Authors: John Bernardo; Wing Wai Yew

Authors: John D. Buckley; Doreen J. Addrizzo-Harris; Alison S. Clay; J. Randall Curtis; Robert M. Kotloff; Scott M. Lorin; Susan Murin; Curtis N. Sessler; Paul L. Rogers; Mark J. Rosen; Antoinette Spevetz; Talmadge E. King; Atul Malhotra; Polly E. Parsons

Rationale: Numerous accrediting organizations are calling for competency-based medical education that would help define specific specialties and serve as a foundation for ongoing assessment throughout a practitioner's career. Pulmonary Medicine and Critical Care Medicine are two distinct subspecialties, yet many individual physicians have expertise in both because of overlapping content. Establishing specific competencies for these subspecialties identifies educational goals for trainees and guides practitioners through their lifelong learning.

Objectives: To define specific competencies for graduates of fellowships in Pulmonary Medicine and Internal Medicine-based Critical Care.

Methods: A Task Force composed of representatives from key stakeholder societies convened to identify and define specific competencies for both disciplines. Beginning with a detailed list of existing competencies from diverse sources, the Task Force categorized each item into one of six core competency headings. Each individual item was reviewed by committee members individually, in group meetings, and conference calls. Nominal group methods were used for most items to retain the views and opinions of the minority perspective. Controversial items underwent additional whole group discussions with iterative modified-Delphi techniques. Consensus was ultimately determined by a simple majority vote.

Measurements and Main Results: The Task Force identified and defined 327 specific competencies for Internal Medicine-based Critical Care and 276 for Pulmonary Medicine, each with a designation as either: (1) relevant, but competency is not essential or (2) competency essential to the specialty.

Conclusions: Specific competencies in Pulmonary and Critical Care Medicine can be identified and defined using a multisociety collaborative approach. These recommendations serve as a starting point and set the stage for future modification to facilitate maximum quality of care as the specialties evolve.

Authors: Sam Bayat; Satu Strengell; Liisa Porra; Tibor Z. Janosi; Ferenc Petak; Heikki Suhonen; Pekka Suortti; Zoltan Hantos; Anssi R. A. Sovijärvi; Walid Habre

Rationale: Methacholine (Mch) is routinely used to assess bronchial hyperreactivity; however, little is known about the differences in the lung response pattern between this provocation and that observed with ovalbumin (Ova) after allergic sensitization.

Objectives: To compare (1) the central versus peripheral effects of Mch and Ova within the lung by combining measurements of airway and tissue mechanics with synchrotron radiation (SR) imaging, and (2) to assess the extent to which mechanical and imaging parameters are correlated.

Methods: We used the low-frequency forced oscillation technique and SR imaging in control (n = 12) and ovalbumin-sensitized (n = 13) rabbits, at baseline, during intravenous Mch infusion (2.5 μg/kg/min, 5.0 μg/kg/min, or 10.0 μg/kg/min), after recovery from Mch, and after intravenous Ova injection (2.0 mg). We compared intravenous Mch challenge with inhaled Mch (125 mg/ml, 90 s) in a separate group of control animals (n = 5).

Measurements and Main Results: Airway conductance and tissue elastance were measured by low-frequency forced oscillation technique. The central airway cross-sectional area, the ventilated alveolar area, and the heterogeneity of specific ventilation were quantified by SR imaging. Mch infusion induced constriction predominantly in the central airways, whereas Ova provocation affected mainly the peripheral airways, leading to severe ventilation heterogeneities in sensitized animals. Mch inhalation affected both conducting and peripheral airways. The correlations between airway conductance and central airway cross-sectional area (R = 0.71) and between tissue elastance and ventilated alveolar area (R = −0.72) were strong.

Conclusions: The pattern of lung response caused by intravenous Mch and Ova are fundamentally different. Although inhaled Mch induces a heterogeneous lung response similar to that observed with intravenous allergen, these similar patterns are due to different mechanisms.

Authors: Samar Farha; Kewal Asosingh; Daniel Laskowski; Jeffrey Hammel; Raed A. Dweik; Herbert P. Wiedemann; Serpil C. Erzurum

Rationale: Angiogenesis is a defining pathologic feature of airway remodeling and contributes to asthma severity. Women experience changes in asthma control over the menstrual cycle, a time when vessels routinely form and regress under the control of angiogenic factors. One vital function modulated over the menstrual cycle in healthy women is gas transfer, and this has been related to angiogenesis and cyclic expansion of the pulmonary vascular bed.

