Authors: Fadlo R. Khuri; Jesse Roman

Author: Lewis J. Rubin

Authors: Ted Cohen; Caroline Colijn; Abigail Wright; Matteo Zignol; Alexander Pym; Megan Murray

The International Union Against Tuberculosis and Lung Disease/World Health Organization Global Project on Anti-Tuberculosis Drug Resistance Surveillance recently released the fourth global survey, which documents the highest burden of multidrug-resistant tuberculosis (TB) yet reported. The best estimate of the number of new cases of multidrug-resistant disease occurring in 2006 is close to half a million and the recent recognition of extensively drug-resistant TB underscores the need for expanded surveillance, especially in areas in which TB control programs have been compromised by an escalating burden of TB and HIV. We review current methods used for drug resistance surveillance and describe methodologic obstacles for estimating the true extent of the problem, particularly in settings where HIV/TB coinfection is common or where a substantial portion of TB cases are treated in the private sector. We highlight practical challenges to the validity of surveillance studies and discuss how additional investment in laboratory capacity, diagnostic technologies, and sentinel site surveillance can improve our ability to estimate of the burden of drug-resistant TB.

Authors: Frank Schaumann; Meike Müller; Armin Braun; Birgit Luettig; David B. Peden; Jens M. Hohlfeld; Norbert Krug

Rationale: Epidemiologic studies have shown that exacerbation of asthma is modulated by environmental endotoxin. High levels of endotoxin are associated with asthma symptoms and the current use of asthma medication. However, the underlying mechanisms by which endotoxin modulates asthma are not completely understood.

Objectives: The aim of the study was to test whether endotoxin enhances the response of individuals with allergic asthma to allergen, and to determine if this interaction is associated with increased numbers of antigen-presenting cells in the airways.

Methods: Seventeen subjects with mild allergic asthma underwent segmental challenge with allergen, endotoxin, and the combination of both in three different lung segments via bronchoscopy. The cellular influx including monocytes, myeloid dendritic cells (mDCs), and plasmacytoid dendritic cells (pDCs), as well as the level of cytokines, were assessed in bronchoalveolar lavage fluid obtained 24 hours after segmental challenge. Monocytes, mDCs, and pDCs were isolated and their capacity to induce T cell proliferation was determined.

Measurements and Main Results: Endotoxin enhanced the cellular response to allergen. The combination of allergen and endotoxin resulted in increased numbers of total cells, lymphocytes, neutrophils, eosinophils, monocytes, and mDCs, as well as increased levels of lipopolysaccharide-binding protein, IL-1α, IL-6, and tumor necrosis factor–α in the bronchoalveolar lavage fluid compared with allergen alone. Isolated mDCs but not pDCs induced a strong T cell proliferation in vitro.

Conclusions: Endotoxin augments the allergic inflammation in the lungs of individuals with asthma, and induces an enhanced influx of monocytes and functionally active antigen-presenting mDCs into the respiratory tract.

Authors: Davina C. M. Simoes; Theodoros Vassilakopoulos; Dimitrios Toumpanakis; Kalomira Petrochilou; Charis Roussos; Andreas Papapetropoulos

Rationale: The angiopoietins (Ang) comprise a family of growth factors mainly known for their role in blood vessel formation and remodeling. The best-studied member, Ang-1, exhibits antiapoptotic and antiinflammatory effects. Although the involvement of Ang-1 in angiogenesis is well recognized, little information exists about its role in respiratory physiology and disease. On the basis of its ability to inhibit vascular permeability, adhesion molecule expression, and cytokine production, we hypothesized that Ang-1 administration might exert a protective role in asthma.

Objectives: To determine changes in the expression of Ang and to assess the ability of Ang-1 to prevent the histologic, biochemical, and functional changes observed in an animal model of asthma.

Methods: To test our hypothesis, a model of allergic airway disease that develops after ovalbumin (OVA) sensitization and challenge was used.

Measurements and Main Results: Ang-1 expression was reduced at the mRNA and protein levels in lung tissue of mice sensitized and challenged with OVA, leading to reduced Tie2 phosphorylation. Intranasal Ang-1 treatment prevented the OVA-induced eosinophilic lung infiltration, attenuated the increase in IL-5 and IL-13, and reduced eotaxin and vascular cell adhesion molecule 1 expression. These antiinflammatory actions of Ang-1 coincided with higher levels of IκB and decreased nuclear factor-κB binding activity. More importantly, Ang-1 reversed the OVA-induced increase in tissue resistance and elastance, improving lung function.

