Paolo Palange

Outcomes for COPD pharmacological trials: from lung function to biomarkers

The American Thoracic Society/European Respiratory Society jointly created a Task Force on “Outcomes for COPD pharmacological trials: from lung function to biomarkers” to inform the chronic obstructive pulmonary disease research community about the possible use and limitations of current outcomes and markers when evaluating the impact of a pharmacological therapy. Based on their review of the published literature, the following document has been prepared with individual sections that address specific outcomes and markers, and a final section that summarises their recommendations.

Recommendations on the use of exercise testing in clinical practice

Evidence-based recommendations on the clinical use of cardiopulmonary exercise testing (CPET) in lung and heart disease are presented, with reference to the assessment of exercise intolerance, prognostic assessment and the evaluation of therapeutic interventions (e.g. drugs, supplemental oxygen, exercise training). A commonly used grading system for recommendations in evidence-based guidelines was applied, with the grade of recommendation ranging from A, the highest, to D, the lowest. For symptom-limited incremental exercise, CPET indices, such as peak O2 uptake (V′O2), V′O2 at lactate threshold, the slope of the ventilation–CO2 output relationship and the presence of arterial O2 desaturation, have all been shown to have power in prognostic evaluation. In addition, for assessment of interventions, the tolerable duration of symptom-limited high-intensity constant-load exercise often provides greater sensitivity to discriminate change than the classical incremental test. Field-testing paradigms (e.g. timed and shuttle walking tests) also prove valuable. In turn, these considerations allow the resolution of practical questions that often confront the clinician, such as: 1) “When should an evaluation of exercise intolerance be sought?”; 2) “Which particular form of test should be asked for?”; and 3) “What cluster of variables should be selected when evaluating prognosis for a particular disease or the effect of a particular intervention?”

Use of exercise testing in the evaluation of interventional efficacy: an official ERS statement.

This document reviews 1) the measurement properties of commonly used exercise tests in patients with chronic respiratory diseases and 2) published studies on their utilty and/or evaluation obtained from MEDLINE and Cochrane Library searches between 1990 and March 2015. Exercise tests are reliable and consistently responsive to rehabilitative and pharmacological interventions. Thresholds for clinically important changes in performance are available for several tests. In pulmonary arterial hypertension, the 6-min walk test (6MWT), peak oxygen uptake and ventilation/carbon dioxide output indices appear to be the variables most responsive to vasodilators. While bronchodilators do not always show clinically relevant effects in chronic obstructive pulmonary disease, high-intensity constant work-rate (endurance) tests (CWRET) are considerably more responsive than incremental exercise tests and 6MWTs. High-intensity CWRETs need to be standardised to reduce interindividual variability. Additional physiological information and responsiveness can be obtained from isotime measurements, particularly of inspiratory capacity and dyspnoea. Less evidence is available for the endurance shuttle walk test. Although the incremental shuttle walk test and 6MWT are reliable and less expensive than cardiopulmonary exercise testing, two repetitions are needed at baseline. All exercise tests are safe when recommended precautions are followed, with evidence suggesting that no test is safer than others. A review of exercise testing to evaluate interventions aimed to improve exercise tolerance in respiratory patients http://ow.ly/U37mQ

Hemopoietic and angiogenetic progenitors in healthy athletes: different responses to endurance and maximal exercise

The effects of endurance or maximal exercise on mobilization of bone marrow-derived hemopoietic and angiogenetic progenitors in healthy subjects are poorly defined. In 10 healthy amateur runners, we collected venous blood before, at the end of, and the day after a marathon race (n = 9), and before and at the end of a 1.5-km field test (n = 8), and measured hemopoietic and angiogenetic progenitors by flow cytometry and culture assays, as well as plasma or serum concentrations of several cytokines/growth factors. After the marathon, CD34(+) cells were unchanged, whereas clonogenetic assays showed decreased number of colonies for both erythropoietic (BFU-E) and granulocyte-monocyte (CFU-GM) series, returning to baseline the morning post-race. Conversely, CD34(+) cells, BFU-E, and CFU-GM increased after the field test. Angiogenetic progenitors, assessed as CD34(+)KDR(+) and CD133(+)VE-cadherin(+) cells or as adherent cells in culture expressing endothelial markers, increased after both endurance and maximal exercise but showed a different pattern between protocols. Interleukin-6 increased more after the marathon than after the field test, whereas hepatocyte growth factor and stem cell factor increased similarly in both protocols. Plasma levels of angiopoietin (Ang) 1 and 2 increased after both types of exercise, whereas the Ang-1-to-Ang-2 ratio or vascular endothelial growth factor-A were little affected. These data suggest that circulating hemopoietic progenitors may be utilized in peripheral tissues during prolonged endurance exercise. Endothelial progenitor mobilization after exercise in healthy trained subjects appears modulated by the type of exercise. Exercise-induced increase in growth factors suggests a physiological trophic effect of exercise on the bone marrow.

