Rifampicin and Isoniazid Maximal Concentrations are Below Efficacy-associated Thresholds in the Majority of Patients: Time to Increase the Doses?

BACKGROUND: The treatment of drug-sensitive tuberculosis (TB) is highly effective; however, many patients have suboptimal drug exposure, which possibly explains treatment failures and selection of resistance. This study aimed to describe the prevalence and determinants of suboptimal maximal concentrations (Cmax) for anti-TB drugs. METHODS: An observational study was conducted in patients receiving first-line anti-TB treatment. At two early time points (T1 and T2), blood samples were withdrawn 2 hours post-dose (Cmax) and drug concentrations were measured. Data were expressed as medians (interquartile ranges). RESULTS: The study included 199 participants: 72.9% were male and the median age was 39.8 years (27.5-51.4). The median Cmax at T1 and T2 were 7950 ng/mL and 7122 ng/mL (rifampicin), 3260 ng/mL and 3185 ng/mL (isoniazid), 4210 ng/mL and 5742 ng/mL (ethambutol), and 31 008 ng/mL and 30 352 ng/mL (pyrazinamide), respectively. Higher doses/kg and other variables (being born in Italy and female gender for rifampicin, older age and proton pump inhibitor use for isoniazid, female gender and older age for pyrazinamide) were identified by multivariate linear regression analysis. Participants with a higher body mass index received lower doses/kg of all anti-TB drugs. Suboptimal Cmax at T1 and T2 were observed in 60% and 66% (rifampicin), 54% and 55% (isoniazid), 33% and 39% (ethambutol), 20% and 11% (pyrazinamide) of patients. Despite 21% of patients at T1 and 24% at T2 showing two or more drugs with suboptimal exposure, no effect on treatment outcome was observed. DISCUSSION: The majority of patients receiving first-line anti-TB drugs had low isoniazid and rifampin Cmax. Increased doses or the use of therapeutic drug monitoring in selected patients may be advised.

Worldwide Effects of Coronavirus Disease Pandemic on Tuberculosis Services, January-April 2020.

Coronavirus disease has disrupted tuberculosis services globally. Data from 33 centers in 16 countries on 5 continents showed that attendance at tuberculosis centers was lower during the first 4 months of the pandemic in 2020 than for the same period in 2019. Resources are needed to ensure tuberculosis care continuity during the pandemic.

Pilot prospective open, single-arm multicentre study on off-label use of tocilizumab in patients with severe COVID-19.

OBJECTIVES: No agent has yet been proven to be effective for the treatment of patients with severe COVID-19. METHODS: We conducted a pilot prospective open, single-arm multicentre study on off-label use of tocilizumab (TCZ) involving 63 hospitalised adult patients (56 males, age 62.6±12.5) with severe COVID-19. Clinical and laboratory parameters were prospectively collected at baseline, day 1, 2, 7 and 14. No moderate-to-severe adverse events attributable to TCZ were recorded. RESULTS: We observed a significant improvement in the levels of ferritin, C-reactive protein, D-dimer. The ratio of the partial pressure of oxygen (Pa02) to the fraction of inspired oxygen (Fi02) improved (mean±SD Pa02/Fi02 at admission: 152±53; at day 7: 283.73±115.9, at day 14: 302.2±126, p<0.05). The overall mortality was 11%; D-dimer level at baseline, but not IL-6 levels were predictors of mortality. TCZ administration within 6 days from admission in the hospital was associated with an increased likelihood of survival (HR 2.2 95%CI 1.3-6.7, p<0.05). CONCLUSIONS: In hospitalised adult patients with severe COVID-19, TCZ could be a safe option. An improvement in respiratory and laboratory parameters was observed. Future controlled trials in patients with severe illness are urgently needed to confirm the definite benefit with IL-6 target therapy.

Formaldehyde, Oxidative Stress, and FeNO in Traffic Police Officers Working in Two Cities of Northern Italy.

