Authors: Oner Dikensoy; Richard W. Light

Author: Pedro Caruso

Authors: Jane Kirkby; Sanja Stanojevic; Janet Stocks

Authors: Andrew Bush; Isabella Annesi-Maesano

Author: Jørgen Vestbo

Authors: Michael C. Iannuzzi; Robert P. Baughman

Authors: Ivan O. Rosas; Naftali Kaminski

Authors: Brian Williams; Dermot Maher

Authors: Matthias Eikermann; Florian M. Vogt; Frank Herbstreit; Mehdi Vahid-Dastgerdi; Michael O. Zenge; Christof Ochterbeck; Armin de Greiff; Jürgen Peters

Rationale: Partial neuromuscular transmission failure by acetylcholine receptor blockade (neuromuscular blockade) or antibody-mediated functional loss (myasthenia gravis), even with a magnitude of muscle weakness that does not evoke respiratory symptoms, can evoke dysphagia and decreased inspiratory airflow, and increases the risk of susceptible patients to develop severe pulmonary complications.

Objectives: To assess whether impaired neuromuscular transmission predisposes individuals to inspiratory upper airway collapse, we assessed supraglottic airway diameter and volume by respiratory-gated magnetic resonance imaging, upper airway dilator muscle function (genioglossus force and EMG), and changes in lung volume, respiratory timing, and peripheral muscle function before, during, and after partial neuromuscular blockade in healthy, awake volunteers.

Measurements and Main Results: Partial neuromuscular blockade (train-of-four [TOF] ratio: 0.5 and 0.8) was associated with the following: (1) a decrease of inspiratory retropalatal and retroglossal upper airway volume to 66 ± 22 and 82 ± 12% of baseline, which was significantly more intense in the retropalatal area; (2) an attenuation of the normal increase in anteroposterior upper airway diameter during forced inspiration to 74 ± 18% of baseline; (3) a decrease in genioglossus activity during maximum voluntary tongue protrusion to 39 ± 19% (TOF, 0.5) and 73 ± 29% (TOF, 0.8) of baseline; and (4) no effects on upper airway size during expiration, lung volume, and respiratory timing.

Conclusions: Thus, impaired neuromuscular transmission, even to a degree insufficient to evoke respiratory symptoms, markedly impairs upper airway dimensions and function. This may be explained by an impairment of the balance between upper airway dilating forces and negative intraluminal pressure generated during inspiration by respiratory “pump” muscles.

Authors: Franca Rusconi; Claudia Galassi; Francesco Forastiere; Marta Bellasio; Manuela De Sario; Giovannino Ciccone; Luigia Brunetti; Elisabetta Chellini; Giuseppe Corbo; Stefania La Grutta; Enrico Lombardi; Silvano Piffer; Fiorella Talassi; Annibale Biggeri; Neil Pearce

Rationale: There is increasing interest in the potential influence of fetal and early life conditions on childhood wheezing.

Objectives: To investigate the associations between maternal complications and procedures in pregnancy and at birth and the risk of various wheezing phenotypes in young children.

Methods: We studied 15,609 children, aged 6–7 yr, enrolled in a population-based study. Standardized questionnaires were completed by the children's mothers.

Results: Of the children, 9.5% (1,478) had transient early wheezing, 5.4% (884) had persistent wheezing, and 6.1% (948) had late-onset wheezing. Maternal hypertension or preeclampsia was associated with an increased risk of all three wheezing phenotypes (for transient early wheezing: odds ratio [OR], 1.40; 95% confidence interval [95% CI], 1.08–1.82; for persistent wheezing: OR, 1.59; 95% CI, 1.15–2.19; and for late-onset wheezing: OR, 1.47; 95% CI, 1.06–2.01). Use of antibiotics for urinary tract infections was associated with transient early wheezing (OR, 1.52; 95% CI, 1.16–2.00), whereas antibiotic administration at delivery was associated with both transient early wheezing (OR, 1.21; 95% CI, 1.01–1.46) and persistent wheezing (OR, 1.39; 95% CI, 1.10–1.75). Children who had a mother with diabetes were also more likely to have persistent wheezing (OR, 1.72; 95% CI, 0.99–3.00). Neither amniocentesis/chorionic villus sampling, nor weight gain in pregnancy, nor cesarean section was associated with the subsequent development of wheezing. Maternal asthma or atopy was not an effect modifier of the associations found.

