The effects of cannabis on lung function remain unclear and may be different from those of tobacco. We compared the associations between use of these substances and lung function in a population-based cohort (n=1,037).
Cannabis and tobacco use were reported at ages 18, 21, 26 and 32 yrs. Spirometry, plethysmography and carbon monoxide transfer factor were measured at 32 yrs. Associations between lung function and exposure to each substance were adjusted for exposure to the other substance.
Cumulative cannabis use was associated with higher forced vital capacity, total lung capacity, functional residual capacity and residual volume. Cannabis was also associated with higher airway resistance but not with forced expiratory volume in 1 s, forced expiratory ratio or transfer factor. These findings were similar among those who did not smoke tobacco. In contrast, tobacco use was associated with lower forced expiratory volume in 1 s, lower forced expiratory ratio, lower transfer factor and higher static lung volumes, but not with airway resistance.
Cannabis appears to have different effects on lung function from those of tobacco. Cannabis use was associated with higher lung volumes, suggesting hyperinflation and increased large-airways resistance, but there was little evidence for airflow obstruction or impairment of gas transfer.
Cannabis; cohort study; marijuana; respiratory function; smoking; tobacco
Derive continuous prediction equations and their lower limits of normal for spirometric indices, which are applicable globally.
Over 160,000 data points from 72 centres in 33 countries were shared with the European Respiratory Society Global Lung Function Initiative. Eliminating data that could not be used (mostly missing ethnic group, some outliers) left 97,759 records of healthy nonsmokers (55.3% females) aged 2.5–95 years.
Lung function data were collated, and prediction equations derived using the LMS (λ, µ, σ) method, which allows simultaneous modelling of the mean (mu), the coefficient of variation (sigma) and skewness (lambda) of a distribution family.
After discarding 23,572 records, mostly because they could not be combined with other ethnic or geographic groups, reference equations were derived for healthy individuals from 3–95 years for Caucasians (N=57,395), African Americans (N=3,545), and North (N=4,992) and South East Asians (N=8,255). FEV1 and FVC between ethnic groups differed proportionally from that in Caucasians, such that FEV1/FVC remained virtually independent of ethnic group. For individuals not represented by these four groups, or of mixed ethnic origins, a composite equation taken as the average of the above equations is provided to facilitate interpretation until a more appropriate solution is developed.
Spirometric prediction equations for the 3–95 age range are now available that include appropriate age-dependent lower limits of normal. They can be applied globally to different ethnic groups. Additional data from the Indian subcontinent, Arab, Polynesian, Latin American countries, and Africa will further improve these equations in the future.
To evaluate, among older persons, the association between respiratory impairment and hospitalization for chronic obstructive pulmonary disease (COPD), based on spirometric Z-scores (Lambda-Mu-Sigma [LMS]) and a competing risk approach.
Using data on 3,563 white participants aged 65–80 years (Cardiovascular Health Study), we evaluated the association of LMS-defined respiratory impairment with incident COPD hospitalization and the competing outcome of death without COPD hospitalization, over a 5-year period. Respiratory impairment included airflow limitation (mild, moderate, and severe) and restrictive-pattern.
Over a 5-year period, 276 (7.7%) participants had incident COPD hospitalization, whereas 296 (8.3%) died without COPD hospitalization. The risk of COPD hospitalization was elevated more than 2-fold in LMS-defined mild and moderate airflow limitation and restrictive-pattern (adjusted hazard ratio [HR]: 2.25 [1.25, 4.05], 2.54 [1.53, 4.22], and 2.65 [1.82, 3.86], respectively), and more than 8-fold in LMS-defined severe airflow limitation (adjusted HR: 8.33 [6.24, 11.12]). Conversely, only LMS-defined restrictive-pattern was associated with the competing outcome of death without COPD hospitalization (adjusted HR: 1.68 [1.22, 2.32]).
