Lower Limit Of Normal Research Articles

Estimating prevalence of chronic obstructive pulmonary disease in the Southern Cone of Latin America: how different spirometric criteria may affect disease burden and health policies

BackgroundChronic obstructive pulmonary disease (COPD) is the fourth leading cause of death worldwide. The study aimed to determine and compare the prevalence of COPD in the general population aged 45-74 years old according to fixed ratio and lower limit of normal (LLN) thresholds in four cities in the Southern Cone of Latin America.MethodsThe Pulmonary Risk in South America (PRISA) study used a 4-stage stratified sampling method to select 5814 participants from 4 cities in the Southern Cone of Latin America (Bariloche and Marcos Paz, Argentina; Temuco, Chile; and Pando-Barros Blancos, Uruguay). Data on demographic information, medical history, risk factors, pre-bronchodilator and post-bronchodilator spirometry were obtained using a standard protocol. According to GOLD, COPD was defined as a post-bronchodilator ratio of forced expiratory volume in one second (FEV1) over forced vital capacity (FVC) less than 70%. The LLN threshold was defined as the lower fifth percentile for predicted FEV1/FVC, and was evaluated as an alternative COPD definition.ResultsOverall COPD prevalence was 9.3% (95% CI 8.4, 10.2%), and men had a higher prevalence [11.8% (95% CI 10.3, 13.3%)] than women [7.3% (95% CI 6.2, 8.3%)] with the fixed ratio. Overall COPD prevalence using LLN was 4.7% (95% CI 4.1, 5.3%), higher in men: 5.8% (95% CI 4.7, 6.8%) than women: 3.9% (95% CI 3.1, 4.7%). COPD prevalence was significantly higher among those who were older, had <high-school education and lower body-mass index, were cigarette smokers, and had self-reported history of asthma and tuberculosis.ConclusionsFirst, COPD and its risk factors are highly prevalent in the general population of Argentina, Chile, and Uruguay. Second, the prevalence of COPD by LLN criterion was significantly lower with lesser degrees of severity compared to fixed ratio of FEV1/FVC. Implementing LLN criterion instead of fixed ratio of FEV1/FVC may reduce the risk of over-diagnosis of COPD, although further prognostic studies of COPD adverse outcomes should be conducted using both definitions. Third, these data suggest that national efforts on the prevention, treatment, and control of COPD should be a public health priority in the Southern Cone of Latin America.

Occupational exposure to vapor, gas, dust, or fumes and chronic airflow limitation, COPD, and emphysema: the Swedish CArdioPulmonary BioImage Study (SCAPIS pilot).

BackgroundThe aim of this study was to estimate the occupational burden of airflow limitation, chronic airflow limitation, COPD, and emphysema.Materials and methodsSubjects aged 50–64 years (n=1,050) were investigated with forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC). Airflow limitation was defined as FEV1/FVC <0.7 before bronchodilation. Chronic airflow limitation was defined after bronchodilation either according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) as FEV1/FVC <0.7 or according to the lower limit of normal (LLN) approach as FEV1/FVC < LLN. COPD was defined as chronic airflow limitation (GOLD) in combination with dyspnea, wheezing, or chronic bronchitis. Emphysema was classified according to findings from computed tomography of the lungs. Occupational exposure was defined as self-reported occupational exposure to vapor, gas, dust, or fumes (VGDF). Odds ratios (OR) were calculated in models adjusted for age, gender, and smoking; population-attributable fractions and 95% CI were also calculated.ResultsThere were significant associations between occupational exposure to VGDF and COPD (OR 2.7, 95% CI 1.4–51), airflow limitation (OR 1.8, 95% CI 1.3–2.5), and emphysema (OR 1.8, 95% CI 1.1–3.1). The associations between occupational exposure to VGDF and chronic airflow limitation were weaker, and for the OR, the CIs included unity. The population-attributable fraction for occupational exposure to VGDF was 0.37 (95% CI 0.23–0.47) for COPD and 0.23 (95% CI 0.05–0.35) for emphysema.ConclusionThe occupational burden of COPD and computed tomography–verified emphysema is substantial.

Reference values for spirometry in Chinese aged 4-80 years.