Conclusions: Some maternal complications during pregnancy and at delivery may increase the risk of developing different phenotypes of wheezing in childhood.

Authors: Luc Thiberville; Sophie Moreno-Swirc; Tom Vercauteren; Eric Peltier; Charlotte Cavé; Genevieve Bourg-Heckly

Rationale: Fibered confocal fluorescence microscopy (FCFM) is a new technique that produces microscopic imaging of a living tissue through a 1-mm fiberoptic probe that can be introduced into the working channel of the bronchoscope.

Objectives: To analyze the microscopic autofluorescence structure of normal and pathologic bronchial mucosae using FCFM during bronchoscopy.

Methods: Bronchial FCFM and spectral analyses were performed at 488-nm excitation wavelength on two bronchial specimens ex vivo and in 29 individuals at high risk for lung cancer in vivo. Biopsies of in vivo FCFM-imaged areas were performed using autofluorescence bronchoscopy.

Results: Ex vivo and in vivo microscopic and spectral analyses showed that the FCFM signal mainly originates from the elastin component of the basement membrane zone. Five distinct reproducible microscopic patterns were recognized in the normal areas from the trachea down to the more distal respiratory bronchi. In areas of the proximal airways not previously biopsied, one of these patterns was found in 30 of 30 normal epithelia, whereas alterations of the autofluorescence microstructure were observed in 19 of 22 metaplastic or dysplastic samples, five of five carcinomas in situ, and two of two invasive lesions. Disorganization of the fibered network could be found on 9 of 27 preinvasive lesions, compatible with early disruptions of the basement membrane zone. FCFM alterations were also observed in a tracheobronchomegaly syndrome and in a sarcoidosis case.

Conclusions: Endoscopic FCFM represents a minimally invasive method to study specific basement membrane alterations associated with premalignant bronchial lesions in vivo. The technique may also be useful to study the bronchial wall remodeling in nonmalignant chronic bronchial diseases.

Authors: Roberto de Marco; Simone Accordini; Isa Cerveri; Angelo Corsico; Josep M. Antó; Nino Künzli; Christer Janson; Jordi Sunyer; Deborah Jarvis; Susan Chinn; Paul Vermeire; Cecilie Svanes; Ursula Ackermann-Liebrich; Thorarinn Gislason; Joachim Heinrich; Bénédicte Leynaert; Françoise Neukirch; Jan P. Schouten; Matthias Wjst; Peter Burney

Rationale: The few prospective studies aimed at assessing the incidence of chronic obstructive pulmonary disease (COPD) in relation to the presence of chronic cough/phlegm have produced contrasting results.

Objectives: To assess the incidence of COPD in a cohort of young adults and to test whether chronic cough/phlegm and dyspnea are independent predictors of COPD.

Methods: An international cohort of 5,002 subjects without asthma (ages 20–44 yr) with normal lung function (FEV1/FVC ratio  70%) from 12 countries was followed from 1991–2002 in the frame of the European Community Respiratory Health Survey II. Incident cases of COPD were those who had an FEV1/FVC ratio less than 70% at the end of the follow-up, but did not report having had a doctor diagnose asthma during the follow-up.

Main Results: The incidence rate of COPD was 2.8 cases/1,000/yr (95% confidence interval [CI], 2.3–3.3). Chronic cough/phlegm was an independent and statistically significant predictor of COPD (incidence rate ratio [IRR], 1.85; 95% CI, 1.17–2.93) after adjusting for smoking habits and other potential confounders, whereas dyspnea was not associated with the disease (IRR = 0.98; 95% CI, 0.64–1.50). Subjects who reported chronic cough/phlegm both at baseline and at the follow-up had a nearly threefold-increased risk of developing COPD with respect to asymptomatic subjects (IRR = 2.88; 95% CI, 1.44–5.79).

