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.

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.

[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.

[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.

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.

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.

Effect of exposure of guinea pigs to cigarette smoke on elastolytic activity of pulmonary macrophages.

STUDY OBJECTIVE: To determine the effect of exposure to cigarette smoke on the elastolytic activity of guinea pigs' alveolar macrophages (AMs), and to compare elastolytic activity of AMs obtained by BAL with that of lung macrophages (LMs) obtained from minced lung tissue. METHODS: AMs were obtained by BAL from seven adult guinea pigs exposed to cigarette smoke for 5 d/wk during 6 weeks, as well as from age-matched control guinea pigs. From each animal, one lung was used to obtain LMs by mincing and teasing the lung, followed by enzymatic digestion and isolation of mononuclear cells by Hypaque-Ficoll separation. The other lung was inflated and fixed to quantitate emphysema by the destructive index (DI). Elastolytic activity (microgram of elastin degraded by 10(6) macrophages) was determined at 24, 48, and 72 h, by culturing AMs and LMs (1 x 10(6) cells in 1 mL of medium) in 3H-elastin-coated wells. RESULTS: In animals exposed to cigarette smoke, the total number of BAL cells (8.6+/-2.1 x 10(6)) and DI (21.8+/-8.1) were significantly higher than in nonexposed animals (6.4+/-1.8 x 10(6), p<0.05 for cells, and 12.1+/-4.1, p<0.01 for DI). Elastolytic activity of AMs from smoke-exposed guinea pigs was significantly higher at 24, 48, and 72 h than elastolytic activity of AMs from control animals (19.0+/-9.4 vs 10.0+/-5.3, p<0.05 at 72 h). Likewise, elastolytic activity of LMs was significantly higher in exposed than nonexposed guinea pigs (11.8+/-7.7 vs 7.4+/-5.0 at 72 h, p<0.05). Elastolytic activity of LMs was not significantly different from elastolytic activity of AMs, both in exposed guinea pigs (11.8+/-7.7 vs 19.0+/-9.4 at 72 h) and nonexposed animals (7.4+/-5.0 vs 10.0+/-5.3 at 72 h). CONCLUSIONS: These results indicate that elastolytic activity of both AMs and LMs of guinea pigs increases significantly after exposure to cigarette smoke and that AMs and LMs have similar elastolytic activities.

Correlation between pulmonary fibrosis and the lung pressure-volume curve.

The severity of pulmonary fibrosis is the main prognostic factor for survival of patients with interstitial lung diseases (ILD). Unfortunately, lung biopsy, which is the best method to assess fibrosis quantitatively, is done only once during the evolution of the disease. In this study we analyzed the relationship between the degree of fibrosis and the exponential constant k, derived from the lung pressure-volume curve (LPVC) in 33 patients with chronic ILD, 19 with pigeon breeder's disease (PBD), and 14 with idiopathic pulmonary fibrosis (IPF). Pulmonary function tests, including the LPVC, were obtained before biopsy. A semiquantitative histologic assessment of the severity of fibrosis was performed on lung tissues. All patients showed a decrease of total lung capacity, residual volume, compliance, and Pao2. The mean value of the constant k was 0.08 +/- 0.06. When expressed as a percent of normal values, 25 patients exhibited values of k lower than 70% of predicted; of the remaining 8 patients whose values were above 70% of predicted, 7 had PBD and only one IPF. On morphologic analysis, 19 patients displayed more than 50% fibrosis. No significant correlations were found between the extent of the lesion or severity of lung fibrosis and the conventional pulmonary function tests. By contrast, a moderate but significant correlation was found between k and the severity of lung fibrosis (r = -0.38, p < 0.05). These findings show that the shape of the LPVC, represented by the constant k, predicts the degree of lung fibrosis and could be useful in the clinical assessment and follow-up of patients with ILD.

The effect of menstruation on the pulmonary carbon monoxide diffusing capacity.