Although there are over 1.34 billion Chinese in the world, nationwide spirometric reference values for Chinese are unavailable, which is usually based on Caucasian conversion. The aim of this study was to establish spirometric reference values for Chinese with a national wide sample. We enrolled healthy non-smokers in 24 centers in Northeast, North, Northwest, Southwest, South, East and Central China from January 2007 to June 2010. Spirometry was performed according to American Thoracic Society and European Respiratory Society guidelines. Reference equations were established using the Lambda-Mu-Sigma (LMS) method for forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), FEV1/FVC, peak expiratory flow (PEF) and maximal midexpiratory flow (MMEF). Popular Caucasian reference values adjusted with ethnic conversion factors were validated with Chinese measured spirometry data. The present study also compared with other published Chinese equations for spirometry. A total of 7,115 eligible individuals aged 4 to 80 years (50.9% females) were recruited. Reference equations against age and height by gender were established, including predicted values and lower limits of normal (LLNs). Validated with Chinese data, the mean percentage differences of Caucasian reference values adjusted with ethnic conversion factors were -10.2% to 1.8%, and the percentages of total subjects under LLNs were 0.1% to 8.9%. Compared with this study, the percentage differences of previous Chinese studies ranged from -17.8% to 11.4%, which were found to significantly overestimate or underestimate lung function. This study established new reference values for better interpretation of spirometry in Chinese aged 4 to 80 years, while Caucasian references with adjustment were inappropriate for Chinese.

Lack of CD4 + T cell percent decrease in alemtuzumab-treated multiple sclerosis patients with persistent relapses

Alemtuzumab, a highly effective treatment for relapsing remitting multiple sclerosis (RRMS), induces lymphopenia especially of CD4+ T cells. Here, we report the atypical CD4+ T population behaviour of two patients with persistent disease activity despite repeated alemtuzumab treatments. Whereas lymphocytes count decreased and fluctuated accordingly to alemtuzumab administration, their CD4+ cell percentage was not or just mildly affected and was slightly below the lowest normal limit already before alemtuzumab. These cases anticipate further studies aimed to investigate whether the evaluation of the CD4+ cell percentage could represent a helpful tool to address the individual clinical response to alemtuzumab.

Prospective study of lung function and abdominal aortic aneurysm risk: The Atherosclerosis Risk in Communities study

Background and aimsNo prospective study has investigated whether individuals with respiratory impairments, including chronic obstructive pulmonary disease (COPD) and restrictive lung disease (RLD), are at increased risk of abdominal aortic aneurysm (AAA). We aimed to prospectively investigate whether those respiratory impairments are associated with increased AAA risk. MethodsIn 1987–1989, the Atherosclerosis Risk in Communities (ARIC) study followed 14,269 participants aged 45–64 years, without a history of AAA surgery, through 2011. Participants were classified into four groups, “COPD” [forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) <lower limit of normal (LLN)], “RLD” (FEV1/FVC ≥ LLN and FVC < LLN), “respiratory symptoms with normal spirometry” (without RLD or COPD), and “normal” (without respiratory symptoms, RLD or COPD, reference group). ResultsDuring the 284,969 person-years of follow-up, 534 incident AAA events were documented. In an age, sex, and race-adjusted proportional hazards model, individuals with respiratory impairments had a significantly higher risk of AAA than the normal reference group. After adjustment for AAA risk factors, including smoking status and pack-years of smoking, AAA risk was no longer significant in the respiratory symptoms with normal spirometry group [HR (95% CI), 1.25 (0.98–1.60)], but was still increased in the other two groups [RLD: 1.45 (1.04–2.02) and COPD: 1.66 (1.34–2.05)]. Moreover, continuous measures of FEV1/FVC, FEV1 and FVC were associated inversely with risk of AAA. ConclusionsIn the prospective population-based cohort study, obstructive and restrictive spirometric patterns were associated with increased risk of AAA independent of smoking, suggesting that COPD and RLD may increase the risk of AAA.

The impact of different spirometric definitions on the prevalence of airway obstruction and their association with respiratory symptoms.