In white older persons, LMS-defined respiratory impairment is strongly associated with an increased risk of COPD hospitalization. These results support the LMS method as a basis for defining respiratory impairment in older persons.
Spirometry; Lambda-Mu-Sigma; COPD hospitalization
Recent epidemiological studies have suggested an increased risk of venous thromboembolism (VTE) in lung fibrosis. Large-scale epidemiological data regarding the risk of VTE in pulmonary fibrosis-associated mortality have not been published.
Using data from the National Center for Health Statistics from 1988–2007, we determined the risk of VTE in decedents with pulmonary fibrosis in the USA.
We analysed 46,450,489 records, of which 218,991 met our criteria for idiopathic pulmonary fibrosis. Among these, 3,815 (1.74%) records also contained a diagnostic code for VTE. The risk of VTE in pulmonary fibrosis decedents was 34% higher than in the background population, and 44% and 54% greater than among decedents with chronic obstructive pulmonary disease and lung cancer, respectively. Those with VTE and pulmonary fibrosis died at a younger age than those with pulmonary fibrosis alone (females: 74.3 versus 77.4 yrs (p<0.0001); males: 72.0 versus 74.4 yrs (p<0.0001)).
Decedents with pulmonary fibrosis had a significantly greater risk of VTE. Those with VTE and pulmonary fibrosis died at a younger age than those with pulmonary fibrosis alone. These data suggest a link between a pro-fibrotic and a pro-coagulant state.
Epidemiology; idiopathic pulmonary fibrosis; mortality; pulmonary fibrosis; venous thromboembolism
Alveolar elastic fibres are key targets of proteases during the pathogenesis of chronic obstructive pulmonary disease (COPD). In the current study, we hypothesised that a response to injury leads to enhanced alveolar elastin gene expression in very severe COPD.
Lung samples obtained from 43 patients, including 11 with very severe COPD (stage 4), 10 donors, 10 with moderate/severe COPD (stage 2–3) and 12 non-COPD subjects, were analysed for elastin mRNA expression by real-time RT-PCR and in situ hybridisation. Alveolar elastic fibres were visualised using Hart's staining of sections of frozen inflated lungs obtained from 11 COPD stage 4 patients and three donor lungs.
Compared with donors, non-COPD and stage 2–3 COPD, elastin mRNA expression was significantly increased in very severe COPD lungs (12-fold change), and localised in situ hybridisation induced elastin expression to alveolar walls. Compared with donors, alveolar elastic fibres also comprised a greater volume fraction of total lung tissue in very severe COPD lungs (p<0.01), but elastic fibre content was not increased per lung volume, and desmosine content was not increased.
The present study demonstrates enhanced alveolar elastin expression in very severe COPD. The efficiency of this potential repair mechanism and its regulation remain to be demonstrated.
Chronic obstructive pulmonary disease; elastin; emphysema; gene expression
Strategies to improve pulmonary endothelial barrier function are needed to reverse the devastating effects of vascular leak in acute respiratory distress syndrome (ARDS). FTY720 is a pharmaceutical analogue of the potent barrier-enhancing phospholipid, sphingosine 1-phosphate (S1P). FTY720 decreases vascular permeability through an incompletely characterized mechanism that differs from S1P. Here we describe its barrier-promoting effects on intracellular signaling and junctional assembly formation in human pulmonary endothelium.
Permeability of cultured human pulmonary endothelial cells was assessed by transendothelial electrical resistance (TER) and dextran transwell assays. Junctional complex formation was assessed by membrane fractionation and immunofluorescence. Pharmacologic inhibitors and siRNA were utilized to determine the effects of individual components on permeability.
Unlike S1P, FTY720 failed to induce membrane translocation of adherens junction or tight junction proteins. β-catenin, occludin, claudin-5, or ZO-1/ZO-2 siRNAs did not alter FTY720-induced barrier enhancement. FTY720 induced FAK phosphorylation and focal adhesion formation with FAK siRNA partially attenuating the prolonged phase of barrier enhancement. Inhibition of Src, PKA, PKG, PKC, or PP2A failed to alter FTY720-induced barrier enhancement. FTY720 increased c-Abl tyrosine kinase activity, and c-Abl siRNA attenuated peak barrier enhancement after FTY720.