Objectives: We hypothesized that changes in gas transfer and the pulmonary vascular bed occur in women with asthma over the menstrual cycle and are associated with worsening airflow obstruction.

Methods: Twenty-three women, 13 with asthma and 10 healthy control subjects, were evaluated over the menstrual cycle with weekly measures of spirometry, gas transfer, nitric oxide, hemoglobin, factors affecting hemoglobin binding affinity, and proangiogenic factors.

Measurements and Main Results: Airflow and lung diffusing capacity varied over the menstrual cycle with peak levels during menses that subsequently declined to nadir in early luteal phase. In contrast to healthy women, changes in lung diffusing capacity (DlCO) were associated with changes in membrane diffusing capacity and DlCO was not related to proangiogenic factors. DlCO did not differ between the two groups, although methemoglobin and carboxyhemoglobin were higher in women with asthma than in healthy women.

Conclusions: Women with asthma experience cyclic changes in airflow as well as gas transfer and membrane diffusing capacity supportive of a hormonal effect on lung function.

Authors: Driss El Kebir; Levente József; Wanling Pan; Lili Wang; Nicos A. Petasis; Charles N. Serhan; János G. Filep

Rationale: Apoptosis is essential for removal of neutrophils from inflamed tissues and efficient resolution of inflammation. Myeloperoxidase (MPO), abundantly expressed in neutrophils, not only generates cytotoxic oxidants but also signals through the β2 integrin Mac-1 to rescue neutrophils from constitutive apoptosis, thereby prolonging inflammation.

Objectives: Because aspirin-triggered 15-epi-lipoxin A4 (15-epi-LXA4) modulates Mac-1 expression, we investigated the impact of 15-epi-LXA4 on MPO suppression of neutrophil apoptosis and MPO-mediated neutrophil-dependent acute lung injury.

Methods: Human neutrophils were cultured with MPO with or without 15-epi-LXA4 to investigate development of apoptosis. Acute lung injury was produced by intratracheal injection of carrageenan plus MPO or intraperitoneal injection of live Escherichia coli in mice, and the animals were treated with 15-epi-LXA4 at the peak of inflammation.

Measurements and Main Results: 15-Epi-LXA4 through down-regulation of Mac-1 expression promoted apoptosis of human neutrophils by attenuating MPO-induced activation of extracellular signal–regulated kinase and Akt-mediated phosphorylation of Bad and by reducing expression of the antiapoptotic protein Mcl-1, thereby aggravating mitochondrial dysfunction. The proapoptotic effect of 15-epi-LXA4 was dominant over MPO-mediated effects even when it was added at 4 hours post MPO. In mice, treatment with 15-epi-LXA4 accelerated the resolution of established carrageenan plus MPO-evoked as well as E. coli–induced neutrophil-dependent pulmonary inflammation through redirecting neutrophils to caspase-mediated cell death and facilitating their removal by macrophages.

Conclusions: These results demonstrate that aspirin-triggered 15-epi-LXA4 enhances resolution of inflammation by overriding the powerful antiapoptosis signal from MPO, thereby demonstrating a hitherto unrecognized mechanism by which aspirin promotes resolution of inflammation.

Authors: Douglas B. White; Leah R. Evans; Christopher A. Bautista; John M. Luce; Bernard Lo

Rationale: Although there is a growing belief that physicians should routinely provide a recommendation to surrogates during deliberations about withdrawing life support, there is a paucity of empirical data on surrogates' perspectives on this topic.

Objectives: To understand the attitudes of surrogate decision-makers toward receiving a physician's recommendation during deliberations about whether to limit life support for an incapacitated patient.

Methods: We conducted a prospective, mixed methods study among 169 surrogate decision-makers for critically ill patients. Surrogates sequentially viewed two videos of simulated physician–surrogate discussions about whether to limit life support, which varied only by whether the physician gave a recommendation.

Measurements and Main Results: The main quantitative outcome was whether surrogates preferred to receive a physicians' recommendation. Surrogates also participated in an in-depth, semistructured interview to explore the reasons for their preference. Fifty-six percent (95/169) of surrogates preferred to receive a recommendation, 42% (70/169) preferred not to receive a recommendation, and 2% (4/169) felt that both approaches were equally acceptable. We identified four main themes that explained surrogates' preferences, including surrogates' perceptions of physicians' appropriate role in life or death decisions and their perceptions of the positive or negative consequences of a recommendation on the physician–surrogate relationship, on the decision-making process, and on long-term regret for the family.