Methicillin-resistant Staphylococcus aureus Necrotizing Pneumonia

To the Editor: Methicillin-resistant Staphylococcus aureus (MRSA) strains account for >40% of all hospital-acquired S. aureus infections in Italy (1). Although cases of community-acquired MRSA (CA-MRSA) infections have been reported in recent years (2), these isolates have not been characterized for Panton-Valentine leukocidin (PVL) (3); therefore, the presence of isolates with the typical characteristics of CA-MRSA (4) in Italy remains unknown. At the beginning of April 2005, a 37-year-old woman was admitted to the University Hospital Policlinico in Rome because of fever, cough, and headache. Her medical history was unremarkable. She was a teacher in a school for foreign students in Rome, smoked 3 cigarettes per day for 15 years, and reported no recent travel abroad. Her 5-year-old daughter had influenzalike symptoms in the previous week. At hospital admission, her temperature was 39°C, heart rate was108 beats/min, respiratory rate was 32 breaths/min, and blood pressure was 105/70 mmHg. Arterial blood gas analysis showed mild hypoxemia and hypocapnia (PaO2 73 mm Hg and PaCO2 34 mm Hg on room air). Leukocyte count was 24,360 cells/μL (81% polymorphonuclear cells), and platelet count was 506,000/μL. Chest radiograph showed infiltrates in the right upper and lower lobes and left lower lobe. Empiric treatment with clarithromycin and ceftriaxone was started, but the patients clinical conditions did not improve. Culture of sputum samples obtained at admission yielded growth of MRSA. Computed tomographic scan showed multiple lung cavitary lesions, indicating necrotizing pneumonia. On day 3 of admission, antimicrobial drug therapy was changed to linezolid (600 mg 2 times a day). Fever resolved, and the patients condition rapidly improved. The patient was discharged after 14 days of linezolid treatment. At discharge, leukocyte count was 6,040 cell/μL (58% polymorphonuclear cells), and arterial blood gas analysis showed PaO2 of 88 mm Hg. The MRSA isolate from sputum was susceptible to all the non–β-lactam antimicrobial drugs tested, including erythromycin, clindamycin, ciprofloxacin, tetracycline, kanamycin, and fusidic acid. With established molecular methods, the isolate was found to harbor SCCmec type IV (5); lukS and lukF, the genes coding for the 2 subunits of the PVL toxin; and hlg, the γ-hemolysin gene (3). The genetic background of the isolate was determined by multilocus sequence typing (MLST) (6) and sequence typing of the tandem repeat region of protein A gene (spa typing) (7). Results showed that the isolate belonged to ST30 according to the MLST database (http://saureus.mlst.net), and spa typing, analyzed by the Ridom Staphtype software (http://www.ridom.de), indicated a novel spa type, to which type 755 was assigned. ST30, 1 of 6 clones more commonly associated with PVL-positive CA-MRSA (4), is designated also the southwest Pacific (SWP) clone, because of the area in which it circulates. Recently, the SWP clone has caused CA-MRSA infections in northern European countries (England, Scotland, the Netherlands, Sweden, and Latvia) (8,9). Molecular analysis suggests that the SWP clone has evolved from a methicillin-susceptible clone of S. aureus, termed phage type 80/81, that was pandemic in the 1950s and considered to be unusually virulent and transmissible (8). In fact, strains belonging to phage type 80/81 carry the PVL gene and appear to have subsequently acquired methicillin resistance through horizontal transfer of SCCmec type IV. The spa type of the Italian isolate comprises 7 nucleotide repeats, indicated by XJ4AKAOM in the alphabetical code. This repeat sequence differs from that of the classical SWP clone, indicated by XKAKAOMQ (8), by only 1 bp in the second repeat and loss of the last Q repeat. In spite of these differences, the spa type is in substantial agreement with the MLST result and indicates that the Italian isolate is either a descendent or a local variant of the SWP clone. The most common clone of CA-MRSA described in Europe is ST80, spa type 44. CA-MRSA belonging to ST80 tend to be more antimicrobial drug resistant than isolates belonging to other clones (4). Resistance to fusidic acid, typical of ST80, has been proposed as a marker for CA-MRSA in Europe (10). In light of our finding, we cannot rely on resistance to fusidic acid to screen for PVL-producing CA-MRSA in our country. To our knowledge, this is the first report from Italy of necrotizing pneumonia caused by PVL-positive CA-MRSA. The presentation was typically that of a severe pneumonia that occurred in a previously healthy, young adult with no risk factors for MRSA acquisition, as described in other cases (11). This is also the first report of a SWP clone isolate in southern Europe; if the strain is circulating in Italy or is occasionally imported from the SWP area, whether our patient acquired it through contact with a foreign contact remains unknown.