FTY720 enhances endothelial barrier function by a novel pathway involving c-Abl signaling.
c-Abl tyrosine kinase; vascular endothelium; FTY720; junctional complexes; vascular permeability
Mutations in bone morphogenetic protein receptor type 2 (BMPR2) cause familial pulmonary arterial hypertension (FPAH), but the penetrance is reduced and females are significantly overrepresented. In addition, gene expression data implicating the oestrogen-metabolising enzyme CYP1B1 suggests a detrimental role of oestrogens or oestrogen metabolites. We examined genetic and metabolic markers of altered oestrogen metabolism in subjects with a BMPR2 mutation.
Genotypes for CYP1B1 Asn453Ser (N453S) were determined for 140 BMPR2 mutation carriers (86 females and 54 males). Nested from those subjects, a case–control study of urinary oestrogen metabolite levels (2-hydroxyoestrogen (2-OHE) and 16α-hydroxyoestrone (16α-OHE1)) was conducted in females (five affected mutation carriers versus six unaffected mutation carriers).
Among females, there was four-fold higher penetrance among subjects homozygous for the wild-type genotype (N/N) than those with N/S or S/S genotypes (p=0.005). Consistent with this finding, the 2-OHE/16α-OHE1 ratio was 2.3-fold lower in affected mutation carriers compared to unaffected mutation carriers (p=0.006).
Our findings suggest that variations in oestrogens and oestrogen metabolism modify FPAH risk. Further investigation of the role of oestrogens in this disease with profound sex bias may yield new insights and, perhaps, therapeutic interventions.
Bone morphogenetic protein receptor 2; CYP1B1; genetic polymorphism; oestrogen; pulmonary hypertension; sex
To investigate age-related changes in sleepiness symptoms associated
with sleep disordered breathing (SDB).
Wisconsin Sleep Cohort participants were assessed with
polysomnography, Epworth Sleepiness Scale (ESS) and Multiple Sleep Latency
Test (MSLT). SDB was defined as an apnea/hypopnea index≥15
events/hour, sleepiness as ESS≥10 and MSLT≤5 minutes. Odds
ratios were calculated using generalized estimating equations associating
sleepiness with SDB, and conditional logistic regression examining changes
in longitudinal sleepiness status (ESS only). Models were, a priori,
stratified by gender.
ESS was measured in 1281 participants and MSLT in 998, at multiple
time points (ESS n=3695; MSLT n=1846). Significant interactions were found
between SDB and age in men, but not women. The odds ratios (OR) modeled for
sleepiness in a 40 year old male with SDB were significant, compared to a
male without SDB (OR: ESS 2.1; MSLT 2.9); however, these associations were
not significant at 60 years. The within-subject odds ratio for sleepiness
was also significant at 40 years (OR: 3.4), but not at 60 years.
The age-related reductions in the association between sleepiness and
SDB may have clinical implications for the diagnosis and treatment of SDB in
older people since sleepiness is often used as a therapeutic marker.
Sleep disordered breathing; Obstructive sleep apnea; Aging; Sleepiness
An unexplained increase in the incidence of parapneumonic empyema (PPE) in pneumonia cases has been reported in recent years. The present study investigated the genetic and biological specifications of new isolates of torque teno mini virus (TTMV) detected in pleural effusion samples from children hospitalised for severe pneumonia with PPE.
A pathogen discovery protocol was applied in undiagnosed pleural effusion samples and led to the identification of three new isolates of TTMV (TTMV-LY). Isolated TTMV-LY genomes were transfected into A549 and human embryonic kidney 293T cells and viral replication was assessed by quantitative real-time PCR and full-length genome amplification. A549 cells were further infected with released TTMV-LY virions and the induced-innate immune response was measured by multiplex immunoassays.