Conclusions: There is no consensus among surrogates about whether physicians should routinely provide a recommendation regarding life support decisions for incapacitated patients. These findings suggest that physicians should ask surrogates whether they wish to receive a recommendation regarding life support decisions and should be flexible in their approach to decision-making.

Authors: Akihisa Mitani; Takahide Nagase; Kazunori Fukuchi; Hiroyuki Aburatani; Ryosuke Makita; Hiroki Kurihara

Rationale: Transcriptional coactivator with PDZ-binding motif (TAZ) is assumed to act as a coactivator of several transcription factors including smad2/3. In the lung, surfactant protein C (Sftpc) is known to be a downstream target of thyroid transcription factor-1 (TTF-1)–TAZ transcriptional coactivation.

Objectives: The lung phenotype of Taz-deficient mice was explored.

Methods: Taz-deficient mice were analyzed pathologically and physiologically. Next, we performed microarray analysis to determine the genes closely related to abnormal lung development. Finally, Taz-heterozygous mice were injected with bleomycin.

Measurements and Main Results: Taz-deficient homozygotes showed abnormal alveolarization during lung development, which caused in adult mice airspace enlargement mimicking emphysema. There was no significant difference in the expression of Sftpc between wild-type and Taz-deficient lungs. Instead, microarray analysis identified some candidate downstream genes related to the pathogenesis, including the connective tissue growth factor (Ctgf) gene, which is required for normal lung development. In vitro studies showed that TAZ up-regulated Ctgf expression not only by reinforcing transforming growth factor-β/smad signals, but also by interfering in the more proximal Ctgf promoter region (from bp −123 to −76), defined as the TAZ response element. Furthermore, Taz-heterozygous mice were resistant to bleomycin-induced lung fibrosis.

Conclusions: The results indicate the importance of TAZ in lung alveolarization and its involvement in the pathogenesis of lung fibrosis.

Authors: Indra Narang; Andrew Bush; Mark Rosenthal

Rationale: After preterm birth, limited data exist in adulthood regarding alveolar–capillary growth and exercise capacity. Gas transfer at rest through exercise is a noninvasive measure of alveolar–capillary development.

Objectives: To determine exercise capacity and gas transfer at rest and during exercise in ex-preterm adults.

Methods: Ex-preterm subjects (n = 60; median gestation, 31.5 wk) recruited at birth underwent exercise testing at 21 years of age and were contemporaneously compared with 50 healthy control subjects.

Measurements and Main Results: Subjects exercised on a cycle ergometer, and measurements of heart rate (HR), FRC, effective pulmonary blood flow (Q·peff), stroke volume (SV), DlCO, V·o2, arteriovenous oxygen difference (AVO), transit time (TT), respiratory rate (Rf), V·co2, V·e, Vt, and respiratory quotient (RQ) were made using a respiratory mass spectrometer. In the index study group and control subjects, the median DlCO (mmol/min/kPa/m²) at rest was 4.33 (95% confidence interval [CI], 4.18–4.62) and 4.75 (95% CI, 4.50–5.10), respectively (P = 0.01), and the median Q·peff (L/min/m²) at rest was 3.26 (95% CI, 3.16–3.49) and 3.59 (95% CI, 3.43–3.81), respectively (P = 0.04). Q·peff and DlCO values normalized during exercise but were reduced and lower than controls after a recovery period. No significant differences were found in exercise capacity between the groups.

Conclusions: The data suggest a long-term effect of premature delivery on resting cardiac output and gas transfer, not due to abnormal cardiac or pulmonary function and with no evidence of exercise limitation.

Authors: Manuel Fischler; Marco Maggiorini; Lorenz Dorschner; Johann Debrunner; Alain Bernheim; Stephanie Kiencke; Heimo Mairbäurl; Konrad E. Bloch; Robert Naeije; Hans Peter Brunner-La Rocca

Rationale: Whether pulmonary hypertension at high altitude limits exercise capacity remains uncertain.

Objectives: To gain further insight into the pathophysiology of hypoxia induced pulmonary hypertension and the resulting reduction in exercise capacity, we investigated if the reduction in hypoxic pulmonary vasoconstrictive response with corticosteroids or phosphodiesterase-5 inhibition improves exercise capacity.

Methods: A cardiopulmonary exercise test and echocardiography to estimate systolic pulmonary artery pressure were performed in 23 subjects with previous history of high altitude pulmonary edema, known to be associated with enhanced hypoxic vasoconstriction. Subjects were randomized to dexamethasone 8 mg twice a day, tadalafil 10 mg twice a day, or placebo (double-blinded), starting the day before ascent.