Conclusions: We conclude that Ang-1 levels are decreased in asthma and that administration of Ang-1 might be of therapeutic value because it prevents the increased responsiveness of the airways to constrictors and ameliorates inflammation.

Authors: Cecilia G. Clement; Scott E. Evans; Christopher M. Evans; David Hawke; Ryuji Kobayashi; Paul R. Reynolds; Seyed J. Moghaddam; Brenton L. Scott; Ernestina Melicoff; Roberto Adachi; Burton F. Dickey; Michael J. Tuvim

Rationale: The lungs are a common site of serious infection in both healthy and immunocompromised subjects, and the most likely route of delivery of a bioterror agent. Since the airway epithelium shows great structural plasticity in response to inflammatory stimuli, we hypothesized it might also show functional plasticity.

Objectives: To test the inducibility of lung defenses against bacterial challenge.

Methods: Mice were treated with an aerosolized lysate of ultraviolet-killed nontypeable (unencapsulated) Haemophilus influenzae (NTHi), then challenged with a lethal dose of live Streptococcus pneumoniae (Spn) delivered by aerosol.

Measurements and Main Results: Treatment with the NTHi lysate induced complete protection against challenge with a lethal dose of Spn if treatment preceded challenge by 4 to 24 hours. Lesser levels of protection occurred at shorter (83% at 2 h) and longer (83% at 48–72 h) intervals between treatment and challenge. There was also some protection when treatment was given 2 hours after challenge (survival increased from 14 to 57%), but not 24 hours after challenge. Protection did not depend on recruited neutrophils or resident mast cells and alveolar macrophages. Protection was specific to the airway route of infection, correlated in magnitude and time with rapid bacterial killing within the lungs, and was associated with increases of multiple antimicrobial polypeptides in lung lining fluid.

Conclusions: We infer that protection derives from stimulation of local innate immune mechanisms, and that activated lung epithelium is the most likely cellular effector of this response. Augmentation of innate antimicrobial defenses of the lungs might have therapeutic value.

Authors: Verena Morgenstern; Anne Zutavern; Josef Cyrys; Inken Brockow; Sibylle Koletzko; Ursula Krämer; Heidrun Behrendt; Olf Herbarth; Andrea von Berg; Carl Peter Bauer; H. Erich Wichmann; Joachim Heinrich

Rationale: In vitro studies, animal experiments, and human exposure studies have shown how ambient air pollution increases the risk of atopic diseases. However, results derived from observational studies are inconsistent.

Objectives: To assess the relationship between individual-based exposure to traffic-related air pollutants and allergic disease outcomes in a prospective birth cohort study during the first 6 years of life.

Methods: We studied 2,860 children at the age of 4 years and 3,061 at the age of 6 years to investigate atopic diseases and allergic sensitization. Long-term exposure to particulate matter (PM2.5), PM2.5 absorbance, and long-term exposure to nitrogen dioxide (NO2) was assessed at residential addresses using geographic information systems based regression models and air pollution measurements. The distance to the nearest main road was used as a surrogate for traffic-related air pollutants.

Measurements and Main Results: Strong positive associations were found between the distance to the nearest main road and asthmatic bronchitis, hay fever, eczema, and sensitization. A distance-dependent relationship could be identified, with the highest odds ratios (ORs) for children living less than 50 m from busy streets. For PM2.5 absorbance, statistically significant effects were found for asthmatic bronchitis (OR, 1.56; 95% confidence interval [CI], 1.03–2.37), hay fever (OR, 1.59; 95% CI, 1.11–2.27), and allergic sensitization to pollen (OR, 1.40; 95% CI, 1.20–1.64). NO2 exposure was associated with eczema, whereas no association was found for allergic sensitization.

Conclusions: This study provides strong evidence for increased risk of atopic diseases and allergic sensitization when children are exposed to ambient particulate matter.