Genetic analyses of the three TTMV-LY genomes revealed a classic genomic organisation but a weak identity (<64%) with known sequences. We demonstrated the in vitro replication of TTMV-LY in alveolar epithelial cells and the effective release of infectious viral particles. We also showed a selective production of inflammatory mediators in response to TTMV infection.
This study reports the description of replicative TTMV-LY isolated from parapneumonic effusions of children hospitalised with PPE, suggesting a potential role of the virus in the pathogenesis of pneumonia.
Vascular endothelial growth factor (VEGF) is an angiogenic factor implicated in asthma severity. The objective of the present study was to determine whether VEGF single nucleotide polymorphisms (SNPs) are associated with asthma, lung function and airway responsiveness.
The present authors analysed 10 SNPs in 458 white families in the Childhood Asthma Management Program (CAMP). Tests of association with asthma, lung function and airway responsiveness were performed using PBAT software (Golden Helix, Inc. Bozeman, MT, USA; available at www.goldenhelix.com). Family and population-based, revpeated measures analysis of airflow obstruction were conducted. Replication studies were performed in 412 asthmatic children and their parents from Costa Rica.
Associations with asthma, lung function and airway responsiveness were observed in both cohorts. SNP rs833058 was associated with asthma in both cohorts. This SNP was also associated with increased airway responsiveness in both populations. An association of rs4711750 and its haplotype with forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio in both cohorts was observed. Longitudinal analysis in CAMP confirmed an association of rs4711750 with FEV1/FVC decline over ~4.5 yrs of observation.
VEGF polymorphisms are associated with childhood asthma, lung function and airway responsiveness in two populations, suggesting that VEGF polymorphisms influence asthma susceptibility, airflow obstruction and airways responsiveness.
Airflow obstruction; asthma; single nucleotide polymorphisms; vascular endothelial growth factor
Polymeric immunoglobulin receptor (pIgR) expression is downregulated in lung cancer, but its implications in lung tumourigenesis remain unknown. We hypothesised that loss of pIgR expression occurs early, and is associated with cell proliferation and poor prognosis.
pIgR expression was evaluated by immunohistochemistry in airways of patients with normal mucosa, pre-invasive lesions and invasive lesions, and correlated with clinical outcomes. 16-HBE and A549 cells stably transfected with pIgR were tested for proliferation, apoptosis and cell cycle progression.
Immunostaining was strong in normal epithelium, but severely reduced in pre-invasive lesions and most lung cancers. Persistent expression was associated with younger age and adenocarcinoma subtype but not survival. pIgR overexpression significantly reduced A549 and 16-HBE proliferation. Growth inhibition was not due to cell cycle arrest, increased apoptosis or endoplasmic reticulum stress, but we observed altered expression of genes encoding for membrane proteins, including NOTCH3. Interestingly, NOTCH3 expression was inversely correlated with pIgR expression in cell lines and tissues.
pIgR expression was lost in most lung cancers and pre-invasive bronchial lesions, suggesting that pIgR downregulation is an early event in lung tumourigenesis. pIgR overexpression in A549 and 16-HBE cells inhibited proliferation. Future investigations are required to determine the mechanisms by which pIgR contributes to cell proliferation.
