Prolonged-release pirfenidone in patients with pulmonary fibrosis as a phenotype of post-acute sequelae of COVID-19 pneumonia. Safety and efficacy.

INTRODUCTION: One of the major concerns with post-acute sequelae of COVID-19 (PASC) is the development of pulmonary fibrosis, for which no approved pharmacological treatment exists. Therefore, the primary aim of this open-label study was to evaluate the safety and the potential clinical efficacy of a prolonged-release pirfenidone formulation (PR-PFD) in patients having PASC-pulmonary fibrosis. METHODS: Patients with PASC-pulmonary fibrosis received PR-PFD 1800 mg/day (1200 mg in the morning after breakfast and 600 mg in the evening after dinner) for three months. Blood samples were taken to confirm the pharmacokinetics of PR-PFD, and adverse events (AEs) were evaluated monthly using a short questionnaire. Symptoms, dyspnea, and pulmonary function tests (spirometry, diffusing capacity for carbon monoxide, plethysmography, and 6-min walk test [6MWT]) were evaluated at baseline, and one and three months after having started the PR-PFD treatment. RESULTS: Seventy subjects with mild to moderate lung restriction were included. The most common AEs were diarrhea (23%), heartburn (23%), and headache (16%), for which no modifications in the drug study were needed. Two patients died within the first 30 days of enrolment, and three opted not to continue the study, events which were not associate with PR-PFD. Pulmonary function testing, 6MWT, dyspnea, symptoms, and CT scan significantly improved after three months of treatment with PR-PFD. CONCLUSION: In patients with PASC pulmonary fibrosis, three months' treatment with PR-PFD was safe and showed therapeutic efficacy. Still, it remains to be seen whether the pulmonary fibrotic process remains stable, becomes progressive or will improve.

Identification of circulating miRNAs profiles that distinguish malignant pleural mesothelioma from lung adenocarcinoma.

Accurate diagnosis of malignant pleura mesothelioma (MPM) is challenging. Differential diagnosis of MPM versus lung adenocarcinoma (AD) is particularly difficult, yet clinically important since the two neoplasias call for different treatment approaches. Circulating miRNA-profiling to identify miRNAs that can be used to distinguish MPM from AD has not been reported. We conducted a wide screening study of miRNA profiles in serum pools of MPM patients (N = 11), AD patients (N = 36), and healthy subjects (N = 45) to identify non-invasive biomarkers for differential diagnosis of MPM and AD, using deep sequencing. Sequencing detected up to 300 known miRNAs and up to 25 novel miRNAs species in the serum samples. Among known miRNAs, 7 were upregulated in MPM and 12 were upregulated in AD compared to healthy controls. Of these, eight were distinctive for AD and three were unique for MPM. Direct comparison of the miRNA profiles for MPM and AD revealed differences in miRNA levels that could be useful for differential diagnosis. No differentially expressed novel miRNAs were found. Further bioinformatics analysis indicated that three upregulated miRNAs in MPM are associated with the p38 pathway. There are unique alterations in serum miRNAs in MPM and AD compared to healthy controls, as well as differences between MPM and AD profiles. Differing miRNA levels between MPM and AD may be useful for differential diagnosis. A potential association to p38 pathway of three upregulated miRNAs in MPM was revealed.

Level of asthma control and healthcare utilization in Latin America.

The purpose of this study was to investigate whether uncontrolled asthma was associated with healthcare outcomes among Latin American patients with asthma. We used data from 2168 patients with asthma who participated in the 2011 Latin America Asthma Insights and Management (AIM) survey. Using Global Initiative for Asthma (GINA) guidelines, patients were categorized as having asthma that was well-controlled, partly controlled, or uncontrolled. Overall, 7% of the patients surveyed had asthma that was classified as well-controlled. Patients whose asthma was not well-controlled were significantly more likely to report use of asthma medications (ORs ranging from 1.6-41) and to have had emergency healthcare visits or hospitalizations for their asthma in the previous year (ORs ranging from 2.1 to 5.9). They also reported decreases in their productivity compared to patients with well-controlled asthma. These associations suggest that emphasis on improving asthma control could have substantial effects on patient productivity and utilization of healthcare resources.

