Claudio M. Sanguinetti

Assessing and accessing the small airways; implications for asthma management

Despite the wealth of experience in the management of asthma, the disease remains inadequately controlled in some patients, who face long-term respiratory impairment and disability. The disease has been characterised as an inflammatory condition affecting first the larger airways and eventually the smaller airways, but there is evidence that peripheral airway involvement defines a particular and more severe phenotype of asthma. For this reason, assessing functional and biological parameters reflective of small airways involvement is important prognostically. No assessment method is universally and directly representative of peripheral airway function, but the traditional spirometric tests, including vital capacity, residual volume and forced vital capacity, are somewhat correlated with this function; useful methods for further assessment include the single-breath nitrogen wash-out test, impulse oscillometry, nitrous oxide and exhaled breath concentrate measurements, as well as computed tomography to reflect air trapping and response to treatment. Formulation advancements have made for easier treatment access to the smaller airways, with the new extrafine formulations resulting in better asthma control compared with non-extrafine formulations.

I costi della broncopneumopatia cronica ostruttiva: la fase prospettica dello Studio ICE (Italian Costs for Exacerbations in COPD)

SummaryIntroductionChronic obstructive pulmonary disease (COPD) is a cause of morbidity and mortality worldwide and imposes a huge individual and social burden. The present article reports the results from the prospective phase (results from the retrospective one were already published) of a multicentre Italian study (ICE, Italian Costs for Exacerbations in COPD). The aim of ICE was to assess the direct and indirect costs due to COPD, particularly regarding its exacerbations.Materials and methodsThe prospective phase was carried out on COPD patients admitted to 25 Hospital Centres (spread throughout over the country) because of an exacerbation occurring during the quarter October–December 2002. A 6-month follow-up following discharge was performed in each patient, via three telephone interviews every second month, based on a standard questionnaire and conducted by a clinical investigator. The sample was statistically stratified by three areas: Northern, Central, and Southern Italy.Results570 patients (mean age = 70.6 years; males = 69.2%) were eventually considered for processing. According to GOLD severity scale, patients were distributed as follows: 2a (moderate) → 36.4%; 2b (moderate-severe) → 31.3%; 3 (severe) → 32.3%. Respiratory failure affected 51.9% of the patients. Disease severity was found to be linked to smoking habits. 42% of exacerbations required hospitalisation. Medical costs for COPD totalled to € 4,645.5 per patient/year (€ 2,423.1 were related to exacerbations, € 2,222.4 to routine treatment); 40.1% of the total amount was for hospitalisations, 30.2% for oxygen therapy, 18% for drugs. Indirect costs (due to productivity losses by the patient and/or caregivers) were € 91.6 per patient/year. Costs resulted positively related to disease severity and to respiratory failure.ConclusionsCOPD is a disease with high costs, chiefly borne by the National Health Service: even a conservative estimate would find COPD responsible for 6% of the whole health care expenditure in Italy. The largest share of costs is for hospitalisations; hence, a strategy might be cost-effective that aimed at reducing exacerbations by improving diagnostic procedures and different treatment strategies, including drug therapy and pulmonary rehabilitation.

INDACO project: a pilot study on incidence of comorbidities in COPD patients referred to pneumology units

BackgroundChronic Obstructive Pulmonary Disease (COPD) is often associated with comorbidities, especially cardiovascular, that have a heavy burden in terms of hospitalization and mortality. Since no conclusive data exist on the prevalence and type of comorbidities in COPD patients in Italy, we planned the INDACO observational pilot study to evaluate the impact of comorbidities in patients referred to the outpatient wards of four major hospitals in Rome.MethodsFor each patient we recorded anthropometric and anamnestic data, smoking habits, respiratory function, GOLD (Global initiative for chronic Obstructive Lung Disease) severity stage, Body Mass Index (BMI), number of acute COPD exacerbations in previous years, presence and type of comorbidities, and the Charlson Comorbidity Index (CCI).ResultsHere we report and discuss the results of the first 169 patients (124 males, mean age 74±8 years). The prevalence of patients with comorbidities was 94.1% (25.2% of cases presented only one comorbidity, 28.3% two, 46.5% three or more). There was a high prevalence of arterial hypertension (52.1%), metabolic syndrome (20.7%), cancers (13.6%) and diabetes (11.2%) in the whole study group, and of anxiety-depression syndrome in females (13%). Exacerbation frequency was positively correlated with dyspnea score and negatively with BMI. Use of combination of bronchodilators and inhaled corticosteroids was more frequent in younger patients with more severe airways obstruction and lower CCI.ConclusionsThese preliminary results show a high prevalence of comorbidities in COPD patients attending four great hospitals in Rome, but they need to be confirmed by further investigations in a larger patients cohort.