Differentiation; lung adenocarcinoma; lung pre-invasive lesions; polymeric immunoglobulin receptor; proliferation
Multiple events are involved in the development of acute inflammation and injury in the lungs. A progressive rise of oxidative stress due to altered reduction-oxidation (redox) homeostasis appears to be one of the hallmarks of lung pathologies such as injury, inflammation and ischemia/reperfusion. However, despite the growing evidence that alteration of the redox balance in the lungs, antioxidant therapy may attenuate acute lung injury and inflammation. We studied the effect of thiol antioxidant compound, amifostine, on acute lung dysfunction and pulmonary endothelial barrier compromise induced by gram-negative bacterial wall lypopolysacharide (LPS). In vitro, LPS as well as other producers of reactive oxygen spices (ROS), interleukin-6 (IL-6) and hydrogen peroxide (H2O2), induced significant reorganization of actin cytoskeleton accompanied by formation of stress fibers and paracellular gaps and associated with decreased transendothelial electrical resistance, a hallmark of endothelial barrier dysfunction. These disruptive effects were inhibited by pretreatment of endothelial monolayer with amifostine. Moreover, amifostine inhibited LPS-mediated ROS production and significantly suppressed LPS-, IL-6-, and H2O2-induced activation of redox sensitive signaling mechanisms including p38 and Erk1/2 MAP kinases, and NFκB pathway. In the murine model of LPS-induced acute lung injury, intraperitoneal administration of amifostine reduced LPS-induced oxidative stress and neutrophil recruitment to the lungs. These studies demonstrate for the first time that amifostine dramatically reduces endothelial cell barrier dysfunction and acute lung injury caused by bacterial products via inhibition of oxidative stress and redox-sensitive inflammatory pathways, and may therefore be considered for therapeutic treatment of lung inflammation.
permeability; endothelium; lung; LPS; ROS; MAPK
Airflow obstruction is independent risk factor for cardiovascular events in the general population. The affected vascular bed and contribution of emphysema to cardiovascular risk are unclear. We examined if an obstructive pattern of spirometry and quantitatively defined emphysema were associated with subclinical atherosclerosis in the carotid, peripheral and coronary circulations.
The Multi-Ethnic Study of Atherosclerosis recruited participants age 45–84 years without clinical cardiovascular disease. Spirometry, carotid intima-media thickness, ankle-brachial index and coronary artery calcium were measured using standard protocols. Percent of emphysema-like lung was measured in the lung windows of cardiac computed tomography scans among 3,642 participants. Multiple linear regression was used to adjust for cardiac risk factors including C-reactive protein.
Decrements in the FEV1 and FEV1/FVC were associated with greater internal carotid intima-media thickness among smokers (P=0.03 and P<0.001, respectively) whereas percent emphysema was associated with reduced ankle-brachial index regardless of smoking history (P=0.004). Coronary artery calcium was associated with neither lung function (prevalence ratio for severe airflow obstruction: 0.99; 95% CI, 0.91 to 1.07) nor percent emphysema.
An obstructive pattern of spirometry and emphysema are associated distinctly and independently with subclinical atherosclerosis in the carotid arteries and peripheral circulation, respectively, and were not independently related to coronary artery calcium.
Increased antioxidant defenses are hypothesized to decrease age- and smoking-related decline in lung function.
The relation of dietary antioxidants, smoking, and forced expiratory volume in the 1st second of effort (FEV1) was investigated in community-dwelling older adults in the Health, Aging, and Body Composition Study. 1,443 participants completed a food frequency questionnaire, self-reported smoking history, and had measurements of FEV1 at both baseline and after 4 years of follow-up. The association of dietary intake of nutrients and foods with antioxidant properties and rate of FEV1 decline was investigated using hierarchical linear regression models.
In continuing smokers (current smokers at both time points), higher vitamin C and higher intake of fruits and vegetables were associated with an 18 and 24 ml/year slower rate of FEV1 decline compared to lower intake (P<0.0001 and 0.003, respectively). In quitters (current smoker at study baseline, quit during follow-up), higher intake was associated with an attenuated rate of decline for each nutrient studied (p<0.003, all models). In non-smoking participants, there was little or no association of diet and rate of decline in FEV1.
The intake of nutrients with antioxidant properties may modulate lung function decline in older adults exposed to cigarette smoke.
Aging; Dietary Intake; Lung Function Measurements; Oxidants/Antioxidants; Smoking and Health
Asthmatics hospitalised because of influenza A infection are less likely to
require intensive care or die compared with nonasthmatics. The reasons for this
We performed a retrospective analysis of data on 1520 patients admitted to 75 UK
hospitals with confirmed influenza A/H1N1 2009 infection. A multivariable model
was used to investigate reasons for the association between asthma and severe
outcomes (intensive care unit support or death).
