Isoniazid preventive treatment: predictors of adverse events and treatment completion.

SETTING: Villa Marelli Institute (VMI), Niguarda Ca'Granda Hospital, Milan, Italy. BACKGROUND: A recent report on the fatal side effects of isoniazid preventive therapy (IPT) from the United States has re-ignited discussion on the safety of this intervention. OBJECTIVE: To evaluate IPT feasibility, treatment completion and adverse events (AE) and their determinants under field conditions. METHODS: Data from consecutive subjects undergoing IPT at the VMI were recorded in an electronic database from 1992 to 2009. Logistic regression analysis was performed to detect completion and AE determinants. RESULTS: A total of 11,963 patients were included in the study. AE (odds ratio [OR] 2.70, 95%CI 2.22-3.28) and human immunodeficiency virus positive status (OR 5.20, 95%CI 2.10-12.93) were the main determinants of treatment interruption among Italians, while social weakness (no housing/job; OR 2.88, 95%CI 2.43-3.42), AEs (OR 1.33, 95%CI 1.15-1.53, 2.22-3.28) and screening in undocumented subjects (OR 1.20, 95%CI 1.01-1.44) prevailed among foreigners. Age was the main determinant of transaminase increase (OR 1.03, 95%CI 1.03-1.04), as were AEs of the gastrointestinal (OR 1.02, 95%CI 1.02-1.03), central nervous (OR 1.02, 95%CI 1.02-1.05) and peripheral nervous systems (OR 1.04, 95%CI 1.02-1.05). CONCLUSION: This analysis demonstrates the feasibility and safety of IPT, with determinants of interruption and AEs being predictable and addressable.

Administration of a negative vaccination induces hyporesponsiveness to islet allografts.

As a result of less than optimal outcomes the use of islet allografts as a standard insulin replacement therapy is limited to adults with a history of extreme glucose dysregulation and hypoglycemia unawareness. In this study, we examined the use of prophylactic immunotherapy to prevent islet allograft rejection in the absence of antirejection drugs. Our protocol to achieve allograft acceptance used a negative vaccination strategy that is comprised of apoptotic donor cells delivered in Incomplete Freund's Adjuvant (IFA) 1 week prior to islet transplantation. The goal of this new protocol is to elicit hyporesponsiveness to alloantigen prior to islet transplantation. First, we examined our protocol without islet allograft transplants and determined that the negative vaccination was not globally immunosuppressive or immunostimulatory. Islet allograft experiments using fully MHC-mismatched islet donors and recipients demonstrated that the negative vaccination strategy induced long-term islet allograft acceptance. Upon rechallenge with alloantigen, the negative vaccination protocol successfully achieved hyporesponsiveness. In addition, the microenvironment at the site of the tolerant allograft revealed a decrease in proinflammatory mediators (IFN-γ, TNF-α) and an increase in the anti-inflammatory mediator IL-10, as well as increased expression of the master regulator of T-regulatory cells, FOXP3. Our data suggest that pretreating allograft recipients with apoptotic donor alloantigen delivered in IFA induced long-term islet allograft acceptance and glycemic control by introducing alloantigen to the recipient immune system in a nonimmunostimulatory manner prior to transplant.

Respiratory changes during defecation in patients with chronic respiratory failure.

Oxygen (O2) desaturation may occur in patients affected by respiratory diseases during daily activities, although most of these activities, e.g. walking, washing and cooking, can be avoided or eventually performed with an external aid. In this prospective study, the respiratory changes induced by the mandatory effort of defecation were assessed in patients with chronic respiratory insufficiency. Twenty-four consecutive patients with chronic respiratory failure due to obstructive or restrictive pulmonary disorders, showing a marked O2 desaturation during the 6-min walk test, were enrolled. Thirteen of them were already established on long-term O2 therapy (LTOT), while 11 were not. O2 saturation (Sa,O2), respiratory rate (RR), cardiac frequency (fC) and dyspnoea were measured at rest, and during and after defecation. Sa,O2 decreased significantly during defecation, while RR, fC and dyspnoea increased, both in the subgroup of patients without significant resting hypoxaemia and in the subgroup of patients receiving their usual resting flow of LTOT, as compared to resting values. In conclusion, the respiratory system of patients with chronic respiratory failure may be significantly strained by defecation.