Personal air formaldehyde (air-FA) was measured as risk factor of airways inflammation and oxidative stress (SO) induction. Overall, 154 police officers were enrolled from two differently urbanised Italian cities, Turin and Pavia. Urinary F2t-isoprostane (15-F2t-IsoP), a prostaglandin-like compound, was quantified as a biomarker of general OS in vivo and fractional exhaled nitric oxide (FeNO) was measured for monitoring local inflammatory processes. Urinary cotinine was quantified as a biomarker of tobacco smoking exposure. Traffic police officers living in Turin showed an increased level of log air-FA (p < 0.001), equal to +53.6% (p < 0.001). Log air-(FA) mean values were 3.38 (C.I. 95% 3.33-3.43) and 2.84 (C.I. 95% 2.77-2.92) in Turin and Pavia, respectively. Log (air-FA) was higher in "outdoor workers" (3.18, C.I. 95% 3.13-3.24, p = 0.035) compared to "indoor workers", showing an increase of +9.3%, even controlling for sex and city. The analyses on 15-F2t-IsoP and FeNO, both adjusted for log air-FA, highlighted that OS and inflammation were higher (+66.8%, p < 0.001 and +75%, p < 0.001, respectively) in Turin traffic police officers compared to those from Pavia. Our findings suggest that even low exposures to traffic-related emissions and urbanisation may influence both general oxidative stress levels and local inflammation.

Greenness Availability and Respiratory Health in a Population of Urbanised Children in North-Western Italy.

Paediatric Asthma contributes in paediatric global burden of diseases, as the most common chronic disease in children. Children are exposed to many environmental risk-factors, able to determine or worsen respiratory diseases, and contributing to asthma and asthma-like symptoms increases, especially in metropolitan areas. In urban settings, surrounding vegetation (greenness) may provide important benefits to health, including the promotion of physical activity and the mitigation of air and noise pollution. The aim of this study was to investigate the association between greenness and respiratory health. A total of 187 children (10-13 yrs old) were recruited in Turin, the north-western part of Italy. The prevalence of asthma and asthma-like symptoms was calculated from self-reported data collected by SIDRIA questionnaire. Spirometry test was performed to obtain respiratory flow measurements. Greenness was measured at individual level through the Normalised Difference Vegetation Index (NDVI) estimations from remote-sensing images. Higher exposure (3rd tertile vs. 1st tertile) to NDVI was associated to significantly lower ORs for asthma [0.13 CI 95% 0.02-0.7, p = 0.019], bronchitis [0.14 CI 95% 0.05-0.45, p = 0.001], and current wheezing [0.25 CI 95% 0.09-0.70, p = 0.008]. A significative positive association was found between greenness and FEF25-75, since children exposed to the 2nd tertile of NDVI reported a significantly decreased FEF25-75 compared to those in the 3rd tertile [B: -2.40; C.I.95%: -0.48-0.01; p = 0.049]. This cross-sectional study provided additional data on still inconsistent literature referring to respiratory health in children and green spaces, attesting a positive effect of greenness in a specific area of Italy. Further research is still needed.

Tobacco Smoke Exposure, Urban and Environmental Factors as Respiratory Disease Predictors in Italian Adolescents.

Risk monitoring in childhood is useful to estimate harmful health effects at later stages of life. Thus, here we have assessed the effects of tobacco smoke exposure and environmental pollution on the respiratory health of Italian children and adolescents using spirometry and the forced oscillation technique (FOT). For this purpose, we recruited 188 students aged 6-19 years living in Chivasso, Italy, and collected from them the following data: (1) one filled out questionnaire; (2) two respiratory measurements (i.e., spirometry and FOT); and (3) two urine tests for Cotinine (Cot) and 15-F2t-Isoprostane (15-F2t-IsoP) levels. We found a V-shape distribution for both Cotinine and 15-F2t-IsoP values, according to age groups, as well as a direct correlation (p = 0.000) between Cotinine and tobacco smoke exposure. These models demonstrate that tobacco smoke exposure, traffic, and the living environment play a fundamental role in the modulation of asthma-like symptoms (p = 0.020) and respiratory function (p = 0.007). Furthermore, the results from the 11-15-year group indicate that the growth process is a protective factor against the risk of respiratory disease later in life. Lastly, the FOT findings highlight the detrimental effects of tobacco smoke exposure and urbanization and traffic on respiratory health and asthma-like symptoms, respectively. Overall, monitoring environmental and behavioral factors in childhood can provide valuable information for preventing respiratory diseases in adulthood.