Measurements and Main Results: Measurements were performed at low and high (i.e., 4,559 m) altitude. Altitude exposure decreased maximum oxygen uptake and oxygen saturation, increased pulmonary artery pressure, and altered oxygen uptake kinetics. Compared with placebo, dexamethasone improved maximum oxygen uptake (% predicted 74 ± 13%; tadalafil 63 ± 13%, placebo 61 ± 11%; P < 0.05), oxygen kinetics (mean response time 41 ± 13 s; tadalafil 46 ± 6 s, placebo 45 ± 10 s; P < 0.05), and reduced the ventilatory equivalent for CO2 (42 ± 4; tadalafil 49 ± 4, placebo 50 ± 5; P < 0.01). Peak oxygen saturation did not differ significantly between the three groups (dexamethasone 66 ± 7%, placebo 62 ± 7%, tadalafil 69 ± 5%; P = 0.08). During echocardiography at low-intensity exercise (40% of peak power), dexamethasone compared with placebo resulted in lower pulmonary artery pressure (47 ± 9 mm Hg; tadalafil 57 ± 11 mm Hg, placebo 68 ± 23 mm Hg; P = 0.05) and higher oxygen saturation (74 ± 7%; tadalafil 67 ± 3%, placebo 61 ± 20; P < 0.02).

Conclusions: Corticosteroids, but not phosphodiesterase-5 inhibition, partially prevented the limitation of exercise capacity in subjects with intense hypoxic pulmonary vasoconstriction at high altitude.

Authors: Markus Roth; Markus Rupp; Simone Hofmann; Manish Mittal; Beate Fuchs; Natascha Sommer; Nirmal Parajuli; Karin Quanz; Dominic Schubert; Eva Dony; Ralph Theo Schermuly; Hossein Ardeschir Ghofrani; Ulrike Sausbier; Katrin Rutschmann; Sarah Wilhelm; Werner Seeger; Peter Ruth; Friedrich Grimminger; Matthias Sausbier; Norbert Weissmann

Rationale: Hypoxic pulmonary vasoconstriction (HPV) is an important mechanism by which pulmonary gas exchange is optimized by the adaptation of blood flow to alveolar ventilation. In chronic hypoxia, in addition to HPV a vascular remodeling process leads to pulmonary hypertension. A complex of heme oxygenase-2 (HO-2) and the BK channel has been suggested as a universal oxygen sensor system.

Objectives: We investigated whether this complex serves as an oxygen sensor for the vascular effects of alveolar hypoxia in the lung.

Methods: The investigations were performed in chronically hypoxic mice, in isolated perfused and ventilated lungs, and on the cellular level, including HO-2- and BK-channel deficient mice.

Measurements and Main Results: Immunohistochemical analysis of mouse lungs identified HO-2 mainly in pulmonary arteries, the bronchial epithelium, and alveolar epithelial cells. BK channel α-subunit (BKα) immunoreactivity was found primarily in the bronchial and vascular smooth muscle layer. Immunofluorescence staining and coimmunoprecipitation suggested only a weak complexation of HO-2 and BKα in pulmonary arterial smooth muscle cells. The strength of acute and sustained HPV, determined in isolated perfused and ventilated lungs, was not different among wild-type, HO-2–deficient, and BKα-deficient mice. Exposure of mice to 3 weeks of chronic hypoxia resulted in a slight down-regulation of HO-2 and no alteration in BKα expression. The degree of pulmonary hypertension that developed, quantified on the basis of right ventricular pressure, right-heart hypertrophy, and the degree of muscularization of precapillary pulmonary arteries, was not different among wild-type, HO-2–deficient, and BKα-deficient mice.

Conclusions: It is demonstrated that neither deletion of HO-2 nor BK channels affect acute, sustained, and chronic vascular responses to alveolar hypoxia in the lung.

Authors: Rose A. Devasia; Amondrea Blackman; Tebeb Gebretsadik; Marie Griffin; Ayumi Shintani; Carolyn May; Teresa Smith; Nancy Hooper; Fernanda Maruri; Jon Warkentin; Ed Mitchel; Timothy R. Sterling

Rationale: Fluoroquinolones are the most commonly prescribed antibiotic class in the United States. They have the potential to become first-line antituberculosis therapy, but the effect of fluoroquinolone use on fluoroquinolone resistance in Mycobacterium tuberculosis is not well characterized.