Effect of varying the pressurisation rate during noninvasive pressure support ventilation.

The aim of the study was to assess the effects of varying the pressurisation rate during noninvasive pressure support ventilation on patients' breathing pattern, inspiratory effort, arterial blood gases, tolerance to ventilation and amount of air leakage. A total of 15 chronic obstructive pulmonary disease patients recovering from an acute episode of hypercapnic acute respiratory failure were studied during four randomised trials with different levels of pressurisation rate. No significant changes were observed in breathing pattern and arterial blood gases between the different runs. The pressure time product of the diaphragm, an estimate of its metabolic consumption, was significantly lower with all pressurisation rates than with spontaneous breathing, but was significantly lowest with the fastest rate. However, air leak, assessed by the ratio between expired and inspired tidal volumes, increased and the patients' tolerance of ventilation, measured using a standardised scale, was significantly poorer with the fastest pressurisation rate. In chronic obstructive pulmonary disease patients recovering from an episode of acute hypercapnic respiratory failure and ventilated with noninvasive pressure support ventilation, different pressurisation rates resulted in different reductions in the pressure time product of the diaphragm; this reduction was greater with the fastest rate, but was accompanied by significant air leaks and poor tolerance.

Immunocytological and mineralogical study of bronchoalveolar lavage in a group of subjects exposed to asbestos.

Twenty-five subjects (24 males and 1 female, mean age 57.4 years) who have been exposed to asbestos underwent chest radiography, high resolution computed tomography (HRCT) of the chest, lung function tests and bronchoalveolar lavage (BAL) for evaluation of cell components (total cell count, percentages of macrophages, lymphocytes, neutrophil and eosinophil granulocytes and the lymphocyte subpopulations CD3+, CD4+, CD8+, CD19+ and HLADR+), soluble factors (IL-8, IL-10, IL-12 and MCP-1 in the supernatant) and concentration of asbestos fibre. The subjects were subdivided according to the degree of their exposure, to the concentration of asbestos fibres in the BAL and to chest X-ray findings using the I.L.O. classification (0/0pl, 0/1 and 1/0 and above). According to the exposure index, we showed statistically significant (p < 0.05) higher lymphocytes percentage in the BAL of subjects with moderate exposure and significantly higher levels of IL-10 (p < 0.05) in the supernatant of subjects showing an absence of asbestos fibres in their BAL. In the group of subjects with a 0/0 and 0/1 radiological profile, the cellular component of the BAL was characterised by a higher percentage of lymphocytes (p < 0.02), whereas a trend toward an increase in the number of neutrophils was noted in subjects with obvious pulmonary fibrosis. The percentage of neutrophils was inversely correlated with some parameters of respiratory function such as vital capacity (p = 0.03) and the partial pressure of oxygen (p = 0.05) in the blood. Investigating the cytokines in the supernatant of the BAL, we found a trend toward lower concentration of IL-10 in the group showing the worst radiological picture (I.L.O. > or = 1/0), and a statistically significant negative correlation between this cytokine and pO2 (p = 0.048). Concerning the other cytokines and chemokines studied (MCP-1, IL-8 and IL-12), no significant differences were found to be associated with the radiological profiles. There were, however, positive correlations between the concentration of IL-8 and the percentage of neutrophils (p = 0.038) and between the concentration of MCP-1 and the percentage of lymphocytes (p = 0.006). A negative relationship between the concentrations of IL-12 and IL-10 has been also observed (p = 0.028). This research allows us to hypothesise that IL-10 may have a pathogenetic role in the evolution of asbestosis.

Orthopnea and inspiratory effort in chronic heart failure patients.

