Mario H. Vargas

Multidrug Resistant Pulmonary Tuberculosis Treatment Regimens and Patient Outcomes: An Individual Patient Data Meta-analysis of 9,153 Patients

Dick Menzies and colleagues report findings from a collaborative, individual patient-level meta-analysis of treatment outcomes among patients with multidrug-resistant tuberculosis.

Familial pulmonary fibrosis is the strongest risk factor for idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a lethal lung disorder of unknown etiology. The disease is likely the result of complex interactions between genetic and environmental factors. Evidence suggests that certain environmental factors, such as cigarette smoking and metal dust exposures, or comorbidities like gastroesophageal reflux, and type 2 diabetes mellitus (DM2) may increase risk to develop IPF. Substantial uncertainty remains, however, regarding these and other putative risk factors for IPF. In this study we performed a case-control analysis including 100 patients with IPF and 263 controls matched for age sex and place of residence. We used a structured questionnaire to identify potential risk factors for IPF, including environmental and occupational exposures as well as the relevance of family history of pulmonary fibrosis. The multivariate analysis revealed that family history of pulmonary fibrosis [OR = 6.1, CI95% 2.3-15.9; p < 0.0001] was strongly associated with increased risk of IPF. Actually, 20% of the cases reported a parent or sibling with pulmonary fibrosis. Gastroesophageal reflux [OR = 2.9, CI: 1.3-6.6; p = 0.007], former cigarette smoking [OR = 2.5, CI: 1.4-4.6, p = 0.003], and past or current occupational exposure to dusts, smokes, gases or chemicals [OR = 2.8, CI: 1.5-5.5; p = 0.002] were also associated with the disease. Despite being a significant risk factor on univariate analysis DM2 was not significant in multivariate analysis. These findings indicate that family history of pulmonary fibrosis is a strong risk factor for IPF. Also, we confirmed that occupational exposures, gastroesophageal reflux and former smoking increase the risk for this disease.

Sweat conductivity and chloride titration for cystic fibrosis diagnosis in 3834 subjects

Sweat test is the standard for cystic fibrosis (CF) diagnosis. Conductivity is an alternative method not yet approved, in spite of its good correlation with chloride concentration. The aim was to assess the capacity of sweat conductivity to discriminate between CF and non-CF subjects. Automated measurements of conductivity and chloride concentration were carried out on the same sweat samples from subjects with clinical suspicion of CF. Sweat samples from 3,834 subjects, median age 1.8 years (range 1 month-54 years) were analysed, and those with chloride titration >60 mmol/l were considered as CF patients (n=294). Conductivity median values in CF and non-CF subjects were 111 mmol/l (82-148) and 36 mmol/l (12-89), respectively. The Spearman correlation between chloride titration and conductivity was r=0.60 (P<0.001). The receiver operating characteristics (ROC) curve showed very high agreement between two methods. The best conductivity cut-off value to diagnose CF was > or =90 mmol/l (sensitivity 99.7%, specificity 100%, positive and negative predictive values of 100% and 99.97%, respectively, and kappa=0.998). Likewise, the best conductivity cut-off value to exclude CF was <75 mmol/l. The sweat conductivity method showed good correlation with chloride titration, and accurately discriminated between subjects with and without CF. In accordance with this, CF diagnosis might be confirmed for conductivity values > or =90 mmol/l and excluded for <75 mmol/l. Values between 75 and 89 mmol/l should correspond to an equivocal range. However, more studies are needed to confirm the role of conductivity in definitive CF diagnosis.

Risk factors for idiopathic pulmonary fibrosis in a Mexican population. A case-control study

The etiology of idiopathic pulmonary fibrosis (IPF) remains poorly understood, but some studies have suggested that cigarette smoking or other occupational or environmental exposures, diabetes mellitus, or gastroesophageal reflux may play a role. In this study we evaluated the clinical records of a group of 97 consecutive patients with IPF, and 560 patients suffering 5 different respiratory disorders that were examined as controls: asthma (n=111), chronic obstructive pulmonary disease (n=132), squamous cell lung carcinoma (n=118), lung adenocarcinoma (n=101) and patients with otorhinolaryngology problems but without lung disease (n=98). In bivariate analyses male sex, diabetes mellitus and being former cigarette smoker were associated with IPF. After adjusting by these variables, multivariate analysis revealed that type 2 diabetes mellitus [11.3% in IPF patients vs 2.9% in controls, OR=4.3 (95% CI: 1.9-9.8), p<0.0001] was an independent risk factor associated to IPF. Our results provide additional evidence of a putative relationship between DM2 and idiopathic pulmonary fibrosis. Experimental research is necessary for thorough assessment of the pathogenic mechanisms involved in this association.

Airway involvement in hypersensitivity pneumonitis.

Exposure to organic particles causes, in a susceptible host, diffuse inflammation of the lung acinus. However, immunopathologic response may not be confined to the alveoli and may also involve the large and peripheral airways. Therefore, after allergen inhalation a clinical spectrum of respiratory disorders may be observed, including hypersensitivity pneumonitis, asthma, chronic airway obstruction, and simple chronic bronchitis. Hypersensitivity pneumonitis is not a uniform disease but a complex syndrome, and the involvement of the airways may occur alone, simultaneously with, or after the parenchymal disease.