Depression is associated with poor control of symptoms in asthma and rhinitis: A population-based study.

BACKGROUND: Although many studies have highlighted the link between asthma/rhinitis and depression, it is still unclear which characteristics of these diseases are associated with the risk of depression. We aimed to explore the relationship between depression and asthma or rhinitis in a representative sample of the Italian general population. METHODS: The data were collected in GEIRD, an Italian multicenter, population-based, multicase-control study. 2227 participants (age 21-86 years, female 50%) underwent standardized interviews, skin prick and lung function tests, and were divided into cases of current asthma (n = 528), rhinitis without asthma (n = 972), and controls (n = 727). Two specific questions from the Patient Health Questionnaire (PHQ-2) were asked to identify symptoms of depressed mood and anhedonia, which were used as a proxy of major depression disorder. RESULTS: The prevalence of depression was 16.7%, 11.9%, and 5.1% in subjects with asthma, rhinitis and controls, respectively. Both in asthma and rhinitis, subjects with depression had worse respiratory-health related quality of life and more frequent disease-related symptoms than their non-depressed counterparts. In asthma, depression was associated with poorer disease control. In rhinitis, depression was significantly associated with a disease-related limitations in daily activities and greater risk of symptom exacerbations and prescriptions of medicines for breathing. Cases of rhinitis with depression were less likely to be atopic. CONCLUSIONS: Our results suggest that rhinitis exacerbations, particularly in non-atopic subjects, and low asthma control are strongly related to the presence of depressed mood in adults from the general population.

Bisphenol A, Tobacco Smoke, and Age as Predictors of Oxidative Stress in Children and Adolescents.

OBJECTIVES: The purpose of this study was to investigate bisphenol A (BPA) and its role in the induction of oxidative stress and confirm the same for tobacco smoke. METHODS: A total of 223 young, healthy students (7-19 years old) were recruited in Chivasso, Italy. A spot of urine of each subject was analyzed to quantify BPA, cotinine, and 15F2t-isoprostane. RESULTS: BPA showed a slight increase of concentration proportional with increasing age, even though the 11-14 years age group had slightly lower results, inducing a V-shape. The same trend was observed for 15F2t-isoprostane and cotinine. The result of piecewise linear robust regression shows a break point of the effect of BPA on 15F2t-isoprostane at 6 ng/mg CREA (p < 0.001). At higher levels, 15F2t-isoprostane shows an exponential increase by more than threefold for each one-log unit of BPA. An increase of oxidative stress due to BPA was observed, but only from 6 ng/mg of CREA up. Passive tobacco smoke is also able to induce an increase in oxidative stress. CONCLUSION: Prevention against BPA and passive tobacco smoke represents an important tool for promoting the highest health standard.

Socioeconomic status and biomedical risk factors in migrants and native tuberculosis patients in Italy.

Action on social determinants is a main component of the World Health Organization End Tuberculosis (TB) Strategy. The aim of the study was to collect information on socioeconomic characteristics and biomedical risk factors in migrant TB patients in Italy and compare it with data collected among Italian TB patients. A cross-sectional study was conducted among TB patients aged ≥18 years over a 12-months enrolment period in 12 major Italian hospitals. Information on education, employment, housing and income was collected, and European Union Statistics on Income and Living Conditions index was used to assess material deprivation. Among migrants, we also analyzed factors associated with severe material deprivation. Migrants were compared with younger (18-64 years) and older (65+ years) Italians patients. Out of 755 patients enrolled (with a median age of 42 years, interquartile range: 31-53), 65% were migrants. Pulmonary, microbiologically confirmed, and new cases were 80%, 73%, and 87% respectively. Prevalence of co-morbidities (i.e. diabetes, chronic kidney disease, neoplastic diseases and use of immunosuppressive drugs) was lower among migrants compared to Italian TB patients, while indicators of socioeconomic status, income and housing conditions were worst in migrants. Forty-six percent of migrants were severely deprived vs. 9% of Italians (p<0.0001, 11.3% and 5.5% among younger and older Italians, respectively). Among migrants, being male, older, irregular, unemployed, with a shorter time spent in Italy, a lower education level, and without a co-morbidity diagnosis were factors associated with severe material deprivation at multi-variable logistic regression. Moreover, socioeconomic indicators for Italian patients did not differ from those reported for the general Italian population, while migrant TB patients seem to have a higher prevalence of severe material deprivation than other migrants residing in Italy. Intervention to address the needs of this population are urgent.