Authors: William D. Travis; Gary Hunninghake; Talmadge E. King; David A. Lynch; Thomas V. Colby; Jeffrey R. Galvin; Kevin K. Brown; Man Pyo Chung; Jean-François Cordier; Roland M. duBois; Kevin R. Flaherty; Teri J. Franks; David M. Hansell; Thomas E. Hartman; Ella A. Kazerooni; Dong Soon Kim; Masanori Kitaichi; Takashi Koyama; Fernando J. Martinez; Sonoko Nagai; David E. Midthun; Nestor L. Müller; Andrew G. Nicholson; Ganesh Raghu; Moisés Selman; Athol Wells

Rationale: The 2002 American Thoracic Society/European Respiratory Society classification of idiopathic interstitial pneumonias identified nonspecific interstitial pneumonia (NSIP) as a provisional diagnosis. Concern was expressed that NSIP was a “wastebasket” category, difficult to distinguish from other idiopathic interstitial pneumonias.

Objectives: The following questions were addressed: (1) Is idiopathic NSIP a distinct entity? 2) If so, what are its clinical, radiologic and pathologic characteristics? (3) What is the role of radiology and pathology in establishing the diagnosis? (4) To make a diagnosis of idiopathic NSIP, what other disorders need to be excluded and how should this be done?

Methods: Investigators who had previously reported cases of idiopathic NSIP were invited to submit cases for review (n = 305). After initial review, cases with complete clinical, radiologic, and pathologic information (n = 193) were reviewed in a series of workshops.

Measurements and Main Results: Sixty-seven cases were identified as NSIP. Mean age was 52 years, 67% were women, 69% were never-smokers, and 46% were from Asian countries. The most common symptoms were dyspnea (96%) and cough (87%); 69% had restriction. By high-resolution computed tomography, the lower lung zones were predominantly involved in 92% of cases; 46% had a peripheral distribution; 47% were diffuse. Most showed a reticular pattern (87%) with traction bronchiectasis (82%) and volume loss (77%). Lung biopsies showed uniform thickening of alveolar walls with a spectrum of cellular to fibrosing patterns. Five-year survival was 82.3%.

Conclusions: Idiopathic NSIP is a distinct clinical entity that occurs mostly in middle-aged women who are never-smokers. The prognosis of NSIP is very good.

Authors: Shoji Kudoh; Harubumi Kato; Yutaka Nishiwaki; Masahiro Fukuoka; Kouichiro Nakata; Yukito Ichinose; Masahiro Tsuboi; Soichiro Yokota; Kazuhiko Nakagawa; Moritaka Suga; Haiyi Jiang; Yohji Itoh; Alison Armour; Claire Watkins; Tim Higenbottam; Fredrik Nyberg

Rationale: Interstitial lung disease (ILD) occurs in Japanese patients with non–small cell lung cancer (NSCLC) receiving gefitinib.

Objectives: To elucidate risk factors for ILD in Japanese patients with NSCLC during treatment with gefitinib or chemotherapy.

Methods: In a prospective epidemiologic cohort, 3,166 Japanese patients with advanced/recurrent NSCLC were followed for 12 weeks on 250 mg gefitinib (n = 1,872 treatment periods) or chemotherapy (n = 2,551). Patients who developed acute ILD (n = 122) and randomly selected control subjects (n = 574) entered a case-control study. Adjusted incidence rate ratios were estimated from case-control data by odds ratios (ORs) with 95% confidence intervals (CIs) using logistic regression. Crude (observed) incidence rates and risks were calculated from cohort data.

Measurements and Main Results: The observed (unadjusted) incidence rate over 12 weeks was 2.8 (95% CI, 2.3–3.3) per 1,000 person-weeks, 4.5 (3.5–5.4) for gefitinib versus 1.7 (1.2–2.2) for chemotherapy; the corresponding observed naive cumulative incidence rates at the end of 12-week follow-up were 4.0% (3.0–5.1%) and 2.1% (1.5–2.9%), respectively. Adjusted for imbalances in risk factors between treatments, the overall OR for gefitinib versus chemotherapy was 3.2 (1.9–5.4), elevated chiefly during the first 4 weeks (3.8 [1.9–7.7]). Other ILD risk factors in both groups included the following: older age, poor World Health Organization performance status, smoking, recent NSCLC diagnosis, reduced normal lung on computed tomography scan, preexisting chronic ILD, concurrent cardiac disease. ILD-related deaths in patients with ILD were 31.6% (gefitinib) versus 27.9% (chemotherapy); adjusted OR, 1.05 (95% CI, 0.3–3.2).