N-acetylcysteine in COPD: why, how, and when?

Oxidants have long been recognized to have an important role in the pathogenesis of COPD, and in this cigarette smoke has a strong responsibility, because it generates a conspicuous amount of oxidant radicals able to modify the structure of the respiratory tract and to enhance several mechanisms that sustain lung inflammation in COPD. In fact, oxidative stress is highly increased in COPD and natural antioxidant capacities, mainly afforded by reduced glutathione, are often overcome. Thus an exogenous supplementation of antioxidant compounds is mandatory to at least partially counteract the oxidative stress. For this purpose N-acetylcysteine has great potentialities due to its capacity of directly contrasting oxidants with its free thiols, and to the possibility it has of acting as donor of cysteine precursors aimed at glutathione restoration. Many studies in vitro and in vivo have already demonstrated the antioxidant capacity of NAC. Many clinical studies have long been performed to explore the efficacy of NAC in COPD with altern results, especially when the drug was used at very low dosage and/or for a short period of time. More recently, several trials have been conducted to verify the appropriateness of using high-dose NAC in COPD, above all to decrease the exacerbations rate. The results have been encouraging, even if some of the data come from the most widely sized trials that have been conducted in Chinese populations. Although other evidence should be necessary to confirm the results in other populations of patients, high-dose oral NAC nevertheless offers interesting perspectives as add-on therapy for COPD patients.

Respiratory involvement in inflammatory bowel diseases

Inflammatory bowel diseases (IBD) include ulcerative colitis (UC) and Crohns disease (CD) and are due to a dysregulation of the antimicrobial defense normally provided by the intestinal mucosa. This inflammatory process may extend outside the bowel to many organs and also to the respiratory tract. The respiratory involvement in IBD may be completely asymptomatic and detected only at lung function assessment, or it may present as bronchial disease or lung parenchymal alterations. Corticosteroids, both systemic and aerosolized, are the mainstay of the therapeutical approach, while antibiotics must be also administered in the case of infectious and suppurative processes, whose sequels sometimes require surgical intervention. The relatively high incidence of bronchopulmonary complications in IBD suggests the need for a careful investigation of these patients in order to detect a possible respiratory involvement, even when they are asymptomatic.RiassuntoLe IBD (inflammatory bowel diseases) includono la colite ulcerosa (UC) e il morbo di Crohn (CD), causate da un’alterazione della difesa antimicrobica normalmente esercitata dalla mucosa gastroenterica. Questo processo infiammatorio può estendersi al di fuori dell’intestino in altri organi e anche all’apparato respiratorio. Il coinvolgimento respiratorio nelle IBD può essere del tutto asintomatico e rilevabile solo all’esame della funzionalità respiratoria, oppure manifestarsi consintomi di patologia delle vie aeree o del parenchima polmonare. I corticosteroidi, sia per via sistemica che inalatoria, sono il caposaldo della terapia, mentre anche gli antibiotici debbono essere somministrati nelle forme infettive e con ampia componente suppurativa, i cui reliquati talvolta richiedono un approccio chirurgico. La relativamente elevata incidenza di complicazioni broncopolmonari nelle IBD suggerisce la necessità di un’accurata valutazione di questi pazienti per rivelare un eventuale coinvolgimento respiratorio, anche in assenza di sintomi.