Conclusions: The incidence of COPD is substantial even in young adults. The presence of chronic cough/phlegm identifies a subgroup of subjects with a high risk of developing COPD, independently of smoking habits.

Authors: Johan Grunewald; Anders Eklund

Motivation: It has been debated whether patients need to have erythema nodosum to be classified as having Löfgren's syndrome. In this study, we have therefore in detail evaluated and compared a large number of patients with an acute onset of sarcoidosis and bilateral hilar lymphadenopathy (BHL), with or without erythema nodosum (EN). This study is important because it may lead to a more accurate definition of Löfgren's syndrome, and an exact phenotype of patients is crucial in modern medical research.

Background: Löfgren's syndrome is commonly regarded as a distinct clinical entity.

Methods: We have in detail evaluated a large group of patients (n = 150) with an acute onset of sarcoidosis with BHL, in most cases with fever, EN, and/or bilateral ankle arthritis or periarticular inflammation. Within this group, 87 patients had EN (EN positive), whereas 63 were without EN (EN negative), though with distinct symmetric ankle inflammation.

Results: EN-positive and EN-negative patients were identical in every aspect except that there were significantly more women in the EN-positive group: 58 women (67%) in the EN-positive group compared with only 17 (27%) women in the EN-negative group (p < 0.0001). In all other aspects, such as age, smoking habits, seasonal clustering of disease onset, rate of positive biopsies, chest radiography, pulmonary function, bronchoalveolar lavage cell distributions including the typically increased CD4/CD8 ratio, and clinical development of the disease, the EN-positive and EN-negative groups were close to identical. The two groups were also identically strongly associated with HLA-DRB1*0301/DQB1*0201, with 60 (69.0%) and 44 (69.8%) patients having this particular HLA type in the EN-positive and EN-negative groups, respectively. Such patients recovered to the same degree—that is, at almost 100%.

Conclusions: We conclude that manifestations of Löfgren's syndrome differ between men and women, with EN found predominantly in women, whereas a marked periarticular inflammation of the ankles or ankle arthritis without EN is seen preferentially in men.

Authors: Ivana V. Yang; Lauranell H. Burch; Mark P. Steele; Jordan D. Savov; John W. Hollingsworth; Erin McElvania-Tekippe; Katherine G. Berman; Marcy C. Speer; Thomas A. Sporn; Kevin K. Brown; Marvin I. Schwarz; David A. Schwartz

Rationale: Idiopathic interstitial pneumonia (IIP) and its familial variants are progressive and largely untreatable disorders with poorly understood molecular mechanisms. Both the genetics and the histologic type of IIP play a role in the etiology and pathogenesis of interstitial lung disease, but transcriptional signatures of these subtypes are unknown.

Objectives: To evaluate gene expression in the lung tissue of patients with usual interstitial pneumonia or nonspecific interstitial pneumonia that was either familial or nonfamilial in origin, and to compare it with gene expression in normal lung parenchyma.

Methods: We profiled RNA from the lungs of 16 patients with sporadic IIP, 10 with familial IIP, and 9 normal control subjects on a whole human genome oligonucleotide microarray.

Results: Significant transcriptional differences exist in familial and sporadic IIPs. The genes distinguishing the genetic subtypes belong to the same functional categories as transcripts that distinguish IIP from normal samples. Relevant categories include chemokines and growth factors and their receptors, complement components, genes associated with cell proliferation and death, and genes in the Wnt pathway. The role of the chemokine CXCL12 in disease pathogenesis was confirmed in the murine bleomycin model of lung injury, with C57BL/6^CXCR4+/− mice demonstrating significantly less collagen deposition than C57BL/6^CXCR4+/+ mice. Whereas substantial differences exist between familial and sporadic IIPs, we identified only minor gene expression changes between usual interstitial pneumonia and nonspecific interstitial pneumonia.