Conclusions: ILD was relatively common in these Japanese patients with NSCLC during therapy with gefitinib or chemotherapy, being higher in the older, smoking patient with preexisting ILD or poor performance status. The risk of developing ILD was higher with gefitinib than chemotherapy, mainly in the first 4 weeks.

Authors: Jaclyn A. Smith; Richard Drake; Angela Simpson; Ashley Woodcock; Andrew Pickles; Adnan Custovic

Rationale: A focus on distinctive collections of symptoms may be more informative of the probability of respiratory disease than individual and possibly transient phenotypes. However, such collections or components of overall symptomatology need to be valid, and their relationship established with the known risk factors and physiologic measures.

Objectives: To analyze detailed parentally reported respiratory symptoms by principal components analysis and derive symptom components; to examine the relationship of such components with measures of lung physiology and atopy.

Methods: An unselected, population-based birth cohort (n = 946).

Measurements and Main Results: Interviewer-administered questionnaires, lung function (specific airway resistance [sRaw]), airway reactivity (dry air challenge), and atopic status were obtained at ages 3 and 5 years; principal components analysis and multivariate analysis of variance were used to analyze the data. The four-component solution (wheeze, cough, colds, chronic symptoms) explained 53.2% of the variance in symptoms at age 3, and the five-component solution (wheeze, wheeze with irritants, wheeze with allergens, cough, chest congestion) explained 49.8% of variance at age 5. The multivariate analysis revealed novel relationships between symptoms, risk factors for asthma, and measures of lung function. At age 3, sRaw and the interaction between maternal asthma and child's atopy were not only related to wheeze but also independently to the cough component. At age 5, overall wheeze and allergic wheeze were related to lung function and airway reactivity; child's atopy was only related to symptoms when considered as a continuous trait.

Conclusions: Our analysis supports the need to move beyond the presence or absence of individual symptoms. Syndromes of coexisting symptoms more likely reflect underlying pathophysiologic processes.

Clinical trial registered with http://www.controlled-trials.com (ISRCTN72673620).

Authors: Paul R. Forfia; Stephen C. Mathai; Micah R. Fisher; Traci Housten-Harris; Anna R. Hemnes; Hunter C. Champion; Reda E. Girgis; Paul M. Hassoun

Rationale: Hyponatremia is associated with decompensated heart failure and poor prognosis in patients with left ventricular systolic dysfunction.

Objectives: We sought to determine if hyponatremia is associated with right heart failure and worse prognosis in patients with pulmonary arterial hypertension (PAH).

Methods: We prospectively followed 40 patients with PAH and examined the relationship between serum sodium and right heart function as well as survival.

Measurements and Main Results: Subjects with hyponatremia (Na  136 mEq/L) were more symptomatic (11/13 World Health Organization [WHO] class III/IV vs. 12/27 WHO class III/IV; P = 0.02), had more peripheral edema (69 vs. 26%; P = 0.009), and had higher hospitalization rates (85 vs. 41%; P = 0.009) than normonatremic subjects. Hyponatremic subjects had higher right atrial pressure (14 ± 6 vs. 9 ± 3 mm Hg; P < 0.001), lower stroke volume index (21 ± 7 vs. 32 ± 10 ml/m²; P < 0.01), larger right ventricular:left ventricular area ratio (1.8 ± 0.4 vs. 1.3 ± 0.4; P < 0.001), and lower tricuspid annular plane systolic excursion (1.4 ± 0.3 vs. 2.0 ± 0.6 cm; P = 0.001), despite similar mean pulmonary artery pressure (49 ± 10 vs. 47 ± 12 mm Hg; P = 0.60). The 1- and 2-year survival estimates were 93% (95% confidence interval [CI], 73–98%) and 85% (95% CI, 65–94%), and 38% (95% CI, 14–63%) and 15% (95% CI, 2–39%) for normonatremic and hyponatremic subjects, respectively (log-rank χ² = 25.19, P < 0.001). The unadjusted risk of death (hazard ratio) in hyponatremic compared with normonatremic subjects was 10.16 (95% CI, 3.42–30.10, P < 0.001). Hyponatremia predicted outcome after adjusting for WHO class, diuretic use, as well as right atrial pressure and cardiac index.