Drug resistance beyond XDR-TB: results from a large individual patient data meta-analysis

The broadest pattern of tuberculosis drug resistance for which a consensus definition exists is extensively drug-resistant tuberculosis (XDR-TB). It is not known if additional drug resistance portends worsened patient outcomes. This study compares treatment outcomes of XDR-TB patients with and without additional resistance to explore the need for a new definition. Individual patient data on XDR-TB outcomes were included in a meta-analysis comparing outcomes between XDR-alone and three non-mutually exclusive XDR-TB patient groups: XDR plus resistance to all the second-line injectables (sli) capreomycin and kanamycin/amikacin (XDR+2sli); XDR plus resistance to second-line injectables and to ≥1 Group 4 drug, i.e. : ethionamide/prothionamide, cycloserine/terizidone or PAS (XDR+sliG4); and XDR+sliG4 plus resistance to ethambutol and/or pyrazinamide (XDR+sliG4EZ). Of 405 XDR-TB cases, 301 were XDR-alone; 68 XDR+2sli; 48 XDR+sliG4; and 42 XDR+sliG4EZ. In multivariate analysis, the odds of cure were significantly lower in XDR+2sli (adjusted Odds Ratio (aOR): 0.4; 95% Confidence Interval: 0.2–0.8) compared to XDR-alone, while odds of failure+death were higher in all XDR patients with additional resistance (aOR range: 2.6–2.8). Patients with additional resistance beyond XDR-TB showed poorer outcomes. Limitations in availability, accuracy and reproducibility of current DST methods preclude the adoption of a useful definition beyond the one currently used for XDR-TB.The broadest pattern of tuberculosis (TB) drug resistance for which a consensus definition exists is extensively drug-resistant (XDR)-TB. It is not known if additional drug resistance portends worsened patient outcomes. This study compares treatment outcomes of XDR-TB patients with and without additional resistance in order to explore the need for a new definition. Individual patient data on XDR-TB outcomes were included in a meta-analysis comparing outcomes between XDR alone and three nonmutually exclusive XDR-TB patient groups: XDR plus resistance to all the second-line injectables (sli) and capreomycin and kanamycin/amikacin (XDR+2sli) XDR plus resistance to second-line injectables and to more than one group 4 drug, i.e. ethionamide/protionamide, cycloserine/terizidone or para-aminosalicylic acid (XDR+sliG4) and XDR+sliG4 plus resistance to ethambutol and/or pyrazinamide (XDR+sliG4EZ). Of 405 XDR-TB cases, 301 were XDR alone, 68 XDR+2sli, 48 XDR+sliG4 and 42 XDR+sliG4EZ. In multivariate analysis, the odds of cure were significantly lower in XDR+2sli (adjusted OR 0.4, 95% CI 0.2–0.8) compared to XDR alone, while odds of failure and death were higher in all XDR patients with additional resistance (adjusted OR 2.6–2.8). Patients with additional resistance beyond XDR-TB showed poorer outcomes. Limitations in availability, accuracy and reproducibility of current drug susceptibility testing methods preclude the adoption of a useful definition beyond the one currently used for XDR-TB.

Main diagnosis and cause of death in a neonatal intensive care unit: do clinicians and pathologists agree?

Aim: To determine the agreement rates between clinical and autopsy diagnoses in a neonatal intensive care unit (NICU), distinguishing between the main diagnosis and cause of death. Methods: Clinical and autopsy records of 75 infants who died in two consecutive years in the NICU (autopsy rate 42.6%) of a pediatric hospital in Mexico City were reviewed. Results: Ninety‐two percent of main clinical diagnoses were confirmed by autopsy. Four conditions (congenital cardiopathy, prematurity, specific congenital syndromes and hyaline membrane disease) accounted for more than two‐thirds of diagnoses. However, for cause of death, the global agreement was only 50%. The most common conditions considered by clinicians (77%) and pathologists (56%) to be the causes of death were cardiogenic, septic or mixed shocks. Additionally, clinicians omitted 34 relevant conditions in 30 (40.0%) patients, and 21 of these conditions possibly played a role in the deaths of 17 (22.7%) patients. The most frequently omitted diagnosis was pneumonia, in 9 (26.5%) patients. Omissions were not related to gestational age, age at death, days as an inpatient, or gender.