Bone marrow-derived progenitors are greatly reduced in patients with severe COPD and low-BMI

Chronic obstructive pulmonary disease (COPD) patients have reduced circulating hemopoietic progenitors. We hypothesized that severity of COPD parallels the decrease in progenitors and that the reduction in body mass index (BMI) could be associated with more severe bone marrow dysfunction. We studied 39 patients with moderate to very severe COPD (18 with low-BMI and 21 with normal-BMI) and 12 controls. Disease severity was associated to a greater reduction in circulating progenitors. Proangiogenetic and inflammatory markers correlated with disease severity parameters. Compared to normal-BMI patients, low-BMI patients showed: greater reduction in circulating progenitors; higher VEGF-A, VEGF-C, HGF, Ang-2, TNF-alpha, IL-6 and MCP-1 levels. Furthermore, among patients with similar pulmonary impairment, those who displayed low-BMI had a more markedly reduced number of CD34(+) cells and late endothelial progenitors. We show that the reduction in hematopoietic and endothelial progenitor cells correlates with COPD severity. Our findings also indicate that, in severe low-BMI COPD patients, bone marrow function seems to be further impaired and may lead to reduced reparative capacity.

COPD: a multifactorial systemic disease

Chronic obstructive pulmonary disease (COPD) has traditionally been considered a disease of the lungs secondary to cigarette smoking and characterized by airflow obstruction due to abnormalities of both airway (bronchitis) and lung parenchyma (emphysema). It is now well known that COPD is associated with significant systemic abnormalities, such as renal and hormonal abnormalities, malnutrition, muscle wasting, osteoporosis, and anemia. However, it is still unclear whether they represent consequences of the pulmonary disorder, or whether COPD should be considered as a systemic disease. These systemic abnormalities have been attributed to an increased level of systemic inflammation. Chronic inflammation, however, may not be the only cause of the systemic effects of COPD. Recent data from humans and animal models support the view that emphysema may be a vascular disease. Other studies have highlighted the role of repair failure, bone marrow abnormality, genetic and epigenetic factors, immunological disorders and infections as potential causes of COPD systemic manifestations. Based on this new evidence, it is reasonable to consider COPD, and emphysema in particular, as ‘a disease with a significant systemic component’ if not a ‘systemic disease’ per se. The aim of this review is to give an overview of the most relevant and innovative hypothesis about the extrapulmonary manifestations of COPD.

Renal and hormonal abnormalities in chronic obstructive pulmonary disease (COPD).