I costi della broncopneumopatia cronica ostruttiva in Italia. Presentazione della prima fase dello studio ICE ( Italian Costs for Exacerbations in COPD)

SummaryObjectiveExacerbations of COPD cause a huge consumption of healthcare resources. Aim of the ICE study is to estimate direct and indirect costs for COPD exacerbations admitted to hospital.MethodsICE is an observational study in two phases, retrospective and prospective. The first retrospective phase was carried out on patients admitted to 24 hospitals throughout Italy from October 2000 to March 2001. Based on medical records, data included the Diagnosis Related Groups (DRGs) and local tariffs, diagnosis (ICD-9) at discharge, hospitalisation time in ordinary or intensive (ICU) care, respiratory failure.Results706 patients were selected (male 66%, mean age 72 years, range 40–93 years). Of selected patients, 49% had respiratory failure, 69.9% fell into DRG 088 (COPD) and 23.6% into DRG 087 (Respiratory failure); of them, 68.9% were referred to ICD-9 code 491.2, and 22.3% to code 518.8, as main diagnosis. The mean time of ordinary hospitalisation for all cases was 11.4 days (CI 10.9–11.9), 10.3 days for DRG 088, 13.2 days for DRG 087 (p < 0.0001). Patients admitted to ICU (4.2% of cases) on average added 9.1 days in ICU to the mean ordinary stay of 13.8 days, totalling 22.9 days of hospitalisation. The mean individual cost for all DRGs was € 3,218 (CI 2,923–3,513). The mean cost for DRG 088 (€ 2,646) was lower (p < 0.001) compared to overall cost and to the cost for DRG 087 (€ 3,50). Mean cost in ICU was € 9,570. Mean cost in South Italy (€ 2,592) was lower (p < 0.0001) compared to North (€ 4,010) and Central Italy (€ 3,159), independently from the prevalence of the different DRGs in the three areas.ConclusionsThe assignment of DRGs was fairly appropriate. The high degree of severity among patients confirmed hospitalisation appropriateness. The prospective phase of the ICE Study now in progress should provide knowledge on factors responsible for costs and regional variations.

Methotrexate-induced pneumonitis in Crohn's disease. Case report and review of the literature

Methotrexate (MTX) is a folate-antagonist used in several neoplastic and inflammatory diseases. Reports of pulmonary complications in patients given low-dose MTX therapy are increasing. Pulmonary toxicity from MTX has a variable frequency and can present with different forms. Most often MTX-induced pneumonia in patients affected by rheumatoid arthritis (RA) is reported.In this paper we describe a case of MTX-related pneumonitis in a relatively young woman affected by Crohns disease who presented non-productive cough, fever and dyspnea on exercise. Chest X-ray demonstrated bilateral interstitial infiltrates and at computed tomography (CT) ground-glass opacities appeared in both lungs. At spirometry an obstructive defect was demonstrated. A rapid improvement of symptoms and the regression of radiographic and spirometric alterations was achieved through MTX withdrawal and the introduction of corticosteroid therapy.RiassuntoIl metotrexate (MTX) è un antagonista dei folati che viene utilizzato in molte malattie neoplastiche e infiammatorie. Negli ultimi anni sono divenute più frequenti le segnalazioni di complicanze polmonari in pazienti sottoposti a terapia con basse dosi di metotrexate. Variabile è l’incidenza della tossicità da metotrexate, che può manifestarsi in diverse forme. Più spesso viene riportata una polmonite indotta da MTX in pazienti affetti da artrite reumatoide (AR).Qui si descrive il caso di una polmonite indotta da metotrexate in una donna relativamente giovane affetta da morbo di Crohn, che presentava tosse non produttiva, febbre e dispnea da sforzo. La radiografia standard del torace mostrava infiltrati interstiziali, mentre alla TAC erano evidenti opacità a vetro smerigliato in entrambi i polmoni. La spirometria documentava un difetto di tipo ostruttivo.Si otteneva un rapido miglioramento dei sintomi e la regressione delle alterazioni radiologiche e funzionali respiratorie con la sospensione del MTX e l’introduzione di una terapia steroidea.