Lung function changes from childhood to adolescence: a seven-year follow-up study.

BACKGROUND: As part of an investigation into the respiratory health in children conducted in Torino, northwestern Italy, our aim was to assess development in lung function from childhood to adolescence, and to assess changes or persistence of asthma symptoms on the change of lung function parameters. Furthermore, the observed lung function data were compared with the Global Lung Function Initiative (GLI) reference values. METHODS: We conducted a longitudinal study, which lasted 7 years, composed by first survey of 4-5 year-old children in 2003 and a follow-up in 2010. Both surveys consisted in collecting information on health by standardized SIDRIA questionnaire and spirometry testing with FVC, FEV1, FEV1/FVC% and FEF25-75 measurements. RESULTS: 242 subjects successfully completed both surveys. In terms of asthma symptoms (AS = asthma attacks or wheezing in the previous 12 months), 191/242 were asymptomatic, 13 reported AS only in the first survey (early transient), 23 had AS only in the second survey (late onset), and 15 had AS in both surveys (persistent). Comparing the lung function parameters observed with the predicted by GLI only small differences were detected, except for FVC and FEF25-75, for which more than 5% of subjects had Z-score values beyond the Z-score normal limits. Furthermore, as well as did not significantly affect developmental changes in FVC and FEV1, the decrease in FEV1/FVC ratio was significantly higher in subjects with AS at the time of follow-up (late onset and persistent phenotypes) while the increase in FEF25-75 was significantly smaller in subjects with persistent AS (p < 0.05). CONCLUSIONS: The GLI equations are valid in evaluating lung function during development, at least in terms of lung volume measurements. Findings also suggest that the FEF25-75 may be a useful tool for clinical and epidemiological studies of childhood asthma.

Adult lung function and long-term air pollution exposure. ESCAPE: a multicentre cohort study and meta-analysis.

The chronic impact of ambient air pollutants on lung function in adults is not fully understood. The objective of this study was to investigate the association of long-term exposure to ambient air pollution with lung function in adult participants from five cohorts in the European Study of Cohorts for Air Pollution Effects (ESCAPE). Residential exposure to nitrogen oxides (NO2, NOx) and particulate matter (PM) was modelled and traffic indicators were assessed in a standardised manner. The spirometric parameters forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) from 7613 subjects were considered as outcomes. Cohort-specific results were combined using meta-analysis. We did not observe an association of air pollution with longitudinal change in lung function, but we observed that a 10 µg·m(-3) increase in NO2 exposure was associated with lower levels of FEV1 (-14.0 mL, 95% CI -25.8 to -2.1) and FVC (-14.9 mL, 95% CI -28.7 to -1.1). An increase of 10 µg·m(-3) in PM10, but not other PM metrics (PM2.5, coarse fraction of PM, PM absorbance), was associated with a lower level of FEV1 (-44.6 mL, 95% CI -85.4 to -3.8) and FVC (-59.0 mL, 95% CI -112.3 to -5.6). The associations were particularly strong in obese persons. This study adds to the evidence for an adverse association of ambient air pollution with lung function in adults at very low levels in Europe.

Urban air and tobacco smoke as conditions that increase the risk of oxidative stress and respiratory response in youth.