Renal and hormonal abnormalities, usually manifested as oedema or hyponatraemia, are encountered frequently in patients with chronic obstructive pulmonary disease (COPD). The exact incidence of clinically significant oedema and hyponatraemia has not been documented. In advanced disease some degree of oedema is observed in a large proportion of patients; the pattern of hyponatraemia parallels that of oedema, but with a lower frequency. In the past, oedema in patients with COPD has been attributed to “cor pulmonale with backward heart failure”—that is, pulmonary hypertension induced by hypoxia and by structural changes in pulmonary arteries, increased systemic venous pressure, and reduced cardiac output. The onset of oedema is a poor prognostic factor; Renzetti and coworkers1 reported a four year mortality rate of 73% in patients with cor pulmonale compared with 53% for the whole group. Whether this reflects the advanced stage of the disease, the indirect effect of chronic diuretic therapy, or some undetermined insult on the function of critical organs is unclear. What is clear is that oedema formation in COPD is not cardiac in origin: in most patients, even when they are frankly oedematous, cardiac output is adequate for the body’s metabolic demands2 3 unless there is significant co-existent cardiac disease. In 1960 Campbell and Short4 pointed out that, in patients with COPD, oedema is almost invariably associated with carbon dioxide (CO2) retention. They concluded that, in hypoxaemic normocapnic patients with chronic diffuse lung disease such as pulmonary fibrosis, oedema is uncommon and, in this setting, transient worsening in blood gas tensions during exercise or sleep, for example, should be suspected and ruled out. Since then sodium (Na+) retention in COPD has been considered to be the result of electrochemical imbalance (enhanced renal tubular H+/Na+ exchange with attendant increase in Na+ …

Lower mortality rate in elderly patients with community-onset pneumonia on treatment with aspirin.

Background Pneumonia is complicated by high rate of mortality and cardiovascular events (CVEs). The potential benefit of aspirin, which lowers platelet aggregation by inhibition of thromboxane A2 production, is still unclear. The aim of the study was to assess the impact of aspirin on mortality in patients with pneumonia. Methods and Results Consecutive patients admitted to the University‐Hospital Policlinico Umberto I (Rome, Italy) with community‐onset pneumonia were recruited and prospectively followed up until discharge or death. The primary end point was the occurrence of death up to 30 days after admission; the secondary end point was the intrahospital incidence of nonfatal myocardial infarction and ischemic stroke. One thousand and five patients (age, 74.7±15.1 years) were included in the study: 390 were receiving aspirin (100 mg/day) at the time of hospitalization, whereas 615 patients were aspirin free. During the follow‐up, 16.2% of patients died; among these, 19 (4.9%) were aspirin users and 144 (23.4%; P<0.001) were aspirin nonusers. Overall, nonfatal CVEs occurred in 7% of patients, 8.3% in nonaspirin users, and 4.9% in aspirin users (odds ratio, 1.77; 95% confidence interval, 1.03 to 3.04; P=0.040). The Cox regression analysis showed that pneumonia severity index (PSI), severe sepsis, pleural effusion, and PaO2/FiO2 ratio <300 negatively influenced survival, whereas aspirin therapy was associated with improved survival. Compared to patients receiving aspirin, the propensity score adjusted analysis confirmed that patients not taking aspirin had a hazard ratio of 2.07 (1.08 to 3.98; P=0.029) for total mortality. Conclusions This study shows that chronic aspirin use is associated with lower mortality rate within 30 days after hospital admission in a large cohort of patients with pneumonia.

Analyses of T cell phenotype and function reveal an altered T cell homeostasis in systemic sclerosis Correlations with disease severity and phenotypes

We investigated in systemic sclerosis (SSc) patients the T cell homeostasis and its relationship with the clinical course of the disease. Distribution of peripheral T cell subsets, thymic output, lymphocyte proliferation and apoptosis were analyzed by flow cytometry or ELISA. Age inappropriate levels of naive CD4(+) T cells and thymic output were observed. Proliferation of CD4(+) T cells, lymphocyte apoptosis and CD4(+) regulatory T (Treg) cell frequency were significantly higher than those observed in controls and significantly correlated with clinical phenotypes and clinical progression parameters i.e., diffusing capacity of the lung for carbon monoxide (DLCO) and disease activity. These data indicate that the evaluation of the T cell homeostasis can represent a valuable prognostic tool for SSc patients and it is useful to distinguish between limited and diffuse phenotypes. A therapeutic intervention targeted at reversing T cell homeostasis abnormalities would therefore potentially be helpful in counteracting disease progression.