The fixed ratio criterion of forced expiratory volume in 1 s/forced vital capacity <0.70 for diagnosing airway obstruction may overdiagnose the condition, particularly in the elderly, so the lower limit of normal (LLN) is recommended as the most appropriate criterion. Our aim was to compare LLN versus fixed ratio on the prevalence of chronic obstructive pulmonary disease (COPD) and examine the association between respiratory symptoms and airway obstruction defined by LLN and fixed ratio.12 449 twins aged 40–80 years participated in a nationwide survey using the Danish Twin Registry. They completed a questionnaire, underwent clinical examination and recorded prebronchodilator spirometry. Individuals with self-reported asthma were excluded. Clinical COPD was defined by respiratory symptoms together with airway obstruction.10 329 individuals were included, with a mean±sd age of 58.4±9.6 years and mean body mass index of 26.6±4.4 kg·m−2; 20% were current smokers, 37% former smokers and 43% never-smokers; and 48% were male. The prevalence of LLN airway obstruction (LLN-AO) and fixed ratio airway obstruction (FR-AO) was 5.6% and 18.0%, respectively (p<0.001). Overall, 26% reported current respiratory symptoms, but 50% of those with LLN-AO had respiratory symptoms compared to 39% with FR-AO, p<0.001. The prevalence of clinical LLN-COPD and fixed ratio COPD was 2.6% and 6.3%, respectively (p<0.001). Individuals with LLN-AO had a significantly higher probability of reporting respiratory symptoms compared with both healthy individuals and FR-AO when adjusted for sex, age and ever-smoking.The use of fixed ratio more than doubled the prevalence of clinical COPD compared with LLN, this being more pronounced with increased age, and identified subjects with a lower prevalence of respiratory symptoms than LLN-AO.

The Effect of Defining Chronic Obstructive Pulmonary Disease by the Lower Limit of Normal of FEV1/FVC Ratio in Tiotropium Safety and Performance in Respimat Participants.

There is continuing debate about whether to define airflow obstruction by a post-bronchodilator ratio of forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) below 0.70, or by ratio values falling below the age-dependent lower limit of normal (LLN) derived from general population data. To determine whether using the LLN criterion affects the classification and outcomes of patients previously defined as having chronic obstructive pulmonary disease by the fixed FEV1/FVC ratio. We applied the LLN definition to pooled data from the Tiotropium Safety and Performance in Respimat study that used the fixed FEV1/FVC ratio for the clinical diagnosis of chronic obstructive pulmonary disease. A total of 17,072 patients were analyzed; of these, 1,807 (10.6%) patients had a ratio greater than or equal to LLN. Patients with a ratio greater than or equal to LLN had similar risks of death from any cause and fatal major adverse cardiovascular (CV) event as those below LLN. Patients with a ratio below LLN had a significantly lower risk of major adverse CV events (hazard ratio = 0.69; 95% confidence interval [CI] = 0.55-0.86; P = 0.001), and had significantly greater risks of moderate to severe exacerbation (rate ratio = 1.48; 95% CI = 1.36-1.61; P < 0.0001) and severe exacerbation (rate ratio = 2.01; 95% CI = 1.68-2.40; P < 0.0001) when compared with patients greater than or equal to LLN. Study outcomes by treatment arm (5 μg tiotropium Respimat vs. 18 μg HandiHaler) were comparable. Using the LLN to define airflow obstruction would have excluded patients in the Tiotropium Safety and Performance in Respimat study with a higher risk of nonfatal major adverse CV events and a lower risk of exacerbation; study outcomes by treatment arm (2.5 μg/5 μg tiotropium Respimat vs. 18 μg HandiHaler) remained similar. Clinical trial registered with www.clinicaltrials.gov (NCT01126437).

Difference in Mortality Risk in Elderly People with Bronchial Obstruction Diagnosed Using a Fixed Cutoff or the Lower Limit of Normal of the FEV1/FVC Ratio

Background: Whether a fixed cutoff or the lower limit of normal of the FEV₁/FVC ratio should be used to diagnose bronchial obstruction is still a matter of debate. This issue is particularly important for elderly people. Objectives: We used equations applicable up to 90 years of age to evaluate the mortality of elderly people diagnosed with bronchial obstruction using either a fixed cutoff of 0.7 or the lower limit of normal (LLN). Methods: Participants in the SaRA (Salute Respiratoria nell'Anziano, Italian for “Respiratory Health in the Elderly”) study were grouped as follows: FEV₁/FVC ≥0.7 and ≥ LLN (n = 535: F^-/L^-), FEV₁/FVC <0.7 but ≥ LLN (n = 118: F⁺/L^-), and FEV₁/FVC <0.7 and < LLN (n = 229: F⁺/L⁺). We estimated the mortality risk in the three groups over 15 years of follow-up. Results: The mean age was 73 years (58% men). The hazard ratio (HR) for mortality was 1.427 (95% CI: 1.09-1.868) in the F⁺/L− group and 2.143 (95% CI: 1.13-1.995) in the F⁺/L⁺ group. After adjustment for potential confounders, we found no increased mortality in the F⁺/L− group (HR: 1.007, 95% CI: 0.755-1.342), while the HR in the F⁺/L⁺ group was still sizeable (1.474, 95% CI: 1.136-1.911). Conclusions: As expected, using a fixed cutoff translates in a larger number of people to be classified as having bronchial obstruction. In our sample the increased mortality in the F⁺/L^- group is due to the confounding effect of age and sex. Our study lends support to the use of LLN in elderly people.

