Effects of bilateral lung transplantation on cardiac autonomic modulation and cardiorespiratory coupling: a prospective study.

BACKGROUND: Although cardiac autonomic modulation has been studied in several respiratory diseases, the evidence is limited on lung transplantation, particularly on its acute and chronic effects. Thus, we aimed to evaluate cardiac autonomic modulation before and after bilateral lung transplantation (BLT) through a prospective study on patients enrolled while awaiting transplant. METHODS: Twenty-two patients on the waiting list for lung transplantation (11 women, age 33 [24-51] years) were enrolled in a prospective study at Ospedale Maggiore Policlinico Hospital in Milan, Italy. To evaluate cardiac autonomic modulation, ten minutes ECG and respiration were recorded at different time points before (T0) and 15 days (T1) and 6 months (T2) after bilateral lung transplantation. As to the analysis of cardiac autonomic modulation, heart rate variability (HRV) was assessed using spectral and symbolic analysis. Entropy-derived measures were used to evaluate complexity of cardiac autonomic modulation. Comparisons of autonomic indices at different time points were performed. RESULTS: BLT reduced HRV total power, HRV complexity and vagal modulation, while it increased sympathetic modulation in the acute phase (T1) compared to baseline (T0). The HRV alterations remained stable after 6 months (T2). CONCLUSION: BLT reduced global variability and complexity of cardiac autonomic modulation in acute phases, and these alterations remain stable after 6 months from surgery. After BLT, a sympathetic predominance and a vagal withdrawal could be a characteristic autonomic pattern in this population.

Bacterial etiology of community-acquired pneumonia in immunocompetent hospitalized patients and appropriateness of empirical treatment recommendations: an international point-prevalence study.

An accurate knowledge of the epidemiology of community-acquired pneumonia (CAP) is key for selecting appropriate antimicrobial treatments. Very few etiological studies assessed the appropriateness of empiric guideline recommendations at a multinational level. This study aims at the following: (i) describing the bacterial etiologic distribution of CAP and (ii) assessing the appropriateness of the empirical treatment recommendations by clinical practice guidelines (CPGs) for CAP in light of the bacterial pathogens diagnosed as causative agents of CAP. Secondary analysis of the GLIMP, a point-prevalence international study which enrolled adults hospitalized with CAP in 2015. The analysis was limited to immunocompetent patients tested for bacterial CAP agents within 24 h of admission. The CAP CPGs evaluated included the following: the 2007 and 2019 American Thoracic Society/Infectious Diseases Society of America (ATS/IDSA), the European Respiratory Society (ERS), and selected country-specific CPGs. Among 2564 patients enrolled, 35.3% had an identifiable pathogen. Streptococcus pneumoniae (8.2%) was the most frequently identified pathogen, followed by Pseudomonas aeruginosa (4.1%) and Klebsiella pneumoniae (3.4%). CPGs appropriately recommend covering more than 90% of all the potential pathogens causing CAP, with the exception of patients enrolled from Germany, Pakistan, and Croatia. The 2019 ATS/IDSA CPGs appropriately recommend covering 93.6% of the cases compared with 90.3% of the ERS CPGs (p < 0.01). S. pneumoniae remains the most common pathogen in patients hospitalized with CAP. Multinational CPG recommendations for patients with CAP seem to appropriately cover the most common pathogens and should be strongly encouraged for the management of CAP patients.

National Survey on the Management of Adult Bronchiectasis in Belgium.

The increasing prevalence and incidence of bronchiectasis leads to a substantial health care burden. Quality standards for the management of bronchiectasis were formulated by the British Thoracic Society following publication of guidelines in 2010. They can be used as a benchmark for quality of care. It is, however, unclear how and whether they apply outside of the UK. Between May and November 2017, we conducted an online survey among respiratory physicians caring for adult bronchiectasis patients in Belgium. About 186 cases were submitted by 117 treating physicians. Patients were mostly female (58%), of Caucasian descent (84%) with a remarkably low median age of 59.8 (IQR 47-73) years. 41% had Pseudomonas aeruginosa, methicillin-resistant Staphylococcus aureus and/or Enterobacteriaceae isolated from respiratory samples in the past. 21% had three or more exacerbations, however, more than 58% were receiving long-term oral antibiotics (of which 90% azithromycin). In 40% of patients the diagnostic testing was insufficient. Surveillance of sputum bacteriology in stable patients and composing a self-management plan was missing in 53% and 68% of patients, respectively. Airway clearance techniques were implemented in 84%. Respiratory physicians complied with 60% or more to five out of the eight applicable quality standards, which is encouraging. Increasing educational act could further raise awareness and increase quality of care.