Asthmatics were less likely than nonasthmatics to have severe outcome
(11.2% versus 19.8%, unadjusted OR 0.51,
95% CI 0.36–0.72) despite a greater proportion requiring
oxygen on admission (36.4% versus 26%,
unadjusted OR 1.63) and similar rates of pneumonia (17.1%
versus 16.6%, unadjusted OR 1.04). The results
of multivariable logistic regression suggest the association of asthma with
outcome (adjusted OR 0.62, 95% CI 0.36–1.05;
p=0.075) are explained by pre-admission inhaled corticosteroid use
(adjusted OR 0.34, 95% CI 0.18–0.66) and earlier
admission (≤4 days from symptom onset) (adjusted OR 0.60,
95% CI 0.38–0.94). In asthmatics, systemic corticosteroids
were associated with a decreased likelihood of severe outcomes (adjusted OR
0.36, 95% CI 0.18–0.72).
Corticosteroid use and earlier hospital admission explained the association of
asthma with less severe outcomes in hospitalised patients.
Asthma; corticosteroids; influenza; inhaled corticosteroid therapy; mortality in asthma; prognosis
To compare strategies for COPD case-finding using data from the Burden of Obstructive Lung Disease (BOLD) study.
Population-based samples of adults aged ≥40 years (n= 9390) from 14 countries completed a questionnaire and spirometry. We compared the screening efficiency of different staged algorithms that used questionnaire data and/or PEF to identify persons at risk for COPD and hence needing confirmatory spirometry. Separate algorithms were fitted for moderate/severe COPD and for severe COPD. We estimated the cost of each algorithm in 1000 people.
For moderate/severe COPD, use of questionnaire data alone permitted high sensitivity (97%), but required confirmatory spirometry on 80% of participants. Use of PEF only required confirmatory spirometry in only 19-22% of subjects with 83-84% sensitivity. For severe COPD, use of PEF achieved 91-93% sensitivity, requiring confirmatory spirometry in <9% of participants. Cost analysis suggested that a staged screening algorithm using only PEF initially, followed by confirmatory spirometry as needed, was the most cost-effective case finding strategy.
Our results support the use of PEF as a simple, cost-effective initial screening tool for conducting COPD case-finding in adults ≥40 years. These findings should be validated in real-world settings such as the primary care environment.
Adult; Chronic Obstructive Pulmonary Disease; Peak Expiratory Flow; questionnaire; screening; epidemiology
Clinical algorithms for evaluating HIV-infected individuals for tuberculosis (TB) prior to isoniazid preventive therapy (IPT) perform poorly, and interferon-γ release assays (IGRAs) have moderate accuracy for active TB. It is unclear whether, when used as adjunct tests, IGRAs add any clinical discriminatory value for active TB diagnosis in the pre-IPT assessment.
779 sputum smear-negative HIV-infected persons, established on or about to commence combined antiretroviral therapy (ART), were screened for TB prior to IPT. Stepwise multivariable logistic regression was used to develop clinical prediction models. The discriminatory ability was assessed by receiver operator characteristic area under the curve (AUC). QuantiFERON®-TB Gold in-tube (QFT-GIT) was evaluated.
The prevalence of smear-negative TB by culture was 6.4% (95% CI 4.9–8.4%). Used alone, QFT-GIT and the tuberculin skin test (TST) had comparable performance; the post-test probability of disease based on single negative tests was 3–4%. In a multivariable model, the QFT-GIT test did not improve the ability of a clinical algorithm, which included not taking ART, weight <60 kg, no prior history of TB, any one positive TB symptom/sign (cough ≥2 weeks) and CD4+ count <250 cells per mm3, to discriminate smear-negative culture-positive and -negative TB (72% to 74%; AUC comparison p=0.33). The TST marginally improved the discriminatory ability of the clinical model (to 77%, AUC comparison p=0.04).