Conclusions: Taken together, our findings indicate that differences in gene expression profiles between familial and sporadic IIPs may provide clues to the etiology and pathogenesis of IIP.

Authors: Ariel Tarasiuk; Sari Greenberg-Dotan; Tzahit Simon-Tuval; Bruria Freidman; Aviv D. Goldbart; Asher Tal; Haim Reuveni

Rationale: Health care use, a reliable measure of morbidity, is noticeably higher 1 yr before obstructive sleep apnea syndrome (OSAS) diagnosis in preschool children. It is not clear at what age OSAS-related morbidity becomes expressed.

Objective: To explore morbidity and health care use among children with OSAS starting from first year of life.

Methods: Case-control study, starting from the first year of life to date of OSAS diagnosis, among 156 patients (age range, 3–5 yr) and their pair-matched healthy control subjects, by age, sex, primary care physician, and geographic location.

Measurements: Patients with OSAS underwent nocturnal polysomnography studies. Medical records during hospital visits were reviewed for diagnosis. Variables of health care use were obtained from computerized databases of Clalit Health Care Services, the largest health maintenance organization in Israel.

Main Results: From the first year of life to date of OSAS diagnosis, children with OSAS had 40% more (p = 0.048) hospital visits, 20% more repeated (two or more) visits (p < 0.0001), and higher consumption of antiinfective and respiratory system drugs (p < 0.0001). Referrals of children with OSAS to otolaryngology surgeons and pediatric pulmonologists were higher from Year 1 (p < 0.0001) to date of OSAS diagnosis, especially in Year 4 (odds ratio, 9.4; 95% confidence interval, 4.2–21.1). The 215% elevation (p < 0.0001) in health care use of the OSAS group was due mainly to higher occurrence of respiratory tract morbidity (p < 0.0001).

Conclusions: Practitioners should be aware that starting in Year 1 until date of diagnosis, children with OSAS have higher health care use, mostly related to respiratory diseases.

Authors: Spyros Zakynthinos; Paraskevi Katsaounou; Maria-Helena Karatza; Charis Roussos; Theodoros Vassilakopoulos

Rationale: The mechanisms by which chemoreceptors process carbon dioxide stimuli are poorly understood. Recent in vitro studies suggest a role of reactive oxygen species in central carbon dioxide chemoreception.

Objectives: We tested the hypothesis that antioxidant treatment modulates the ventilatory response to carbon dioxide in healthy humans, either during unloaded breathing or after strenuous resistive breathing.

Methods: In the first experiment of this randomized, double-blind, placebo-controlled study, 14 healthy males completed hyperoxic carbon dioxide rebreathing, received either antioxidants (vitamins E, A, and C for 2 mo, allopurinol for 15 d, and N-acetylcysteine for 3 d) (n = 7) or placebo (n = 7), and repeated rebreathing 3 mo later. In the second experiment, 18 healthy males completed a series of rebreathing tests before and after strenuous resistive breathing. Subjects repeated the same protocol 3 mo later, after they had received antioxidants (n = 9) or placebo (n = 9).

Main Results: After antioxidants, the sensitivity of the ventilatory (minute ventilation) response to carbon dioxide increased (mean [± SEM], 3.2 ± 0.5 vs. 1.7 ± 0.4 L/min/mm Hg; p < 0.001). Antioxidants also increased the sensitivity to carbon dioxide before and at 5, 30, and 120 min after resistive breathing (p = 0.01). This effect was entirely due to increased tidal volume. Antioxidants did not influence the breathing pattern during resting breathing or the rapid shallow breathing response to carbon dioxide at 5 min after resistive breathing.

Conclusions: Antioxidants, by augmenting the tidal volume, increase the sensitivity of the ventilatory response to carbon dioxide, either during unloaded breathing or after resistive breathing.