902P - Prognostic factors for overall survival of patients with advanced renal cell carcinoma – data from the German prospective RCC-Registry

Background: The identification of prognostic factors is a central question in oncology. They help to predict the course of disease and ideally support the oncologist in treatment decision making in clinical practice. We analysed prognostic factors identified by MSKCC and additional factors for the overall survival (OS) of patients (pts) treated with currently approved agents. Methods: The prospective German renal cell carcinoma (RCC) Registry includes pts with advanced or metastatic renal cell carcinoma at start of systemic first-line therapy. > 300 oncologists are recruiting pts since 2007. Pts and tumour characteristics, data on all systemic therapies and outcome are collected. The prognostic factors for OS were assessed using a multivariate cox regression model. Results: Median OS of the 1039 pts (median age 70 years) was 18.6 months (95% CI 16.0 - 20.5 months, 55% events). Median OS in months for low, intermediate and high risk pts according to MSKCC 1999 was 27.3 (23.7-33.8, 48% events), 16.0 (12.7-18.8, 58% events) and 5.3 (3.7-7.2, 74% events). The following factors were significantly associated with shorter OS (p < 0.05: *; p < 0.01: **; p < 0,001: ***): higher age*, non-clear cell histology**, grading G3/4 at diagnosis*, Karnofsky Performance Status <80%***, haemoglobin < lower limit of normal (LLN)***, LDH >1.5x upper limit of normal (ULN)***. Factors significantly associated with longer OS were time from primary diagnosis to metastasis***, BMI 25-30 versus (vs) <25***, BMI>30 vs < 25***, lung metastasis only at start of treatment*, non-visceral metastasis only at start of treatment* and hypertension*. Factors not significantly associated with OS were sex, tumour stage at diagnosis (IV vs <IV), total calcium >ULN, tumour localisation (right/left), congestive heart failure, renal disease, diabetes and total nephrectomy. Conclusions: 3 out of 5 MSKCC factors were significantly associated with OS in our cohort. Still, a clear separation of OS between pts with low, intermediate and high risk according to MSKCC could be confirmed. In addition, we identified novel factors also associated with OS. Clinical trial identification: ClinicalTrial.gov registry: study number: NCT00610012 Legal entity responsible for the study: iOMEDICO AG Funding: Bayer Vital GmbH, GlaxoSmithKline GmbH & Co. KG, Novatis Pharma GmbH, Pfizer Pharma GmbH, Roche Pharma AG Disclosure: P.J. Goebell: Received honoraria for paticipation in expert rounds and honoraria/support as a speaker from Astellas, AstraZeneca, Bayer, Bristol-Myers Squib, Eisai, Ipsen, Janssen, Novartis, Pfizer, Sanofi. M. Staehler: Consultant, Honoria and Research Funding: Pfizer, GlaxoSmithKline, Novartis, Bayer, AVEO, Ipsen, Exelixis, EISAI Consultant and Honoria: EUSAPharm, Astellas, Pelloton Consultant and Research funding: Roche Research funding: Immatics, Wilex. N. Marschner: Employed by iOMEDICO which performs the tumorregistry RCC as an CRO Member of advisory boards regarding RCC treatment and Travel grants: Roche, Novartis, Pfizer, Bayer, GSK Corporate sponsored research: Novartis, Pfizer Roche. All other authors have declared no conflicts of interest.

Utilidad del límite inferior de normalidad de la espirometría en pacientes diagnosticados de EPOC