STUDY OBJECTIVE: Orthopnea is a typical feature of patients with chronic heart failure (CHF), the factors contributing to it are not completely understood. We investigated changes in dyspnea and other respiratory variables, induced by altering posture (from sitting to supine) in 11 CHF patients (NYHA classes II-IV) and 10 control subjects. METHODS AND RESULTS: We measured dyspnea (Borg scale) the diaphragm pressure time product per minute (PTPdi/m, index of metabolic consumption), and mechanical properties of the lung (lung compliance (C,L) and resistances (R,L). CHF patients also underwent a trial of non-invasive mechanical ventilation (NIMV) in the supine position in order to ascertain whether unloading the inspiratory muscles could somehow relieve dyspnea. While sitting the PTPdi/min was significantly higher in CHF patients than in controls (181 +/- 54 cm H2O x s/min vs. 96 +/- 32; P<0.05). Assuming a supine position caused no major changes in controls, whereas CHF patients showed a significant worsening in dyspnea, a rise in PTPdi/min (243 +/- 97 p<0.01) and R,L (4.7 +/- 1.2 cm H2O/L x s sitting vs. 7.9 +/- 2.5 supine; P<0.01) and a decrease in C,L (0.08 +/- 0.02 L/cm H2O sitting vs. 0.07 +/- 0.01 supine; P<0.05). Applying NIMV to supine CHF patients significantly reduced the PTPdi/min to 81 +/- 42 (P<0.001). Changes in dyspnea, produced by varying position or applying NIMV, were significantly correlated with PTPdi/min (r=0.80, P<0.005 and r=0.58, P<0.01, respectively). CONCLUSIONS: CHF patients had a higher PTPdi/min than controls when sitting, and assuming a supine position induced severe dyspnea, a large rise in R,L, and a reduction in C,L so that PTPdi/min increased further. Orthopnea was strongly correlated with the increased diaphragmatic effort.

Sudden improvement of respiratory failure in a woman with carcinoma of the colon.

We present a case of bronchial and endotracheal metastases completely blocking the left main bronchus and partially occluding the middle lobe bronchus contributing to severe respiratory failure. The patient's lack of consent to laser resection of the mass led to the use of chemotherapy; after the first cycle of treatment a neoplastic mass about 3 cm long was spontaneously expelled with a cough. The expulsion of the metastasis caused rapid improvement of the dyspnea and gas exchange; however, the continuation of the chemotherapy did not bring any further benefit to the patient, who died 115 days after diagnosis.

Acute exacerbations of COPD: is inflammation central to prevention and treatment strategies?

Acute exacerbations (AE) represent one of the hallmarks of Chronic Obstructive Pulmonary Disease (COPD). They are characterised by increased from baseline dyspnoea, cough and sputum production and/or purulence, variably associated with fever and systemic symptoms. As in stable COPD, airway inflammation is an important part of the disease underlying the clinical manifestations. Studies on airway inflammation in AE by means of invasive methodologies (e.g. fiberoptic bronchoscopy with bronchial biopsy and/or bronchoalveolar lavage) are difficult due to clinical, practical and ethical issues. New and less- (sputum) or non-invasive methodologies (exhaled markers) are becoming increasingly applied also to the study of AE in COPD. The overall data on airway inflammation during AE seems to indicate an "acute on chronic" picture of inflammation, with increased proportions of inflammatory cells in tissue and lavage/sputum samples and with the change in the proportions of some of the cell types, such as a substantial increase in the numbers of eosinophils. Cytokines and inflammatory mediators involved in AE seem to be those related to PMN chemotaxis (IL-8 and LT) and those related to eosinophilic inflammation. A more precise categorisation of the event causing AE (e.g. viral vs. bacterial), and of the baseline patients' characteristics (e.g. severe vs. mild-moderate stage) associated with a wider application of well-standardised non-invasive methodologies could bring us in the future better clues on the pattern of airway inflammation during AE.