The lungs need to be deflated: effects of glycopyrronium on lung hyperinflation in COPD patients

Chronic obstructive pulmonary disease (COPD) is characterized by persistent airflow limitation caused by bronchial alterations, small airways disease and parenchymal destruction. In patients with COPD the structural and functional lung alterations can progress more or less rapidly from the initial small airways disease to an overt COPD where a severe expiratory flow limitation takes place. In these conditions, lung hyperinflation develops characterized by increase in functional residual capacity (FRC) and decrease in inspiratory capacity (IC). Thus, IC is an easy and reliable index to monitor lung hyperinflation and to assess the efficacy of bronchodilator drugs. When FRC increases, tidal volume (VT) is located in a more flatted upper part of the P –V curve of the respiratory system and respiratory muscles must sustain a greater elastic workload. Furthermore, due to inadequate time for expiration, there is a positive alveolar pressure at the end of expiration (PEEPi). This represents a further elastic workload for the inspiratory muscles. This impairment of ventilatory mechanics generates dyspnea that in most severely compromised patients occurs also for small efforts causing activity limitation and worst health-related quality of life (HRQoL). Due to these respiratory alterations, bronchodilators are the cornerstone of the long-term treatment of COPD in order to decrease airways resistances, lung hyperinflation and exacerbation rate, and improve patient’s symptoms, exercise tolerance and health status. Long-acting antimuscarinic bronchodilators (LAMAs) have proven to be very useful in terms of lung deflation and exercise tolerance. Recently, new LAMAs with several positive characteristics have been introduced into clinical use among which glycopyrronium bromide has shown to be particularly effective. Glycopyrronium has a longer-lasting effect compared to other anticholinergic drugs, therefore it allows a single daily administration and facilitates the therapy of a disease that needs a chronic bronchodilation by decreasing the mechanic stress of the airways determined by repeated bronchoconstriction and increasing patient’s adherence to treatment plan with better clinical results. Several studies demonstrated that glycopyrronium is able to positively and significantly decrease lung hyperinflation, symptoms, and improve psycho-physical status of COPD patients, with a low rate of adverse events, similar to that of placebo.

Idiopathic pulmonary fibrosis: the need for early diagnosis

Idiopathic pulmonary fibrosis (IPF), a chronic fibrosing lung disease of a progressive nature and unknown etiology, has the largest epidemiological impact and the worst prognosis among the idiopathic interstitial pneumonias (IIP). Despite the progress in pathogenetic knowledge, many aspects are still dubious, in particular the biomolecular mechanisms activated in the early stages of the disease. Early diagnosis is desirable not only to better define aspects of the natural history of the disease, but also to customize treatment protocols. An early diagnosis of IPF should necessarily be based on the ability to highlight a number of features drawn not only from a careful composition of specific anamnestic data with clinical, functional and radiological parameters, but also from biological markers that, in a proper context, can provide guidance and confirm a clinical-anamnestic suspicion. The identification of specific biomarkers for IPF is a modern and attractive look for the potential clinical implications in terms of diagnosis, prediction of disease progression and prognosis. Biomolecular investigations on IPF were performed selectively on tissue samples, bronchoalveolar lavage (BAL), or blood: nowadays the “multi-omic” approach may allow studying individual constitutional profiles resorting to a series of biomolecular disciplines, the so-called “omics”, which focuses on responses of the entire genomic complex, in line with the current trend to quantitatively analyze the interactions of all components of a biological system. Such refined investigations are an essential base for research now, but they might become a routine in the near future, allowing a more precise classification of patients suffering from a disease of unclear taxonomy.

Bacterial agents of lower respiratory tract infections (LRTIs), β-lactamase production, and resistance to antibiotics in elderly people

Abstract This study determined the etiology of lower respiratory tract infections in the elderly and assessed whether the growth of β-lactamase producing bacteria is particularly favoured in these patients. Between December 1998 and May 1999, 187 patients with community-acquired pneumonia (CAP), and 887 patients with acute exacerbations of chronic obstructive pulmonary disease (AECOPD) were enrolled. The mean age was 74 years (range of 65–94 year). Sputum and bronchial aspirate for microbiological investigation were obtained. Besides organisms commonly involved in bacterial infections of the lower respiratory tract (i.e. Streptococcus pneumoniae, Haemophilus influenzae , and Moraxella catarrhalis ), Enterobacteriaceae and Pseudomonas spp. were also found. A high percentage of these bacteria were β-lactamase producers. These data along with the clinical presentation, severity of infection, and epidemiological knowledge, might represent a guide for the choice of empiric antimicrobial treatment.