Conclusions: Hyponatremia is strongly associated with right heart failure and poor survival in PAH.

Authors: Jean-Paul Richalet; Maria Rivera-Ch; Maxime Maignan; Catherine Privat; Isabelle Pham; Jose-Luis Macarlupu; Olivier Petitjean; Fabiola León-Velarde

Rationale: Monge's disease is characterized by an excessive erythrocytosis, frequently associated with pulmonary hypertension, in high-altitude dwellers. It has a considerable impact on public health in high-altitude regions. A preliminary study demonstrated the efficiency of acetazolamide (Acz) (250 mg/d for 3 wk) in reducing serum erythropoietin and hematocrit.

Objectives: Evaluate the efficacy and tolerance of a 6-month treatment with 250 mg Acz that could be chronically implemented and its effects on pulmonary artery pressure and cardiac function.

Methods: A two-phase study was performed in patients (hematocrit  63%) from Cerro de Pasco, Peru (4,300 m). First phase: a double-blind, placebo-controlled study in 55 patients who received a single dose of either 250 mg Acz (n = 40) or placebo (n = 15) by daily oral administration for 12 weeks. Second phase (open label): after a 4-week washout period, all patients received 250 mg Acz for 12 weeks. Hematocrit, blood gases, clinical outcome, and pulmonary artery circulation were evaluated.

Measurements and Main Results: First phase: Acz decreased by 44% the number of polycythemic subjects (P = 0.02), decreased hematocrit from 69 to 64% (P < 0.001), and increased arterial O2 pressure from 42 to 45 mm Hg (P < 0.001). No severe adverse effect or hypokalemia was recorded. The second phase reproduced the effects observed during the first phase, without cumulative effects on hematocrit. A 4-week washout restored basal hematocrit. Only patients who received Acz for 6 months showed a clear reduction in pulmonary vascular resistance.

Conclusions: Acz reduces erythrocytosis and improves pulmonary circulation in Monge's disease without adverse effects. Its implementation as a chronic treatment for this disease appears efficient and safe.

Clinical trial registered with www.clinicaltrials.gov (NCT 00424970).

Authors: Benjamin Sztrymf; Florence Coulet; Barbara Girerd; Azzedine Yaici; Xavier Jais; Olivier Sitbon; David Montani; Rogério Souza; Gerald Simonneau; Florent Soubrier; Marc Humbert

Rationale: Germline mutations in the gene encoding for bone morphogenetic protein receptor 2 (BMPR2) are a cause of pulmonary arterial hypertension (PAH).

Objectives: We conducted a study to determine the influence, if any, of a BMPR2 mutation on clinical outcome.

Methods: The French Network of Pulmonary Hypertension obtained data for 223 consecutive patients displaying idiopathic or familial PAH in whom point mutation and large size rearrangements of BMPR2 were screened for. Clinical, functional, and hemodynamic characteristics, as well as outcomes, were compared in BMPR2 mutation carriers and noncarriers.

Measurements and Main Results: Sixty-eight BMPR2 mutation carriers (28 familial and 40 idiopathic PAH) were compared with 155 noncarriers (all displaying idiopathic PAH). As compared with noncarriers, BMPR2 mutation carriers were younger at diagnosis of PAH (36.5 ± 14.5 vs. 46.0 ± 16.1 yr, P < 0.0001), had higher mean pulmonary artery pressure (64 ± 13 vs. 56 ± 13 mm Hg, P < 0.0001), lower cardiac index (2.13 ± 0.68 vs. 2.50 ± 0.73 L/min/m², P = 0.0005), higher pulmonary vascular resistance (17.4 ± 6.1 vs. 12.7 ± 6.6 mm Hg/L/min/m², P < 0.0001), lower mixed venous oxygen saturation (59 ± 9% vs. 63 ± 9%, P = 0.02), shorter time to death or lung transplantation (P = 0.044), and younger age at death (P = 0.002), but similar overall survival (P = 0.51).