Cell proliferation kinetics and genotoxicity in lymphocytes of smokers living in Mexico City.

Genotoxicity caused by tobacco smoke was assessed in peripheral blood lymphocytes of smokers living in Mexico City by determining sister chromatid exchange (SCE), cell proliferation kinetics (CPK), replication index (RI) and mitotic index (MI). Nicotine levels, and its major metabolite cotinine, were also estimated in urine samples using gas-chromatography-mass spectrometry to quantify smoking intensity. The outcome of the analysis and the comparison of the 77-smoker group with a non-smoking control group showed that moderate and heavy smokers exhibited significant differences (P < 0.001 and P < 0.05, respectively) in CPK, with an underlying delay in the cellular cycle; similarly, RI was significantly different in these groups (P < 0.001 and P < 0.0001, respectively). There were significant correlations (P < 0.05) between age and number of years the subject had been smoking, as well as between RI and nicotine and cotinine levels and between CPK (M1, M2 and M3) and nicotine and cotinine levels. Smokers were classified for the analysis according to the nicotine levels (it is in relation to number of cigarettes smoked per day) found in urine (ng/mL) as: light (10-250), moderate (251-850) and heavy (851-4110). Significant differences in CPK were found (P < 0.05) between moderate and heavy smokers and non-smokers. Significant differences in RI were found between moderate (P < 0.001) and heavy smokers (P < 0.0001) and non-smokers, but not for the light smoking group. MI was determined in 57 of the smokers, whereas SCE frequency was only recorded in 34 smokers. Both parameters yielded no significant differences, nor correlations with any of the assessed variables. In conclusion, cytokinetic and cytostatic effects were mainly detected in heavy and moderate smokers. Cell cycle delay and RI decrease were found in all ;healthy' smokers. The nicotine and cotinine exposure (causing oxidative damage to DNA) may have implications in the decrease in cell replication due to direct damage to DNA and/or a decrease in the DNA repair mechanisms. Alternatively, nicotine and cotinine may possibly induce apoptosis.

Efficacy and safety of budesonide/formoterol in the management of chronic obstructive pulmonary disease.

The efficacy and safety of budesonide/formoterol in a single inhaler compared with placebo, budesonide and formoterol were evaluated in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD). In a 12-month, randomised, double-blind, placebo-controlled, parallel-group study in 812 adults (mean age 64 yrs, mean forced expiratory volume in one second (FEV1) 36% predicted normal), patients received two inhalations twice daily of either budesonide/formoterol (Symbicort) 160/4.5 microg (delivered dose), budesonide 200 microg (metered dose), formoterol 4.5 microg or placebo. Severe exacerbations and FEV1 (primary variables), peak expiratory flow (PEF), COPD symptoms, health-related quality of life (HRQL), mild exacerbations, use of reliever beta2-agonist and safety variables were recorded. Budesonide/formoterol reduced the mean number of severe exacerbations per patient per year by 24% versus placebo and 23% versus formoterol. FEV1 increased by 15% versus placebo and 9% versus budesonide. Morning PEF improved significantly on day 1 versus placebo and budesonide; after 1 week, morning PEF was improved versus placebo, budesonide and formoterol. Improvements in morning and evening PEF versus comparators were maintained over 12 months. Budesonide/formoterol decreased all symptom scores and use of reliever beta2-agonists significantly versus placebo and budesonide, and improved HRQL versus placebo. All treatments were well tolerated. These results suggest a role for budesonide/formoterol in the long-term management of moderate-to-severe chronic obstructive pulmonary disease.

Surfactant protein gene A, B, and D marker alleles in chronic obstructive pulmonary disease of a Mexican population.