QFT-GIT does not improve the discriminatory ability of current TB screening clinical algorithms used to evaluate HIV-infected individuals for TB ahead of preventive therapy. Evaluation of new TB diagnostics for clinical relevance should follow a multivariable process that goes beyond test accuracy.
Diagnostic research; HIV; incremental value; interferon-γ release assay; Mycobacterium tuberculosis; QuantiFERON®-TB Gold in-tube
Previous animal models of acute lung injury (ALI) are limited as they only reproduce part of the complex pathobiology of clinical ALI. Here we develop a translational mouse model of ALI, which not only reflects the major clinical and pathological features but also enables investigation into ALI resolution.
Anaesthetised mice underwent orotracheal instillation of hydrochloric acid. During the immediate period after instillation, mice were carefully maintained with supplemental oxygen to avoid mortality. At specified time points, lung injury was assessed by blood gases, respiratory mechanics, analysis of bronchoalveolar lavage fluid, alveolar fluid clearance and lung histology.
Animals exhibited significant weight loss, decreased oxygenation, increased respiratory elastance, and pulmonary inflammation (intra-alveolar leucocyte influx/ cytokine levels and histological injury scores). Moreover, mice displayed alveolar-capillary barrier dysfunction/epithelial injury as reflected by increased alveolar protein, lung wet/dry weight ratio and soluble Receptor for Advanced Glycation End-products, as well as reduced alveolar fluid clearance. These injury parameters peaked between days 1-3, followed by almost complete recovery over days 5-10. Histology showed evidence of fibrosis at day 10.
The results indicate that this resolving model of acid aspiration represents a powerful experimental tool to investigate the injurious, inflammatory, fibrotic, and resolving and reparative processes of ALI.
Acid aspiration; Acute respiratory distress syndrome; Alveolar epithelium; Alveolar fluid clearance; Inflammation; Pulmonary oedema
The supplemental oxygen flow rate is a common bedside measure of gas exchange impairment. We aimed to determine whether a titrated oxygen requirement predicted mortality in idiopathic pulmonary fibrosis.
We examined 104 adults with idiopathic pulmonary fibrosis enrolled in a prospective cohort study and a validation cohort of 151 adults with a variety of interstitial lung diseases. The titrated oxygen requirement was defined as the lowest oxygen flow rate required to maintain an oxyhemoglobin saturation of 96% while standing. Cox proportional hazards models and time-dependent receiver operating characteristic curves were used to examine survival time.
A higher titrated oxygen requirement was associated with a greater mortality rate independent of forced vital capacity and six-minute walk test results in idiopathic pulmonary fibrosis (adjusted hazard ratio per 1 L/min = 1.10, 95% confidence interval 1.01 to 1.20). The titrated oxygen requirement was at least as accurate as pulmonary function and six-minute walk testing at predicting 1-year mortality. Findings were similar in other interstitial lung diseases.
The titrated oxygen requirement is a simple, inexpensive bedside measurement that aids prognostication in idiopathic pulmonary fibrosis.
Idiopathic pulmonary fibrosis; Interstitial lung diseases; Outcome prediction; Pulmonary fibrosis; Pulmonary gas exchange
Investigation of contacts of patients with tuberculosis (TB) is a priority for TB control in high-income countries, and is increasingly being considered in resource-limited settings. This review was commissioned for a World Health Organization Expert Panel to develop global contact investigation guidelines.
We performed a systematic review and meta-analysis of all studies reporting the prevalence of TB and latent TB infection, and the annual incidence of TB among contacts of patients with TB.