AimTo evaluate the differences in COPD patients below the lower limit of normal (LLN) of the fixed ratio FEV1/FVC < 0.70 and those above this limit. Patients and methodsCross-sectional study. COPD patients between 40 and 85 years old included in primary care clinical record database were randomly selected. Baseline and postbronchodilator spirometries were performed. Two groups of patients were established: FEV1/FVC<0.70 and ≤LIN (group1) and FEV/FVC<0.70 and >LIN (group 2). Sociodemographic, clinical, pulmonary obstruction, quality of life and attendance to health services variables were measured. The results of both groups were compared. Results22.3% of the subjects were misdiagnosed FEV1/FVC < 0,70. Patients in group 2 (FEV1/FVC<0.70 y > LLN) are diagnosed at an older age, they have a lower exposure to tobacco and better pulmonary function (FEV1: 74.9% vs 54.6%). 35.5% of those patients belong to stage i of GOLD, vs 8.5%, this patients have an increased comorbidity. Patients in group 1 have more COPD exacerbations, worse quality of life, a higher BODEx index 2,3 (1.8) vs 1.1 (1.5); 55.1% of those patients were high risk patients (GoldC or Gold D). Diagnose before being 56 years old, an increased exposure to tobacco, the FEV>50%, and a lower comorbidity are associated with a greater chance of suffering COPD with LLN criteria. ConclusionWe obtain two groups of patients with differentiated clinical characteristics if we use LLN. Subjects with FEV1/FVC<0.7 and >LLN have less obstruction, less severity and more comorbidity, suggesting the possibility of overdiagnosis or misdiagnosis. On the other hand, younger age at the time of diagnosis, higher tobacco consumption and more severe obstruction are related with FEV1/FVC >0.70 and<LLN (group 1).

Validating Reference Equations for Impulse Oscillometry in Healthy Mexican Children.

The impulse oscillometry system (IOS) measures the impedance (Z) of the respiratory system, but proper interpretation of its results requires adequate reference values. The objectives of this work were: (1) to validate the reference equations for the IOS published previously by our group and (2) to compare the adjustment of new available reference equations for the IOS from different countries in a sample of healthy children. Subjects were healthy 4-15-y-old children from the metropolitan area of Mexico City, who performed an IOS test. The functional IOS parameters obtained were compared with the predicted values from 12 reference equations determined in studies of different ethnic groups. The validation methods applied were: analysis of the differences between measured and predicted values for each reference equation; correlation and concordance coefficients; adjustment by Z-score values; percentage of predicted value; and the percentage of patients below the lower limit of normality or above the upper limit of normality. Of the 224 participants, 117 (52.3%) were girls, and the mean age was 8.6 ± 2.3 y. The equations that showed the best adjustment for the different parameters were those from the studies by Nowowiejska et al (2008) and Gochicoa et al (2015). The equations proposed by Frei et al (2005), Hellinckx et al (1998), Kalhoff et al (2011), Klug and Bisgaard (1998), de Assumpção et al (2016), and Dencker et al (2006) overestimated the airway resistance of the children in our sample, whereas the equation of Amra et al (2008) underestimated it. In the analysis of the lower and upper limits of normality, Gochicoa et al equation was the closest, since 5% of subjects were below or above percentiles 5 and 95, respectively. The study found that, in general, all of the equations showed greater error at the extremes of the age distribution. Because of the robust adjustment of the present study reference equations for the IOS, it can be recommended for both clinical and research purposes in our population. The differential adjustment of other equations underlines the need to obtain local reference values.

Global Lung Function Initiative 2012 reference values for spirometry in South Italian children.

Despite the widespread use of the Global Lung Function Initiative (GLI) 2012 reference values, there is still the need of testing their applicability in local areas. The aims of this study are to evaluate applicability of GLI reference equations in a large population-based sample of normal schoolchildren from Sicily, and to compare GLI and previous prediction equations in terms of spirometry test interpretation. GLI equations were evaluated in 1243 normal schoolchildren, 49% males, aged 7-16 years, height 116-187cm. Normality assumptions for the GLI z-scores (FEV1, FVC, FEV1/FVC) were tested, and bootstrap confidence intervals for the mean (0 expected) and the variance (1 expected) were derived. GLI and other reference equations were compared in terms of probabilities to fall below the lower limit of normal (LLN). The GLI z-score normality assumption held for males but not for females (p<0.001). According to the mean z-score, predicted values were: slightly underestimated for FEV1 (0.15 in males, 0.07 in females); overestimated for FVC (-0.27 in males,-0.32 in females); highly underestimated for FEV1/FVC (0.75 in males, 0.81 in females). Variability was correctly estimated. The probability of FEV1<LLN correctly approached 0.05 when using GLI, Hankinson and Quanjer equations. Wang equations yielded correct probabilities of abnormal FVC; Pistelli equations yielded correct probabilities of abnormal FEV1/FVC for females. GLI 2012 references underestimate FEV1/FVC predicted values in a sample of normal South Italian children. Physicians interpreting spirometry should be aware to test reference values prior to their use in a local area.