Chronic obstructive pulmonary disease (COPD) is characterized by chronic inflammation. It is most likely the result of complex interactions of environmental and genetic factors. Because pulmonary surfactant components play important roles in normal lung function, innate host defence, and inflammation in the lung, this study investigated the hypothesis that the surfactant protein genes are involved in certain cases of COPD. Genotype analysis of surfactant protein (SP)-A, SP-B, SP-B-linked microsatellite, and SP-D marker alleles was performed in patients with COPD (n=97) and smoker (n=82) or nonsmoker (n=99) controls. Univariate and multiple logistic regression analyses were performed. The regression analysis results between COPD and smokers revealed several COPD susceptibility alleles (AA62_A, B1580_C, D2S388_5), based on an odds ratio (OR >2.5). The predictive ability of this model for developing COPD is good (c=0.926). Allele-allele (B1580_C and D2S388_5) and allele-environment (i.e. smoking) interactions were detected. When smoker controls were compared to nonsmoker controls, marker D2S388 5 appeared to be smoking-independent (p=0.874), whereas marker alleles AA62_A (p=0.045) and B1580_5 (p=0.007) were smoking-dependent. Males were at higher risk (OR=6.05, p=0.001), and smoking (>50 packs x yr(-1)) increased risk (OR=5.38, p=0.007). Males and alleles of loci flanking SP-B were associated with more severe cases (forced expiratory volume in one second/forced vital capacity < or = 40%). The present results indicate that the surfactant protein alleles may be useful in chronic obstructive pulmonary disease by either predicting the disease in a subgroup and/or by identifying disease subgroups that may be used for therapeutic intervention. These observations should now be confirmed in a larger study, designed according to strict epidemiological criteria.

[Severity of dyspnea during exercise: similarities and differences between patients with COPD or pulmonary fibrosis]. / Similitudes y diferencias en el grado de disnea durante el ejercicio en pacientes con EPOC y fibrosis pulmonar.

To understand the mechanisms leading to dyspnea during exercise and to identify possible predictive factors, we compared dyspnea at rest (baseline)and during exercise in 27 patients with chronic obstructive pulmonary disease (COPD) and 39 pulmonary fibrosis (PF) patients. We also compared spirometry and blood gases at rest and after exercise,which consisted of a 12-minute walking test (12 WT). Heart rate and oxygen saturation (SaO2) were recorded every two minutes during the 12 WT. Distance walked was also recorded. Although dyspnea changed during the 12 WT in both groups (p < 0.001),the maximum level of dyspnea reached in the two groups was not statistically different. COPD patients walked farther than did PF patients (782 +/- 182 m vs. 618 +/- 225 m, respectively;p = 0.002) and paused less often during the 12 WT than did PF patients(0.18 +/- 0.55 vs. 0.82 +/- 1.55, respectively; p <0.05). After adjusting for diagnosis, age, sex, baseline dyspnea,distance walked and pauses during the 12 WT, we found that only SaO2 was significantly related to severity of dyspnea during exercise. We conclude that there are important differences in degree of dyspnea experienced during exercise by COPD and PF patients and that SaO2 is the only variable that predicts severity of dyspnea.

Similitudes y diferencias en el grado de disnea durante el ejercicio en pacientes con EPOC y fibrosis pulmonar / Severity of dyspnea during exercise: similarities and differences between patients with COPD or pulmonary fibrosis

Con el objeto de entender los mecanismos de la disnea durante el ejercicio y posibles factores de predicción, evaluamos la disnea basal y en ejercicio en 27 pacientes con enfermedad pulmonar obstructiva crónica (EPOC) y 39 con fibrosis pulmonar. Además, se realizó una espirometría, una medición de gases arteriales en reposo y una caminata de 12 min (PC12). Durante la PC12 se midió la frecuencia cardíaca, la saturación de oxígeno (SaO2) cada 2 min y la distancia recorrida. Aunque hubo cambios en la disnea a lo largo de la prueba de ejercicio en ambos grupos (p < 0,001), el grado máximo de disnea no fue estadísticamente significativo entre los grupos estudiados. Los pacientes con EPOC recorrieron distancias mayores que los individuos con fibrosis pulmonar (782 ñ 182 y 618 ñ 225 m, respectivamente; p = 0,002) y evidenciaron un menor número de pausas durante la PC12 que los sujetos con fibrosis pulmonar (0,18 ñ 0,55 frente a 0,82 ñ 1,55, respectivamente; p < 0,05). Después de ajustar por diagnóstico, edad, sexo, disnea basal, distancia total recorrida y pausas en la PC12, sólo la SaO2 se asoció significativamente con el grado de disnea durante el ejercicio. En resumen, hay diferencias importantes en el grado de disnea durante el ejercicio entre pacientes con EPOC y fibrosis pulmonar, y la SaO2 es la única variable capaz de predecirla. (AU)

