GBM antibody-mediated damage (mainly immunoglobulin G-1) resulting in progressive crescentic glomerulonephritis and, frequently, diffuse pulmonary alveolar hemorrhage. It may be regarded as a "conformeropathy" where the quaternary structure of the α345NC1 hexamer that constitutes GBM undergoes a conformational change, exposing pathogenic epitopes on the α3 and α5 chains, eliciting a pathogenic autoantibody anti-GBM response. Goodpasture's disease accounts for 20% of all patients presenting with a pulmonary-renal syndrome and may be associated with detectable perinuclear antineutrophil cytoplasmic autoantibody positivity in up to a third of patients. Associated triggers may include tobacco smoking, hydrocarbon solvent exposure, and cocaine abuse. Cough, hemoptysis, and dyspnea with fatigue are the commonest presenting features. It is critical to rapidly distinguish Goodpasture's disease from other causes of pulmonary-renal syndromes such as Wegener's granulomatosis. Early and intensive treatment with plasmapheresis and immunosuppression with systemic corticosteroids pending results of diagnostic testing, and later cyclophosphamide, is often beneficial, with 90% of patients surviving the acute presentation of Goodpasture's disease. The need for hemodialysis on initial presentation, a serum creatinine >5 mg/dL, and 50% to 100% crescents on renal biopsy, portend the necessity of long-term hemodialysis. Further elucidation of the molecular pathobiology of Goodpasture's disease, particularly the regulation of involved antigen-specific T cells, may improve early diagnosis, treatment, and outcomes in this rare but potentially lethal autoimmune disorder.

Myeloperoxidase-dependent oxidative metabolism of nitric oxide in the cystic fibrosis airway.

BACKGROUND: Decreased expired nitric oxide (eNO) is commonly observed in cystic fibrosis (CF) patients and is usually explained by dysregulation of NO synthase (NOS) isoforms in respiratory tract epithelium. Later stages of this disease are accompanied by intense airway infiltration of phagocytes with high NOS activity, abundant levels of the hemoprotein myeloperoxidase (MPO) and significant production of significant reactive oxygen species. METHODS: This study characterizes the contribution of the high airway levels of MPO to decreased eNO levels in adult CF patients. NO metabolites (NO(x)) and MPO levels in fresh sputum of control and adult CF patients were determined and related to measurements of eNO and to in vitro consumption of NO in CF sputum. RESULTS: Despite essentially equal levels of NO(x) in sputum, eNO was 2- to 3-fold lower in CF patients compared to healthy controls. In CF patients, eNO levels were negatively associated with sputum peroxidase activity. In vivo correlations were confirmed by ex vivo studies of NO consumption by MPO in CF sputum. Immunodepletion studies confirmed MPO as the major heme peroxidase in CF sputum contributing to the hydrogen peroxide (H(2)O(2))-dependent consumption of NO. CONCLUSIONS: In CF airways MPO acts as a phagocyte-derived NO oxidase that diminishes NO bioavailability at airway surfaces, possibly identifying this peroxidase as a potential target for therapeutic intervention.

Do airway metallic stents for benign lesions confer too costly a benefit?

BACKGROUND: The use of self-expanding metallic stents (SEMAS) in the treatment benign airway obstruction is controversial. METHODS: To evaluate the safety and efficacy of SEMAS for this indication, we conducted a 10-year retrospective review at our tertiary medical centre. RESULTS: Using flexible bronchoscopy, 82 SEMAS (67% Ultraflex, 33% Wallstent) were placed in 35 patients with inoperable lesions, many with significant medical comorbidities (88%). 68% of stents were tracheal, and 83% of patients showed immediate symptomatic improvement. Reversible complications developed in 9% of patients within 24 hrs of stent placement. Late complications (>24 hrs) occurred in 77% of patients, of which 37% were clinically significant or required an interventional procedure. These were mainly due to stent migration (12.2%), fracture (19.5%), or obstructive granulomas (24.4%). The overall granuloma rate of 57% was higher at tracheal sites (59%) than bronchial ones (34%), but not significantly different between Ultraflex and Wallstents. Nevertheless, Wallstents were associated with higher rates of bleeding (5% vs. 30%, p = 0.005) and migration (7% vs. 26%, p = 0.026). Of 10 SEMAS removed using flexible bronchoscopy, only one was associated with incomplete removal of fractured stent wire. Median survival was 3.6 +/- 2.7 years. CONCLUSION: Ill patients with inoperable lesions may be considered for treatment with SEMAS.