We studied variations in DLCO during the menstrual cycle in 14 healthy women with a mean age of 29 (SD, 7) yr. Eight were using oral contraceptives, and six were not. DLCO was determined 1 to 7 d before the onset of menses, daily during each of the first 4 d of menses, and 5 to 10 d after onset of menses. In both groups of subjects, the highest values for DLCO were obtained before menses, the lowest were on the third day of menses, whereas after completion of menses the values increased but were not as high as prior to menses. The mean DLCO for all subjects was 23.1 (SD, 3.2) ml/min/mm Hg before menses, 20.9 (SD, 3.0) on the third day of menstruation, and 21.6 (SD, 3.3) 5 to 10 d after onset of menses. The mean percent difference between DLCO before and on the third day of menses in all 14 subjects was 9.2 (SD, 4.4) %. There were no significant changes in hemoglobin on these days to account for the changes in DLCO. Pulmonary capillary blood volume determined in 10 of the subjects did not show a significant change. It is concluded that DLCO can vary significantly during the menstrual cycle, with the highest values occurring prior to menses and the lowest values occurring on the third day of menses, with a mean difference between them of 9%. These variations need to be considered when evaluating DLCO in female patients in the menstrual age group.

Reversal of digital clubbing after lung transplantation.

Digital clubbing is a common sign in a variety of lung diseases. Although its pathogenesis remains unclear, it is known that the degree of clubbing might vary and even disappear, particularly when the underlying disease is a malignant neoplasm that has been removed. By contrast, because of the short expectancy of life in patients with pulmonary fibrosis, it is unusual to observe regression of clubbing. In this work, we report a case of reversible clubbing after lung transplantation.

Acute effect of cigarette smoking on the carbon monoxide diffusing capacity of the lung.

To determine the acute effect of smoking on DLCO, we studied 12 smokers (mean age, 36 yr; range, 19 to 52 yr, six men and six women) before and after they had smoked as many cigarettes as they could (mean, 6.0; SD, 1.9) over a period of 1 h. Blood COHb was estimated using a rebreathing-breathholding technique after a vital capacity inhalation of O2. Capillary blood volume (VC) was determined from DLCO performed at inspired O2 concentrations of 25 and 90%. DLCO (in ml/min/mm Hg) corrected for COHb back pressure decreased from 22.5 (SD, 6.6) before smoking to 21.0 (SD, 6.6) after smoking (p = 0.003). After correction for the "anemia effect" of COHb, DLCO still significantly decreased, from 22.8 (SD, 6.3) before smoking to 21.8 (SD, 6.4) after smoking p = 0.01). VC (corrected for the reduction in hemoglobin by COHb) was 52.0 (SD, 20.1) ml before smoking and 46.4 (SD, 22.7) ml after smoking; this difference did not achieve statistical significance (p = 0.056). There was no significant change in DLCO or VC in six control subjects tested before and after 1 h of sham smoking of an unlit cigarette. In 12 control subjects studied before and after inhalation of 0.1% CO to result in mean COHb levels of 10.6% (SD, 1.4%), there was a slight but significant decrease in VC (mean change, 21%) and in DLCO (mean change, 4%) after correction for COHb back pressure and reduction in available hemoglobin, suggesting that CO inhalation may have a direct effect on DLCO by reducing VC.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of smoking cessation on pulmonary carbon monoxide diffusing capacity and capillary blood volume.

We studied 16 smokers, with a mean age of 41 yr (SD, 12 yr) and a mean DLCO of 81% predicted (SD, 19%), before and after smoking cessation. Two subjects were able to stop smoking for only 24 h, whereas 14 subjects abstained for 1 wk, 11 for 1 month, and five for 3 months. The initial mean DLCO in ml/min/mm Hg was 18.9 (SD, 4.6) after correction for COHb back pressure and the reduction in hemoglobin because of COHb. A week after smoking cessation there was a significant increase in DLCO, to 20.8 (SD, 5.4), p = 0.001. There was no further increase in DLCO at 1 month or at 3 months. In four subjects tested while they were still smoking and 24 h after smoking cessation, there was a significant increase in DLCO after correction for COHb, from 17.4 (SD, 1.5) to 19.8 (SD, 1.3), p = 0.02. These results indicate that after smoking cessation there is a rapid improvement in DLCO, suggesting that smoking had previously decreased DLCO. However, there may also be an irreversible component to the reduction of DLCO in some of the subjects in whom the DLCO remained abnormal even after continued smoking cessation for 1 month.