Conclusions: BMPR2 mutation carriers with PAH present approximately 10 years earlier than noncarriers, with a more severe hemodynamic compromise at diagnosis.

Authors: Robert B. Banzett; Sarah H. Pedersen; Richard M. Schwartzstein; Robert W. Lansing

Rationale: It is hypothesized that the affective dimension of dyspnea (unpleasantness, emotional response) is not strictly dependent on the intensity of dyspnea.

Objectives: We tested the hypothesis that the ratio of immediate unpleasantness (A1) to sensory intensity (SI) varies depending on the type of dyspnea.

Methods: Twelve healthy subjects experienced three stimuli: stimulus 1: maximal eucapnic voluntary hyperpnea against inspiratory resistance, requiring 15 times the work of resting breathing; stimulus 2: PetCO2 6.1 mm Hg above resting with ventilation restricted to less than spontaneous breathing; stimulus 3: PetCO2 7.7 mm Hg above resting with ventilation further restricted. After each trial, subjects rated SI, A1, and qualities of dyspnea on the Multidimensional Dyspnea Profile (MDP), a comprehensive instrument tested here for the first time.

Measurements and Main Results: Stimulus 1 was always limited by subjects failing to meet a higher ventilation target; none signaled severe discomfort. This evoked work and effort sensations, with relatively low unpleasantness (mean A1/SI = 0.64). Stimulus 2, titrated to produce dyspnea ratings similar to those subjects gave during stimulus 1, evoked air hunger and produced significantly greater unpleasantness (mean A1/SI = 0.95). Stimulus 3, increased until air hunger was intolerable, evoked the highest intensity and unpleasantness ratings and high unpleasantness ratio (mean A1/SI = 1.09). When asked which they would prefer to repeat, all subjects chose stimulus 1.

Conclusions: (1) Maximal respiratory work is less unpleasant than moderately intense air hunger in this brief test; (2) unpleasantness of dyspnea can vary independently from perceived intensity, consistent with the prevailing model of pain; (3) separate dimensions of dyspnea can be measured with the MDP.

Authors: Kwok C. Chang; Chi C. Leung; Wing W. Yew; Tat Y. Lau; Cheuk M. Tam

Rationale: Relatively little is known about the hepatotoxicity of pyrazinamide.

Objectives: We compared continuation-phase regimens incorporating pyrazinamide, isoniazid, and/or rifampin with those containing isoniazid and rifampin to evaluate the hepatotoxicity of pyrazinamide.

Methods: Cohort and nested case-control analyses were conducted on a cohort of 3,007 patients with active tuberculosis (TB) managed at government chest clinics under a TB control program with treatment started from January 1 through June 30, 2001. Cases included all patients with probable hepatotoxicity from 12 or more weeks after starting treatment. Hepatotoxicity was considered probable when serum alanine transaminase exceeded three times the upper limit of normal. Each case was matched by sex and age with three control subjects selected randomly from the rest of the cohort. Treatment regimens of cases within 4 weeks preceding hepatotoxicity were compared with those of matched control subjects in comparable periods relative to the date of commencing treatment.

Measurements and Main Results: Hepatotoxicity occurred in 150 (5.0%) patients at any time including 48 (1.6%) cases. From 12 or more weeks after starting treatment, the estimated risk of hepatotoxicity was 2.6% for regimens incorporating pyrazinamide, isoniazid, and/or rifampin, and 0.8% for standard regimens containing isoniazid and rifampin. Multivariable conditional logistic analysis showed a significant association between hepatotoxicity and, respectively, hepatitis B, previous hepatotoxicity, and treatment regimens. The adjusted odds ratio (95% confidence interval) of hepatotoxicity for regimens incorporating pyrazinamide, isoniazid, and/or rifampin relative to standard regimens was 2.8 (1.4–5.9).

Conclusions: Adding pyrazinamide to isoniazid and rifampin increases the risk of hepatotoxicity appreciably.

Authors: Wim A. Wuyts; Michiel Thomeer; Lieven J. Dupont; Geert M. Verleden

Authors: Arata Azuma; Koichi Hagiwara; Shoji Kudoh

Authors: Harold R. Collard; Fernando J. Martinez

Authors: Stijn L. Verhulst; Jan De Backer; Luc Van Gaal; Wilfried De Backer; Kristine Desager