The “C test” for tritan discrimination

AbstractThe aim of this study was to develop and evaluate a clinical standard capable of generating ordinal measures of monocular tritan discrimination. A novel pseudoisochromatic plate test was developed, called the “C test.” It contains 10 progressively desaturated plates arranged in perceptually distinct steps that provide a standard for analyzing the threshold for tritan discrimination. The most difficult plate that can be detected is the “C score.” Relevant diagnostic findings including the C score, Logmar acuity, Pelli‐Robson score, and LOCS III lens grading were prospectively recorded in 568 eyes. A total of 355 normal eyes were selected for statistical analysis. The correlations between C score, Logmar acuity, and Pelli‐Robson score with LOCS III grading were analyzed with Spearman rank analysis. The strongest correlations were between the Logmar acuity with posterior subcapsular cataract (PSC) (0.68), the C score with nuclear colour (NC) (–0.58), and the Logmar acuity with NC (0.57). The lower normal limit for the C score was 9 in pseudophakes and phakic eyes with NC &lt; 3, 7 for eyes with NC = 3, but undetermined for eyes with NC &gt; 3. A comparison of C score distribution between three distinct age ranges of pseudophakic eyes (n = 136) showed no significant variation (P = .486). The Spearman rank correlation between C score and Logmar acuity was 0.028, and between C score and Pelli‐Robson score was 0.012. The normal limit for the C score used under 800 Lux is 9 when NC &lt; 3 and 7 when NC = 3 in all age groups.

Biochemical characteristics of newborns with carnitine transporter defect identified by newborn screening in California.

Carnitine transporter defect (CTD; also known as systemic primary carnitine deficiency; MIM 212140) is due to mutations in the SLC22A5 gene and leads to extremely low carnitine levels in blood and tissues. Affected individuals may develop early onset cardiomyopathy, weakness, or encephalopathy, which may be serious or even fatal. The disorder can be suggested by newborn screening. However, markedly low newborn carnitine levels can also be caused by conditions unrelated to CTD, such as the low carnitine levels often associated with normal pregnancies and some metabolic disorders occurring in the mother. In order to clarify the biochemical characteristics most useful for identification of CTD in newborns, we examined California Department of Public Health newborn screening data for CTD from 2005 to 12 and performed detailed chart reviews at six metabolic centers in California. The reviews covered 14 cases of newborn CTD, 14 cases of maternal disorders (CTD, 6 cases; glutaric aciduria, type 1, 5; medium-chain acyl CoA dehydrogenase deficiency, 2; and cobalamin C deficiency, 1), and 154 false-positive cases identified by newborn screening. Our results show that newborns with CTD identified by NBS exhibit different biochemical characteristics, compared to individuals ascertained clinically. Newborns with CTD may have NBS dried blood spot free carnitine near the lower cutoff and confirmatory plasma total and free carnitine levels near the normal lower limit, particularly if obtained within two weeks after birth. These findings raise the concern that true cases of CTD may exist that could have been missed by newborn screening. CTD should be considered as a possible diagnosis in cases with suggestive clinical features, even if CTD was thought to be excluded in the newborn period. Maternal plasma total carnitine and newborn urine total carnitine values are the most important predictors of true CTD in newborns. However, biochemical testing alone does not yield a discriminant rule to distinguish true CTD from low carnitine in newborns due to other causes. Because of this biochemical variability and overlap, molecular genetic testing is imperative to confirm CTD in newborns. Additionally, functional testing of fibroblast carnitine uptake remains necessary for cases in which other confirmatory testing is inconclusive. Even with utilization of all available diagnostic testing methods, confirmation of CTD ascertained by NBS remains lengthy and challenging. Incorporation of molecular analysis as a second tier step in NBS for CTD may be beneficial and should be investigated.

Occupational exposure to pesticides are associated with fixed airflow obstruction in middle-age

RationalePopulation-based studies have found evidence of a relationship between occupational exposures and Chronic Obstructive Pulmonary Disease (COPD), but these studies are limited by the use of prebronchodilator spirometry. Establishing this...