BACKGROUND: Air pollution and tobacco smoke can induce negative effects on the human health and often leads to the formation of oxidative stress. OBJECTIVE: The purpose of this study was to clarify the role of the urbanization degree and of passive exposure to tobacco smoke in the formation of oxidative stress. Thus, a group of non-smoking adolescents was recruited among those who live and attend school in areas with three different population densities. To each subject a spot of urine was collected to quantify 15-F2t isoprostane as a marker of oxidative stress and cotinine as a marker of passive exposure to tobacco smoke. Furthermore, respiratory functionality was also measured. RESULTS: Multiple linear regression analysis results showed a direct correlation (p<0.0001) of 15-F2t isoprostane with both the urbanization and passive smoke. Lung function parameters proved significantly lower for the subjects living in the most populous city of Torino. CONCLUSION: This remarks the negative effect that urbanization has on the respiratory conditions. Lastly, lung functionality presented a low inverse correlation with 15-F2t isoprostane, suggesting an independent mechanism than that of the urban factor.

Socioeconomic inequalities in smoking habits are still increasing in Italy.

BACKGROUND: Socioeconomic inequalities in smoking habits have stabilized in many Western countries. This study aimed at evaluating whether socioeconomic disparities in smoking habits are still enlarging in Italy and at comparing the impact of education and occupation. METHODS: In the frame of the GEIRD study (Gene Environment Interactions in Respiratory Diseases) 10,494 subjects, randomly selected from the general population aged 20-44 years in seven Italian centres, answered a screening questionnaire between 2007 and 2010 (response percentage = 57.2%). In four centres a repeated cross-sectional survey was performed: smoking prevalence recorded in GEIRD was compared with prevalence recorded between 1998 and 2000 in the Italian Study of Asthma in Young Adults (ISAYA). RESULTS: Current smoking was twice as prevalent in people with a primary/secondary school certificate (40-43%) compared with people with an academic degree (20%), and among unemployed and workmen (39%) compared with managers and clerks (20-22%). In multivariable analysis smoking habits were more affected by education level than by occupation. From the first to the second survey the prevalence of ever smokers markedly decreased among housewives, managers, businessmen and free-lancers, while ever smoking became even more common among unemployed (time-occupation interaction: p = 0.047). At variance, the increasing trend in smoking cessation was not modified by occupation. CONCLUSION: Smoking prevalence has declined in Italy during the last decade among the higher socioeconomic classes, but not among the lower. This enlarging socioeconomic inequality mainly reflects a different trend in smoking initiation.

Yield of tuberculosis contact investigation in a low-incidence country.

BACKGROUND: Tuberculosis (TB) contact tracing is a valid public health measure to control the spread of TB infection in low-burden settings. The aim of this study was to assess the yield of the Piedmont TB contact investigation program and to evaluate the role of its main determinants. METHODS: The Piedmont TB notification systems were used to identify index TB cases. All cases were classified by contagiousness (sputum-smear-positive, AFB+; culture-positive, CULT+; other-than-defined). TB contacts were screened for active and latent TB infection by clinical manifestations and Tuberculin Skin Test (TST). RESULTS: 833 index TB cases with at least one contact were identified; 4441 contacts were screened, and 3942 (82.8%) were evaluated. TB contacts aged ≤ 35 years, regular and household contacts had a higher probability of being evaluated; foreign-born TB contacts were the least traceable. Higher rates of TB infection were observed in contacts at 35 years of age or younger who also lived in the same household with index cases or exposed to AFB+ or CULT+ index cases. CONCLUSION: More efforts should be focused on young TB contacts, since they are likely to be new infections. An early identification and treatment of TB Infection in this group contributes to the prevention and control of TB transmission. The program should also be extended to the contacts of CULT+ cases.

Oxidative stress in adolescent passive smokers living in urban and rural environments.