After screening 9,555 titles, we included 203 published studies. In 95 studies from low- and middle-income settings, the prevalence of active TB in all contacts was 3.1% (95% CI 2.2–4.4%, I2=99.4%), microbiologically proven TB was 1.2% (95% CI 0.9–1.8%, I2=95.9%), and latent TB infection was 51.5% (95% CI 47.1–55.8%, I2=98.9%). The prevalence of TB among household contacts was 3.1% (95% CI 2.1–4.5%, I2=98.8%) and among contacts of patients with multidrug-resistant or extensively drug-resistant TB was 3.4% (95% CI 0.8–12.6%, I2=95.7%). Incidence was greatest in the first year after exposure. In 108 studies from high-income settings, the prevalence of TB among contacts was 1.4% (95% CI 1.1–1.8%, I2=98.7%), and the prevalence of latent infection was 28.1% (95% CI 24.2–32.4%, I2=99.5%). There was substantial heterogeneity among published studies.
Contacts of TB patients are a high-risk group for developing TB, particularly within the first year. Children <5 yrs of age and people living with HIV are particularly at risk. Policy recommendations must consider evidence of the cost-effectiveness of various contact tracing strategies, and also incorporate complementary strategies to enhance case finding.
Contact tracing; early diagnosis; human; Mycobacterium tuberculosis; systematic review; tuberculosis
Pre-eclamptic toxaemia (PET) may be associated with both endothelial dysfunction (ED) and sleep-disordered breathing (SDB). It was hypothesised that females with PET would demonstrate both SDB and ED, and that a correlation between these two would suggest a potential causative association.
A total of 17 females with PET and 25 matched females with uncomplicated pregnancy were studied. They underwent a nocturnal ambulatory sleep study (using Watch_PAT100) and noninvasive evaluation of endothelial function utilising the reactive hyperaemia test (using Endo_PAT 2000). A higher ratio of post- to pre-occlusion pulse-wave amplitude (endothelial function index (EFI)) indicated better endothelial function.
Females with PET had a significantly higher respiratory disturbance index (RDI) and lower EFI than controls (18.4±8.4 versus 8.3±1.3·h−1, and 1.5±0.1 versus 1.8±0.1, respectively). Blood pressure significantly correlated with RDI and with EFI. EFI tended to correlate with RDI.
In conclusion, these results suggest that both sleep-disordered breathing and endothelial dysfunction are more likely to occur in females with pre-eclamptic toxaemia than in females with uncomplicated pregnancies. The current authors speculate that respiratory disturbances contribute to the functional abnormality of the blood vessels seen in females with pre-eclamptic toxaemia, although causality cannot be determined based on this study.
Endothelial dysfunction; hypertension; pre-eclampsia; sleep-disordered breathing
We hypothesised that pentobarbital would improve upper airway mechanics based on an increase in latency to arousal and amplitude of the phasic genioglossus electromyogram (EMG), and a decrease in the active upper airway critical closing pressure (Pcrit).
12 healthy subjects received pentobarbital (100 mg) or placebo in a double-blind, crossover protocol. During wakefulness, we measured the genioglossus reflex response to negative pressure pulses. During sleep, carbon dioxide was insufflated into the inspired air. Airway pressure was then decreased in a stepwise fashion until arousal from sleep.
With basal breathing during sleep: flow rate was lower in volunteers given pentobarbital; end-tidal CO2 concentration and upper airway resistance were greater; and Pcrit was unaffected (pentobarbital mean±sd -11.7±4.5 versus placebo -10.25±3.6 cmH2O; p=0.11). Pentobarbital increased the time to arousal (297±63s versus 232±67 s; p<0.05), at which time phasic genioglossus EMG was higher (6.2±4.8% maximal versus 3.1±3%; p<0.05) as were CO2 levels. The increase in genioglossus EMG after CO2 administration was greater after pentobarbital versus placebo. Pentobarbital did not affect the genioglossus negative-pressure reflex.
Pentobarbital increases the time to arousal and stimulates genioglossus muscle activity, but it also increases upper airway resistance during sleep.
Airway; arousal threshold; lung; obstructive sleep apnoea/hypopnoea syndrome; sleep-disordered breathing