L-arginine supplementation enhances exhaled NO, breath condensate VEGF, and headache at 4,342 m.

We examined the effect of dietary supplementation with L-arginine on breath condensate VEGF, exhaled nitric oxide (NO), plasma erythropoietin, symptoms of acute mountain sickness, and respiratory related sensations at 4,342 m through the course of 24 h in seven healthy male subjects. Serum L-arginine levels increased in treated subjects at time 0, 8, and 24 h compared with placebo, indicating the effectiveness of our treatment. L-arginine had no significant effect on overall Lake Louise scores compared with placebo. However, there was a significant increase in headache within the L-arginine treatment group at 12 h compared with time 0, a change not seen in the placebo condition between these two time points. There was a trend (p = 0.087) toward greater exhaled NO and significant increases in breath condensate VEGF with L-arginine treatment, but no L-arginine effect on serum EPO. These results suggest that L-arginine supplementation increases HIF-1 stabilization in the lung, possibly through a NO-dependent pathway. In total, our observations indicate that L-arginine supplementation is not beneficial in the prophylactic treatment of AMS.

Pharmacokinetics and clinical effects of mono-L-aspartyl chlorin e6 (NPe6) photodynamic therapy in adult patients with primary or secondary cancer of the skin and mucosal surfaces.

BACKGROUND/PURPOSE: Mono-L-aspartyl chlorin e6 (NPe6) is a photosensitizer that exhibits chemical purity, absorption at 664 nm wavelength and may be useful in photodynamic therapy (PDT). METHODS: This open label phase I clinical trial at the University of California, Davis Medical Center examined the pharmacokinetic properties of Npe6 and clinical response to PDT with this photosensitizer. A single intravenous dose of Npe6 was administered to 14 cancer patients with superficial malignancies (basal cell carcinoma = 22 lesions, squamous cell cancer = 13 lesions, papillary carcinoma = 14 lesions). Patients received one of five ascending doses (0.5 mg/kg (n = 4), 1.0 mg/kg (n = 3), 1.65 mg/kg (n = 3), 2.5 mg/kg (n = 3), or 3.5 mg/kg (n = 1)) 4-8 h prior to light activation. The total light dose (range 25-200 J/cm2) depended on the tumor shape and size. Light was delivered using an argon-pumped tunable dye laser. Serum NPe6 concentrations were measured over a 28-day period. The toxicity and cutaneous clinical efficacy of NPe6 were observed. RESULTS: Four weeks post-PDT, 20 of 22 basal cell carcinoma tumors (91%) showed a complete response. Eighteen of 27 other malignant cutaneous tumors showed a complete (n = 15/27, 56%) or partial (n = 3/27, 11%) response. Fewer non-responders were seen at an Npe6 dose level of 1.65 mg/kg or higher. Only 2 of 14 patients experienced an adverse event that was definitely related to NPe6 administration. Photosensitivity resolved within 1 week of NPe6 dosing in 12 of 14 patients. Analysis of serum levels of 11 individual patients indicated that a two-compartment model with a residual phase best fits the data. The mean alpha, beta, and terminal half-lives were 8.63+/-2.92, 105.90+/-37.59 and 168.11+/-53.40 h (+/-1 SD), respectively. The observed mean volume of distribution was 5.94+/-2.55 l, and the mean clearance was 0.0394+/-0.0132 l/h. These values were independent of the dose administered. CONCLUSION: The photosensitizer, NPe6, was well tolerated with minimal phototoxic side effects, and demonstrated preliminary efficacy against cutaneous malignancies.