[Hypersensitivity pneumonitis in Mexico City]. / Neumonitis por hipersensibilidad en la ciudad de México.

OBJECTIVE: To investigate the association between the urban area of origin of patients and the prevalence of hypersensitivity pneumonitis (HP), induced by avian antigens. MATERIAL AND METHODS: A case-control study was conducted in 1999 at the National Institute of Respiratory Diseases (NIRD). Cases were 109 consecutive HP patients and controls were 184 patients: 39 with idiopathic pulmonary fibrosis (IPF), 63 with pulmonary tuberculosis (PTB), and 82 with asthma. Mexico City and surrounding counties (SC) were divided into 5 geographical areas: 1) Downtown; 2) North-East (NE); 3) South-East (SE); 4) North-West (NW) and 5) South-West (SW). Statistical analysis consisted of calculation of disease prevalence by urban area; associations were assessed with odds ratios and 95% confidence intervals. Multivariate analysis with multiple logistic regression was performed to adjust for age, gender and socioeconomic level. RESULTS: Eighty HP cases were located in the NE southernmost and SE northernmost areas of Mexico City (48 and 32, respectively) (OR = 3.86; 95% CI 2.17-6.96). Thirty-six controls with asthma came from the SW area, (where NIRD is located) (p < 0.05), and four from SC. Controls with PTB and IPF were scattered throughout the study area. CONCLUSIONS: The NE southernmost and SE northernmost areas were associated with HP. The cause of HP may not be geographical; a garbage dump used to be located in this area, suggesting that exposure to organic particles might contribute to the development of HP in susceptible individuals.

[Smoking among Mexican physician. A comparative analysis with smokers who are not physicians]. / Tabaquismo en médicos mexicanos. Un análisis comparativo con fumadores que no son médicos.

OBJECTIVES: To determine prevalence, addiction knowledge and attitude on tobacco smoking in a group of smoking physicians (MF) and to compare these variables with smoking non-physicians (FNM) and non-smoking physicians (MNF) from the National Institutes of Health in Mexico (Insalud). MATERIAL AND METHODS: The results of a questionnaire among the three groups were compared. RESULTS: The prevalence of MF (22%) was significantly lower than in FNM (28%), (OR = 0.72, CI = 0.61-0.85). No significant differences regarding addiction and attitudes were found between them. The MNF had better knowledge and attitudes and agreed that their Institute should be a non-smoking area. CONCLUSION: Prevalence of smoking is lower among physicians than among FNM and the similarities between them suggest that addiction can provoke them and that a program for tobacco control is required.

Prevalence of cigarette smoking among employees of the Mexican National Institutes of Health.

OBJECTIVE: To determine the prevalence of cigarette smoking at the National Institutes of Health in Mexico (NIHM). MATERIAL AND METHODS: A survey was performed among workers who voluntarily answered a questionnaire. Smokers were identified with two specific questions, and type of employment was classified as physicians, administrative staff, investigators and support personnel. RESULTS: Total prevalence smoking was 28% (of 4,422 answered questionnaires). It was significantly higher among females, among administrative staff, and common-law and separated workers. It was significantly higher at the Mexican Institute of Psychiatry than at the remaining Institutes, even after adjusting for confounding. The prevalence was also higher among physicians from the same Institute. Of the smokers, 46% do so in their work areas and 78% of them would like to quit. CONCLUSIONS: The prevalence of smokers at the NIHM is as high as in the general population and a broad educational program for tobacco control and prevention is needed.