Objectives: To determine the prevalence of and risk factors for fluoroquinolone-resistant tuberculosis in a large United States population.

Methods: We identified all people with culture-confirmed tuberculosis enrolled in TennCare (Medicaid) and reported to the Tennessee Department of Health from January 2002 to December 2006. People with fluoroquinolone-resistant M. tuberculosis isolates (cases) were compared with those with susceptible isolates (control subjects). Fluoroquinolone resistance was determined by agar proportion using ofloxacin 2 μg/ml. Outpatient fluoroquinolone exposure in the 12 months before tuberculosis diagnosis was ascertained from TennCare pharmacy data.

Measurements and Main Results: Of 640 study patients, 116 (18%) had fluoroquinolone exposure in the 12 months before diagnosis, and 16 (2.5%; 95% confidence interval [CI], 1.4–4.0%) M. tuberculosis isolates were fluoroquinolone resistant. Among the 54 patients with more than 10 days of fluoroquinolone exposure, 7 (13%) had fluoroquinolone resistance. In multivariable logistic regression analyses using propensity score to control for age, sex, race, HIV serostatus, and site of disease, more than 10 days of fluoroquinolone exposure before tuberculosis diagnosis was associated with fluoroquinolone resistance (odds ratio 7.0; 95% CI, 2.3–20.6; P = 0.001). Fluoroquinolone exposure for more than 10 days that occurred more than 60 days before tuberculosis diagnosis was associated with the highest risk of resistance (20.8%; odds ratio 17.0; 95% CI, 5.1–56.8; P < 0.001 compared with no exposure).

Conclusions: Overall, fluoroquinolone resistance was relatively low. However, receipt of fluoroquinolones for more than 10 days, particularly more than 60 days before tuberculosis diagnosis, was associated with a high risk of fluoroquinolone-resistant tuberculosis.

Authors: Kathy N. Williams; Steven J. Brickner; Charles K. Stover; Tong Zhu; Adam Ogden; Rokeya Tasneen; Sandeep Tyagi; Jacques H. Grosset; Eric L. Nuermberger

Rationale: We recently reported strong bactericidal activity of the oxazolidinone PNU-100480 and its ability to increase the initial bactericidal effect of various combinations of first-line tuberculosis drugs and moxifloxacin in a murine model.

Objectives: To investigate whether the addition of PNU-100480 to the standard first-line regimen of rifampin, isoniazid, and pyrazinamide could shorten the duration of treatment necessary to prevent relapse after treatment discontinuation.

Methods: Following aerosol infection with Mycobacterium tuberculosis H37Rv and a 13-day incubation period, control mice were treated with the first-line regimen while test mice received the same regimen with PNU-100480 or linezolid added for the first 2 or 4 months. Efficacy was assessed on the basis of quantitative cultures of lung homogenates performed monthly during treatment and 3 months after completion of 3, 4, 5, or 6 months of treatment to determine the relapse rate.

Measurements and Main Results: After 2 months of treatment, mice receiving PNU-100480 in addition to the first-line regimen had lung CFU counts two orders of magnitude lower than control mice receiving the first-line regimen alone. Relapse rates after 4 months of treatment were 90, 35, and 5% when PNU-100480 was added to the first-line regimen for 0, 2, and 4 months, respectively. When the total treatment duration was 3 months, relapse rates were 85 and 35 to 45% when mice received PNU-100480 for 2 and 3 months, respectively; all control mice remained culture positive at the time of treatment completion with 17 to 72 CFU per lung. Addition of linezolid to the first-line regimen had an antagonistic effect resulting in higher CFU counts and failure to render mice culture-negative in 4 months of treatment.

Conclusions: Together with previous findings, these results confirm that PNU-100480, which is now in Phase I clinical testing, has sterilizing activity in the murine model and suggest that it may be capable of shortening treatment duration for drug-susceptible as well as drug-resistant tuberculosis in humans.

Authors: Anastassios C. Koumbourlis; Donna J. Lee; Ada Lee

Authors: Joanna E. MacLean; Hartmut Grasemann; Padmaja Subbarao

Authors: H. James Ford; Robert M. Aris; Kenneth Andreoni

Authors: Jérôme Le Pavec; Marc Humbert; Philippe Hervé; Gérald Simonneau; Olivier Sitbon

Authors: Paolo Spagnolo; Fabrizio Luppi; Giulio Rossi; Luca Richeldi

Authors: Shinichiro Ohshimo; Josune Guzman; Francesco Bonella; Ulrich Costabel

Author: Edward Abraham