Purpose of this study was to study the oxidative stress status through the urinary 15-F(2t)-isoprostane (15-F(2t)-isoP) among a group of 168 adolescents, differently exposed to passive tobacco smoke. Subjects were enrolled, with written informed consent, between two populations of students living and attending school in two areas with different levels of urbanization in Piedmont Region, North-Western Italy. A general linear model (GLM) analysis was performed to evaluate the role of air pollution, dependent from selected degree of urbanization and of passive exposure to tobacco smoke, quantified through cotinine, in the synthesis of 15-F(2t)-isoP, measured with ELISA technique. Formaldehyde (FA) concentration in air was also evaluated as a primary confounding factor in oxidative stress but no significant differences between the two sites were found. Conversely, direct relationship between oxidative stress status and residence of adolescents was found: oxidative stress level was 31% higher for adolescents living in Chivasso (urban site) than for those living in Casalborgone (countryside area). Furthermore, also passive tobacco smoke exposure proved to play another important direct role in the distribution of 15-F(2t)-isoP levels (p<0.0001). Lastly, an inversely proportional relationship was found between the age of adolescents and 15-F(2t)-isoP (p<0.0001). Finally, the detection of such a sensitive biological response as a consequence of limited differences of environmental pollution and exposure to tobacco smoke passively breathed could provide new and useful knowledge for the appraisal of preventive strategies, particularly for young subjects.

Spirometry centile charts for young Caucasian children: the Asthma UK Collaborative Initiative.

RATIONALE: Advances in spirometry measurement techniques have made it possible to obtain measurements in children as young as 3 years of age; however, in practice, application remains limited by the lack of appropriate reference data for young children, which are often based on limited population-specific samples. OBJECTIVES: We aimed to build on previous models by collating existing reference data in young children (aged 3-7 yr), to produce updated prediction equations that span the preschool years and that are also linked to established reference equations for older children and adults. METHODS: The Asthma UK Collaborative Initiative was established to collate lung function data from healthy young children aged 3 to 7 years. Collaborators included researchers with access to pulmonary function test data in healthy preschool children. Spirometry centiles were created using the LMS (lambda, micro, sigma) method and extend previously published equations down to 3 years of age. MEASUREMENTS AND MAIN RESULTS: The Asthma UK centile charts for spirometry are based on the largest sample of healthy young Caucasian children aged 3-7 years (n = 3,777) from 15 centers across 11 countries and provide a continuous reference with a smooth transition into adolescence and adulthood. These equations improve existing pediatric equations by considering the between-subject variability to define a more appropriate age-dependent lower limit of normal. The collated data set reflects a variety of equipment, measurement protocols, and population characteristics and may be generalizable across different populations. CONCLUSIONS: We present prediction equations for spirometry for preschool children and provide a foundation that will facilitate continued updating.

[Obstructive lung disease prevalence estimated using a standard algorithm based on electronic health data in various areas of Italy]. / Stima della prevalenza di malattie polmonari cronico-ostruttive basata su dati sanitari correnti mediante un algoritmo comune in differenti aree italiane.

OBJECTIVE: development of an algorithm to estimate the prevalence of obstructive lung diseases (OLD) through record linkage of administrative health data sources in three Italian areas. SETTING: AULSS 12 Veneziana, city of Torino, ASL10 Firenze. PARTICIPANTS: all residents in the three areas in the period 2002-2004 (N = 1,944,471 on 30th June 2003). MAIN OUTCOME: crude prevalence, standardized prevalence with 95% confidence intervals. METHODS: the following data sources were used to identify OLD cases: hospital discharges (HD), health-tax exemptions (HTE), death causes (DC) and drug prescriptions (DP). All patients diagnosed with (from HD) or dead because of chronic bronchitis, emphysema and asthma have been included in the analysis. We defined as a prevalent case a subject found in each year in at least one of the four data sources. We reported the absolute and relative contribution of each information system by area, age, gender and year of interest. We performed a sensitivity analysis using more restrictive criteria to identify prevalent cases (two or more DPs per year). RESULTS: DP was the most relevantsource in identifying cases (from 86 to 88%). The relative contribution ofHD ranged from 3 to 5%. In 2003, standardized prevalence of OLD ranged from 5.35% in Firenze to 6.02% in Venezia. Venezia showed a higher prevalence in children aged 0-14years and a lower prevalence in older age groups (> 64 years) compared to other centers. Overall, the prevalence was higher among males. The use of more restrictive criteria in case identification substantially reduces the estimated prevalence, particularly in younger age-groups and to a lesser extent, in older age-groups. CONCLUSIONS: the algorithm provides estimates with differences between centres. The validity of this algorithm (in terms of sensitivity and positive predictive value) needs to be evaluated through further ad hoc studies.