Percentages of the measured value vs.the expected value of pulmonary function parameters in healthy children aged 5-14 years in Beijing

Objective To investigate the distribution of measured value and the expected value of spirometry parameters in healthy children aged 5-14 years old in Beijing, and to provide evidence for clinical interpretation precisely. Methods Four hundred healthy children (198 boys and 202 girls) aged 5 to 14 years from the kindergartens and the primary schools in Beijing were selected as subjects.All of the parameters were measured by using Jaeger Masterscreen spirometry machine(Germany). Pulmonary function parameters including forced vital capacity(FVC), forced expiatory volume in 1 second (FEV1), FEV1/FVC, peak expiratory flow(PEF), forced expiratory flow at 50% of vital capacity(FEF50), forced expiratory flow at 75% of vital capacity(FEF75), and the maximal midexpiratory flow(MMEF) were collected for analysis.The expected values of the 7 parameters above were calculated according to Zapletal prediction equations(4-18 years old). The measured value vs.the expected value was calculated. Results Children aged 5 to 12 years had similar height and weight between boys and girls, and the differences were not significant(all P>0.05); while boys were taller and heavier than girls in 13-<14 years old group and 14 years old group, and the diffe-rences were significant(t=3.35, 2.05, 5.99, 2.67; all P<0.05). The mean measured value vs.the expected value of PEF, FVC, FEV1, FEV1/FVC of children in different gender and age groups ranged between 105.0%-114.7%, 95.4%-106.8%, 104.6%-115.4% and 105.8%-112.6%, respectively.The mean measured value vs.the expected value of small airway function parameters FEF50, FEF75, MMEF was as follows respectively: 79.7%-103.7%, 70.2%-110.5%, and 81.6%-114.7%.The low limit of normal(LLN) measured value vs.the expected value of the 7 pulmonary function parameters was as follows: PEF 85.0%, FVC 84.7%, FEV1 92.4%, FEV1/FVC 98.4%, FEF50 67.7%, FEF75 60.1%, and MMEF 71.0%. Conclusions The pulmonary function parameters of the healthy children in Beijing are higher than those of the Zapletal prediction.The measured value vs.the expected value of FEV1 92.4%, FEV1/FVC 98.4%, PEF 85.0%, FVC 84.7%, FEF50 67.7%, FEF75 60.1%, and MMEF 71.0% can be used as LLN in 5-14 years old children. Key words: Child; Pulmonary function parameter; Lower limit of normal

Health-related quality of life and risk factors associated with spirometric restriction.

The restrictive spirometric pattern is associated with a substantial morbidity and mortality burden. We sought to determine to what extent spirometric restriction is associated with impaired quality of life.We used data from two large population-based European cohorts: 6698 European Community Respiratory Health Survey (ECRHS) and 6069 Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults (SAPALDIA) adult participants. The restrictive pattern was defined as forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ≥lower limit of normal (LLN) and FVC <LLN; an obstructive pattern was defined as FEV1/FVC <LLN independent of FVC. The Physical Component Summary and Mental Component Summary of quality of life were computed using the Short Form-36 questionnaire.In both cohorts, the restrictive pattern was associated with heavy smoking, being underweight or obese and the coexistence of respiratory symptoms. In univariate analyses, compared with the normal group, both the restrictive and obstructive pattern had significant Physical Component Summary deficits (-2.77 and -2.08, respectively, in ECRHS; -3.25 and -2.14, respectively, in SAPALDIA; all p-values <0.001). However, in models adjusted for sex, age, education, body mass index, smoking, comorbidities and respiratory symptoms, only the restrictive pattern remained significantly associated with Physical Component Summary deficits (p=0.004 in ECRHS; p=0.001 in SAPALDIA).The restrictive spirometric pattern is associated with deficits in the physical component of quality of life that are partly independent of the presence of respiratory symptoms.

The Association of Lung Clearance Index with COPD and FEV1 Reduction in ‘Men Born in 1914’

ABSTRACTLung Clearance Index (LCI) provides an overall measurement of ventilation inhomogeneity. This population-based study examines whether LCI predicts pulmonary obstruction and incidence of chronic obstructive pulmonary disease (COPD) events over a long-term follow-up. Multiple breath nitrogen washout and spirometry were performed in 674 men from the cohort “Men born in 1914” at age 55 years. Subjects were classified into quartiles (Q) of LCI and according to LCI above and below upper limit of normal (ULN). Incidence of COPD events (COPD hospitalisations or COPD-related deaths) were monitored over the remaining life span of the men, by linkage with national hospital registers. In addition, development of pulmonary obstruction (i.e., FEV1/vital capacity below lower limit of normal (LLN)) was studied in 387 men who were re-examined with spirometry at 68 years of age. Over 44 years of follow-up, there were 85 incident COPD events. Hazards ratios (HRs) for COPD across quartiles of LCI were: Q1 1.00 (reference), Q2 1.30 (95% confidence interval: 0.61–2.74), Q3 1.97 (0.97–3.98) and Q4 3.99 (2.06–7.71) (p value for trend <0.001). This relationship remained significant after adjustments for confounding factors, including smoking and FEV1 (HR, Q4 vs Q1: 2.34 (1.17–4.69); p value for trend: 0.006). Reduction of FEV1 between 55 and 68 years of age and incidence of pulmonary obstruction was highest in those with high LCI. High LCI is associated with future development of pulmonary obstruction and incidence of COPD hospitalisations in men from the general population.