Authors: Jason D. Christie; Nancy Robinson; Lorraine B. Ware; Michael Plotnick; Joao De Andrade; Vibha Lama; Aaron Milstone; Jonathan Orens; Ann Weinacker; Ejigayehu Demissie; Scarlett Bellamy; Steven M. Kawut

Background: Acute lung injury is characterized by hypercoagulability and impaired fibrinolysis. We hypothesized that lower protein C and higher type 1 plasminogen activator inhibitor (PAI-1) levels in plasma would be associated with primary graft dysfunction (PGD) after lung transplantation.

Design: Prospective, multicenter cohort study.

Methods: We measured plasma levels of protein C and PAI-1 before lung transplantation and 6, 24, 48, and 72 h after allograft reperfusion in 128 lung transplant recipients at six centers. The primary outcome was grade 3 PGD (PaO2/FiO2 < 200 with alveolar infiltrates) 72 h after transplantation. Biomarker profiles were evaluated using logistic regression and generalized estimating equations.

Results: Patients who developed PGD had lower protein C levels 24 h posttransplantation than did patients without PGD (mean ± SD [relative to control]: 64 ± 27 vs. 92 ± 41%, respectively; p = 0.002). Patients with PGD also had PAI-1 levels that were almost double those of patients without PGD at 24 h (213 ± 144 vs. 117 ± 89 ng/ml, respectively; p < 0.001). Throughout the 72-h postoperative period, protein C levels were significantly lower (p = 0.007) and PAI-1 levels were higher (p = 0.026) in subjects with PGD than in others. These differences persisted despite adjustment for potential confounders in multivariate analyses. Higher recipient pulmonary artery pressures, measured immediately pretransplantation, were associated with higher PAI-1 levels and increased risk of PGD.

Conclusion: Lower postoperative protein C and higher PAI-1 plasma levels are associated with PGD after lung transplantation. Impaired fibrinolysis and enhanced coagulation may be important in PGD pathogenesis.

Authors: Kevin P. Cain; Connie A. Haley; Lori R. Armstrong; Katie N. Garman; Charles D. Wells; Michael F. Iademarco; Kenneth G. Castro; Kayla F. Laserson

Rationale: In the United States, the number of annual reported cases of tuberculosis (TB) among U.S.-born persons declined by 62% from 1993 to 2004, but increased by 5% among foreign-born persons. Over half of all reported cases of TB in the United States occur among foreign-born persons, most of these due to activation of latent TB infection (LTBI). Current guidelines recommend targeting only foreign-born persons who entered the United States within the previous 5 yr for LTBI testing.

Objective: We sought to assess the epidemiologic basis for this guideline.

Methods: We calculated TB case rates among foreign-born persons, stratified by duration of United States residence and world region of origin. We determined the number of cases using 2004 U.S. TB surveillance data, and calculated case rates using population data from the 2004 American Community Survey.

Measurements and Main Results: In 2004, a total of 14,517 cases of TB were reported; 3,444 (24%) of these were among foreign-born persons who had entered the United States more than 5 yr previously. The rate of TB disease among foreign-born persons was 21.5/100,000, compared with 2.7/100,000 for U.S.-born persons, and varied by duration of residence and world region of origin.

Conclusions: Almost one-quarter of all TB cases in the United States occur among foreign-born persons who have resided in the United States for longer than 5 yr; case rates for such persons from selected regions of origin remain substantially elevated. To eliminate TB, we must address the burden of LTBI in this high-risk group.

Authors: Otto D. Schoch; Philippe Rieder; Claudia Tueller; Ekkehardt Altpeter; Jean-Pierre Zellweger; Hans L. Rieder; Martin Krause; Robert Thurnheer

Rationale: To assess feasibility and yield of diagnostic procedures after active case finding for tuberculosis with radiologic screening at the three main entry points for asylum seekers to Switzerland.