Values of Impulse Oscillometry in Healthy Mexican Children and Adolescents

BACKGROUND: The impulse oscillometry system (IOS) is increasingly used to evaluate lung function, but individual results must be compared with appropriate reference values. We aimed to obtain such reference values in Mexican children and adolescents. METHODS: Healthy subjects were recruited from kindergartens and schools after their parents signed a consent letter. Respiratory system impedances (Zrs), resistances (Rrs), and reactances (Xrs) were measured at 5, 10, 15, and 20 Hz, and the resonant frequency, reactance area, and difference between Rrs5 minus Rrs20 were also calculated. RESULTS: After exclusion of 4 children who were unable to perform an acceptable IOS recording, the final population comprised 283 children (153 females) 2.7–15.4 y of age. As a group, girls tended to have lower Xrs5 and higher Zrs20 and Rrs20 values. In bivariate analyses, all IOS variables had good correlation with age, height, and weight, and a better straight-line fitting was obtained through data transformation to the log10 (age) or reciprocal (height and weight) values. Comparison of regression lines revealed small differences between males and females, especially in Xrs. Multiple linear regression analysis identified height as the most influential variable in the majority of IOS variables, but age also accounted for a moderate-to-large influence in the regression models in many IOS variables. CONCLUSIONS: In this study, we generated reference equations for each IOS variable in healthy children and adolescents. Although these equations were generated in a Mexican population, they are probably also applicable in other Latin American populations with the same ethnic background.

Non‐quantal release of acetylcholine in guinea‐pig airways: role of choline transporter

In the resting state, motor neurons continuously release ACh through quantal and non‐quantal mechanisms, the latter through vesicular ACh transporter (VAChT) and choline transporter (ChT). Although in skeletal muscle these mechanisms have been extensively studied, the non‐quantal release (NQR) from parasympathetic neurons of airway smooth muscle has not been described. Here we corroborated that the organophosphate paraoxon (acetylcholinesterase inhibitor) induced a contraction blocked by atropine (muscarinic antagonist) in guinea‐pig tracheal rings. This contraction was not modified by two blockers of evoked quantal release, tetrodotoxin (voltage‐dependent Na+ channel blocker) and ω‐conotoxin GVIA (N‐type Ca2+ channel blocker), nor by the nicotinic blocker hexamethonium, suggesting that acetylcholine NQR could be responsible of the paraoxon‐induced contraction. We confirmed that tetrodotoxin, and to some extent ω‐conotoxin, abolished the evoked quantal ACh release induced by electrical field stimulation. Hemicholinium‐3 (ChT inhibitor), but not vesamicol (VAChT inhibitor), caused a concentration‐dependent inhibition of the response to paraoxon. The highest concentration of hemicholinium‐3 left ∼75% of the response to electrical field stimulation, implying that inhibition of paraoxon‐induced contraction was not due to depletion of neuronal vesicles. Non‐neuronal sources of ACh released through organic cation transporters were discarded because their inhibition by quinine or corticosterone did not modify the response to paraoxon. Calcium‐free medium abolished the effect of paraoxon, and NiCl2, 2‐aminoethyl diphenyl‐borate and SKF 96365 partly inhibited it, suggesting that non‐specific cation channels were involved in the acetylcholine NQR. We concluded that a Ca2+‐dependent NQR of ACh is present in cholinergic nerves from guinea‐pig airways, and that ChT is involved in this phenomenon.

Acetylcholine and tachykinins involvement in the caffeine‐induced biphasic change in intracellular Ca2+ in bovine airway smooth muscle

Caffeine has been widely used as a pharmacological tool to evaluate Ca2+ release from the sarcoplasmic reticulum in isolated smooth muscle cells. However, in nervous tissue this drug also causes neurotransmitters release, which might cause additional effects when smooth muscle strips are evaluated. To assess this last possibility, simultaneous measurements of contraction and cytosolic Ca2+ concentration (using Fura–2/AM) were carried out in bovine airway smooth muscle strips during caffeine stimulation. A first stimulation (S1, n=11) with caffeine (10 mM) induced a biphasic change in cytosolic Ca2+, which consisted of a transient Ca2+ peak (254±40 nM, X±SEM) followed by a plateau (92±13 nM), and a transient contraction (204.72±31.56 mg tension mg tissue−1). A second caffeine stimulation (S2) produced a similar response but these parameters had a different magnitude. The S2/S1 ratios for these parameters were 0.69±0.02, 0.83±0.06 and 1.01±0.03, respectively. Addition of ω‐conotoxin GVIA (1 μM) and tetrodotoxin (3.1 μM) before S2 significantly diminished these S2/S1 ratios (0.26±0.05, 0.26±0.09 and 0.64±0.11, respectively, n=5, P<0.05), implicating the neurotransmitters release involvement in the response to caffeine. A similar effect (P<0.01) was observed with atropine (1 μM, n=4), the fragment 4–11 of substance P (SP) (an SP receptor antagonist, 10 μM, n=5), and with both substances (n=4). We discarded a direct effect of ω‐conotoxin GVIA (1 μM) plus tetrodotoxin (3.1 μM) or of atropine (1 μM) plus SP fragment 4–11 on smooth muscle cells because they did not modify caffeine responses in isolated tracheal myocytes. We confirmed by HPLC that caffeine increased the release of acetylcholine (from 0.43±0.19 to 2.07±0.56 nM mg tissue−1, P<0.02) in bovine airway smooth muscle strips. Detection of substance P by ELISA was not statistically different after caffeine stimulation (geometric means before and after caffeine, 0.69 vs. 1.97 pg ml−1 mg tissue−1, respectively, P=0.053). We concluded that acetylcholine and tachykinins release are involved in the caffeine‐induced biphasic changes in cytosolic Ca2+ concentration.