Resting Physiological Correlates of Reduced Exercise Capacity in Smokers with Mild Airway Obstruction

ABSTRACTSmokers with minor spirometric abnormalities can experience persistent activity-related dyspnea and exercise intolerance. Additional resting tests can expose heterogeneous physiological abnormalities, but their relevance and association with clinical outcomes remain uncertain. Subjects included sixty-two smokers (≥20 pack-years), with cough and/or dyspnea and minor airway obstruction [forced expiratory volume in one-second (FEV1) ≥80% predicted and >5th percentile lower limit of normal (LLN) (i.e., z-score >−1.64) using the 2012-Global Lung Function Initiative equations]. They underwent spirometry, plethysmography, oscillometry, single-breath nitrogen washout, and symptom-limited incremental cycle exercise tests. Thirty-two age-matched nonsmoking controls were also studied. Thirty-three (53%) of smokers had chronic obstructive pulmonary disease by LLN criteria. In smokers [n = 62; age 65 ± 11 years; smoking history 43 ± 19 pack-years; post-bronchodilator FEV1 z-score −0.60 ± 0.72 and FEV1/FVC z-score −1.56 ± 0.87 (mean ± SD)] versus controls, peak oxygen uptake (̇VO2) was 21 ± 7 vs. 32 ± 9 ml/kg/min, and dyspnea/̇VO2 slopes were elevated (both p < 0.0001). Smokers had evidence of peripheral airway dysfunction and maldistribution of ventilation when compared to controls. In smokers versus controls: lung diffusing capacity for carbon monoxide (DLCO) was 85 ± 22 vs. 105 ± 17% predicted, and residual volume (RV)/total lung capacity (TLC) was 36 ± 8 vs. 31 ± 6% (both p < 0.01). The strongest correlates of peak ̇VO2 were DLCO% predicted (r = 0.487, p < 0.0005) and RV/TLC% (r = −0.389, p = 0.002). DLCO% predicted was also the strongest correlate of dyspnea/̇VO2 slope (r = −0.352, p = 0.005). In smokers with mild airway obstruction, associations between resting tests of mechanics and pulmonary gas exchange and exercise performance parameters were weak, albeit consistent. Among these, DLCO showed the strongest association with important outcomes such as dyspnea and exercise intolerance measured during standardized incremental exercise tests.

Tyrosine kinase inhibitor therapy-induced changes in humoral immunity in patients with chronic myeloid leukemia.

Tyrosine kinase inhibitors (TKIs) have well-characterized immunomodulatory effects on T and NK cells, but the effects on the humoral immunity are less well known. In this project, we studied TKI-induced changes in B cell-mediated immunity. We collected peripheral blood (PB) and bone marrow (BM) samples from chronic myeloid leukemia (CML) patients before and during first-line imatinib (n = 20), dasatinib (n = 16), nilotinib (n = 8), and bosutinib (n = 12) treatment. Plasma immunoglobulin levels were measured, and different B cell populations in PB and BM were analyzed with flow cytometry. Imatinib treatment decreased plasma IgA and IgG levels, while dasatinib reduced IgM levels. At diagnosis, the proportion of patients with IgA, IgG, and IgM levels below the lower limit of normal (LLN) was 0, 11, and 6% of all CML patients, respectively, whereas at 12 months timepoint the proportions were 6% (p = 0.13), 31% (p = 0.042) and 28% (p = 0.0078). Lower initial Ig levels predisposed to the development of hypogammaglobulinemia during TKI therapy. Decreased Ig levels in imatinib-treated patients were associated with higher percentages of immature BM B cells. The patients, who had low Ig levels during the TKI therapy, had significantly more frequent minor infections during the follow-up compared with the patients with normal Ig values (33% vs. 3%, p = 0.0016). No severe infections were reported, except recurrent upper respiratory tract infections in one imatinib-treated patient, who developed severe hypogammaglobulinemia. TKI treatment decreases plasma Ig levels, which should be measured in patients with recurrent infections.