Method: Prospective multicenter study on the value of symptoms, spontaneous and induced sputum, and bronchoscopy for the confirmation of tuberculosis in radiologically selected cases.

Results: Among 101 asylum seekers examined, spontaneous sputum was collected “on the spot” in 83 and yielded 7 (54%) of 13 smear-positive and 13 (39%) of 33 culture-positive cases. Morning sputum, collected in 84, yielded 8 (62%) and 16 (49%), and the two spontaneous sputa combined 9 (69%) and 20 (61%), respectively. Two additional induced sputa, collected in 91 persons, yielded no additional smear-positive, but yielded seven culture-positive cases (yield, 82%). Bronchoscopy, performed in 87 of 92 sputum smear–negative cases, yielded four additional smear-positive and six culture-positive cases. Culture confirmation was independently and significantly predicted by obtaining a specimen using bronchoscopy (adjusted odds ratio, 11.0; 95% confidence interval, 1.9–62) and a prior decision to treat (adjusted odds ratio, 3.0; confidence interval, 1.1–8.1).

Conclusion: Radiographic anomalies compatible with tuberculosis found during screening are a poor guide to initiation of treatment. Respiratory and systemic symptoms correlated weakly with culture confirmation of tuberculosis. All radiologically selected cases must be examined with on-the-spot and early-morning sputum, regardless of symptoms. If both specimens are smear negative, the yield is increased by bronchoscopy and, to a lesser extent, by two samples of induced sputum. The examination of any single specimen has a low yield of 36 to 63% and is insufficient to exclude active tuberculosis.

Authors: Robin Wood; Keren Middelkoop; Landon Myer; Alison D. Grant; Andrew Whitelaw; Stephen D. Lawn; Gilla Kaplan; Robin Huebner; James McIntyre; Linda-Gail Bekker

Background: Although failure of tuberculosis (TB) control in sub-Saharan Africa is attributed to the HIV epidemic, it is unclear why the directly observed therapy short-course (DOTS) strategy is insufficient in this setting. We conducted a cross-sectional survey of pulmonary TB (PTB) and HIV infection in a community of 13,000 with high HIV prevalence and high TB notification rate and a well-functioning DOTS TB control program.

Methods: Active case finding for PTB was performed in 762 adults using sputum microscopy and Mycobacterium tuberculosis culture, testing for HIV, and a symptom and risk factor questionnaire. Survey findings were correlated with notification data extracted from the TB treatment register.

Results: Of those surveyed, 174 (23%) tested HIV positive, 11 (7 HIV positive) were receiving TB therapy, 6 (5 HIV positive) had previously undiagnosed smear-positive PTB, and 6 (4 HIV positive) had smear-negative/culture-positive PTB. Symptoms were not a useful screen for PTB. Among HIV-positive and -negative individuals, prevalence of notified smear-positive PTB was 1,563/100,000 and 352/100,000, undiagnosed smear-positive PTB prevalence was 2,837/100,000 and 175/100,000, and case-finding proportions were 37 and 67%, respectively. Estimated duration of infectiousness was similar for HIV-positive and HIV-negative individuals. However, 87% of total person-years of undiagnosed smear-positive TB in the community were among HIV-infected individuals.

Conclusions: PTB was identified in 9% of HIV-infected individuals, with 5% being previously undiagnosed. Lack of symptoms suggestive of PTB may contribute to low case-finding rates. DOTS strategy based on passive case finding should be supplemented by active case finding targeting HIV-infected individuals.

Authors: Wilmore C. Webley; Paul S. Salva; Chester Andrzejewski; Frances Cirino; Corrie A. West; Yaphet Tilahun; Elizabeth S. Stuart

Author: Wayne Mitzner

Authors: Shinya Tsuchida; Brian P. Kavanagh

Authors: Elianne J. L. E. Vrijlandt; Jorrit Gerritsen; H. Marike Boezen; René G. Grevink; Eric J. Duiverman