Colchicine, D-penicillamine, and prednisone in the treatment of idiopathic pulmonary fibrosis: a controlled clinical trial.

STUDY OBJECTIVE: We compared the long-term efficacy of the combination of colchicine and/or D-penicillamine with prednisone, in comparison to prednisone alone in patients with idiopathic pulmonary fibrosis (IPF). DESIGN: Nonrandomized prospective study in patients with IPF confirmed by biopsy specimen. SETTING: National Institute of Respiratory Diseases, Mexico. PATIENTS: Fifty-six IPF patients were included in this study. Patients received either colchicine/ prednisone (n=19), D-penicillamine/prednisone (n=11), D-penicillamine/colchicine/prednisone (n=11), or prednisone alone (n=15). Prednisone therapy was started at 1.0 mg/kg/d for 1 month followed by a biweekly taper to a maintenance dose of 15 mg/d. Colchicine was administered at a daily dose of 1.0 mg, and D-penicillamine was given at a daily dose of 600 mg. MEASUREMENTS AND RESULTS: Response to therapy was assessed by changes in lung function test results as measured by total and vital lung capacities, arterial blood gas analysis at rest breathing room air, and survival. No significant differences either in lung mechanics or in arterial gases were found in any group relative to the baseline measurement. Thirteen of the 56 patients died during the first 2 years, and 29 were dead at 5 years follow-up. Comparison of survival curves by Cox regression model showed no statistically significant difference among the four groups. Known side effects attributable to prednisone were more common and severe than those attributable to the other drugs. CONCLUSIONS: Our results suggest that neither colchicine nor D-penicillamine modified the progressive course of prednisone-treated IPF, and that the search for new drugs is imperative.

Utility of a provocation test for diagnosis of chronic pigeon Breeder's disease.

Chronic hypersensitivity pneumonitis (CHP) can be difficult to differentiate from other interstitial lung diseases (ILD). To determine the diagnostic usefulness of a provocation test (PT), 17 patients with CHP induced by avian antigens, 17 with other ILD, and five healthy control subjects were challenged with pigeon serum. After PT, an increase in body temperature (BT) and a decrease in FVC, PaO2 and SaO2% were observed in all patients with CHP and in three with ILD. No reaction was noticed in healthy subjects. ROC curves showed that for FVC the best cut point was a drop of 16% displaying sensitivity (S): 76%, specificity (SP): 81%, positive predictive value (PPV): 81%, and negative predictive value (NPV): 83%. For a drop of 3 mm Hg in PaO2 or 3% SaO2, S was 88% for both, SP was 82 and 86%, PPV was 81 and 82%, and NPV was 82 and 86%, respectively. An increase of BT > 0.5(o) C showed S, 100%; SP, 82%; PPV, 100%; NPV, 86%. A univariate regression analysis confirmed that changes in BT and FVC are predicting values of CHP: RR, 82.5 (CI, 10.43 to 651.76) and 1.21 (CI, 1.06 to 1.36). There were no challenge test complications. These findings suggest that PT is a useful tool for diagnosis of CHP.

Consenso Latinoamericano sobre infecciones en bronquitis crónica / Latin American consensus on infections in chronic bronchitis

Dos tercios de las exacerbaciones agudas de la bronquitis crónica (EABC) se asocian con infección bacteriana y se caracterizan por recrudecimiento súbito de la tos, disnea y aumento en el volumen y el aspecto purulento del esputo. Las infecciones bacterianas crónicas o recurrentes, inician y perpetúan un círculo vicioso de daño a las vías aéreas, que se produce mediante la estimulación persistente de la cascada inflamatoria por los productos bacterianos. De los microorganismos causales, el más común es H. influenzae. Otros patógenos frecuentes incluyen M. catarrhalis, la mayoría resistentes a aminopenicilinas y S. Pneumoniae, el cual ha incrementado recientemente a su resistencia a penicilinas y macrólidos a nivel orbital. Si bien algunos estudios recientes han demostrado de manera clara el beneficio del tratamiento antibiótico de los EABC, existen ciertas dudas relacionadas con la manera de clasificar la enfermedad y con los criterios utilizados para la inclusión y exclusión de los pacientes, que permitan esclarecer de manera definitiva el beneficio del antimicrobiano en cada uno de los grupos en los que se ha clasificado su severidad. Con el fin de lograr un consenso sobre algunas de estas variables y establecer lineamientos racionales que permitan abordar el tratamiento de estos pacientes, se reunieron recientemente (noviembre del 96 y marzo del 97) un grupo de destacados expertos latinoamericanos en infectología y neumología. El consenso identificó una serie de factores de riesgo que permitieron diseñar una clasificación de EABC que establece cuatro grados de severidad; estos a su vez están relacionados con un grupo específico de microorganismos que varían con las circunstancias y desde luego en la sensibilidad a los antibióticos. Asimismo el grupo de expertos estableció que la resistencia de los gérmenes que comúnmente afectan a estos enfermos (H. influenzae, S. pneumoniae y M. catarrhalis) requieren de antimicrobianos que sean activos contra más del 90 por ciento de las cepas causantes. Como lineamientos prácticos terapéuticos, se sugirió que la traqueobronquitis aguda (clase I) no requiere en general de antibióticos; que la amoxicilina permanece como el tratamiento de elección para las exacerbaciones leves (clase II), mientras que para la bronquitis crónica complicada (clase III), algunas fluoroquinolonas (p.ej.: ciprofloxacina), los nuevos macrólidos, combinaciones con inhibidores de betalactamasa o cefalosporina orales de 3º generación...

Relationship of alveolar macrophage plasminogen activator and elastase activities to lung function and CT evidence of emphysema.

OBJECTIVE: To evaluate the relationship between alveolar macrophage (AM) elastase and plasminogen activator (PA) activities (considered to be potential pathogenetic factors in emphysema) and the development of emphysema in smokers. PARTICIPANTS: Thirty-four healthy smokers >35 years of age (mean+/-SD, 46+/-7 years), with a mean+/-SD of 33+/-10 pack-years of smoking, who were recruited as volunteers. METHODS: Subjects had lung function testing and BAL to obtain AMs; limited high-resolution CT scans of the chest were obtained in 32 subjects to assess the presence of emphysema. Macrophage PA and elastase were determined using AM cultured on (131)I-fibrin-coated plates and 3H-elastin-coated plates, respectively. RESULTS: The number of AMs recovered per milliliter of BAL was significantly greater in the 16 subjects with CT evidence of mild emphysema than the 16 subjects without evidence of emphysema (669+/-301 x 10(3)/mL vs 414+/-268x 10(3)/mL; p=0.01). There was no significant difference between AM elastase or PA activities in the 16 subjects with CT evidence of mild emphysema, when compared with the 16 subjects who had no CT evidence of emphysema (elastase, 2.72+/-1.35 microg vs 2.49+/-0.91 microg elastin per 10(6) AMs per first 24 h; PA, 0.375+/-0.126 vs 0.344+/-0.096 urokinase units/10(6) AMs). There was no significant correlation between levels of PA or elastase activities and FEV1, FEV1/FVC, forced expiratory flow rate between 25% and 75% of the FVC; PA activity but not elastase activity had a significant negative correlation (r=-0.47, p<0.01) with diffusion of carbon monoxide (DCO). The macrophage count in BAL had a significant negative correlation with DCO percent predicted (r=-0.61, p<0.001). CONCLUSIONS: The findings suggest that the number of AMs recovered per milliliter of BAL (presumably indicating the number in the alveolar spaces) is related to the development of emphysema in smokers as indicated by CT scan of the chest and DCO. The results also suggest that the level of PA enzyme activity in AMs may be a pathogenetic factor in the decrease in DCO in smokers.