A New SERPINA-1 Missense Mutation Associated with Alpha-1 Antitrypsin Deficiency and Bronchiectasis.

Alpha-1-antitrypsin deficiency (AATD) is a genetic condition caused by SERPINA1 mutations, which culminates into lower protease inhibitor activity in the serum and predisposes to emphysema. Clinical manifestations of AATD are often associated to ZZ (p.Glu342Lys) and SZ (p.Glu264Val) genotypes and less frequently to rare deficiency or null alleles in heterozygous and homozygous states. We report a case of a 52-year-old woman with bronchiectasis without other potential causes other than an electrophoresis that showed a decrease of alpha-1 globin band and AAT levels below the normal value (78 mg/dl; v.n. 90-200 mg/dl). No S or Z mutation was identified, but sequencing analysis found a novel missense variant Ile74Asn (c.221T > A) in heterozygous state on an M3 allele (Glu400Asp) in the exon 2 of the SERPINA-1gene, probably leading to a dysfunctional protein. This mutation has never been previously identified, and it is interesting to note the association with bronchiectasis in the absence of emphysema.

Multidimensional severity assessment in bronchiectasis: an analysis of seven European cohorts.

INTRODUCTION: Bronchiectasis is a multidimensional disease associated with substantial morbidity and mortality. Two disease-specific clinical prediction tools have been developed, the Bronchiectasis Severity Index (BSI) and the FACED score, both of which stratify patients into severity risk categories to predict the probability of mortality. METHODS: We aimed to compare the predictive utility of BSI and FACED in assessing clinically relevant disease outcomes across seven European cohorts independent of their original validation studies. RESULTS: The combined cohorts totalled 1612. Pooled analysis showed that both scores had a good discriminatory predictive value for mortality (pooled area under the curve (AUC) 0.76, 95% CI 0.74 to 0.78 for both scores) with the BSI demonstrating a higher sensitivity (65% vs 28%) but lower specificity (70% vs 93%) compared with the FACED score. Calibration analysis suggested that the BSI performed consistently well across all cohorts, while FACED consistently overestimated mortality in 'severe' patients (pooled OR 0.33 (0.23 to 0.48), p<0.0001). The BSI accurately predicted hospitalisations (pooled AUC 0.82, 95% CI 0.78 to 0.84), exacerbations, quality of life (QoL) and respiratory symptoms across all risk categories. FACED had poor discrimination for hospital admissions (pooled AUC 0.65, 95% CI 0.63 to 0.67) with low sensitivity at 16% and did not consistently predict future risk of exacerbations, QoL or respiratory symptoms. No association was observed with FACED and 6 min walk distance (6MWD) or lung function decline. CONCLUSION: The BSI accurately predicts mortality, hospital admissions, exacerbations, QoL, respiratory symptoms, 6MWD and lung function decline in bronchiectasis, providing a clinically relevant evaluation of disease severity.

Bacteremic pneumococcal pneumonia: clinical outcomes and preliminary results of inflammatory response.

PURPOSE: Further examination of clinical outcomes and inflammatory response of bacteremic pneumococcal community-acquired pneumonia (CAP) is of great interest to enhance the care of patients with pneumococcal CAP. METHODS: This is a secondary analysis of the Community Acquired Pneumonia Organization (CAPO) to compare the time to clinical stability (TCS), length of hospital stay (LOS), and in-hospital mortality of hospitalized pneumococcal CAP patients with and without bacteremia. To measure the effect of bacteremia in pneumococcal CAP patients on outcomes, we modeled all-cause in-hospital mortality using a Poisson regression model, and TCS and LOS using Cox proportional hazards models. Adjusted multivariate regression models were also used to predict the probability of occurrence of each of the study outcomes. To investigate the inflammatory response, we measured the plasma levels of pro- and anti-inflammatory cytokines [tumor necrosis factor (TNF)-α, interleukin (IL)-1rα, IL-6, IL-8, IL-10], inflammatory biomarkers [C-reactive protein (CRP), pro-calcitonin (PCT), and B-type natriuretic peptide (BNP)], and peripheral blood neutrophil responses in 10 patients, 4 bacteremic and 6 non-bacteremic pneumococcal CAP, upon admission and every other day during the first 6 days of hospitalization. Functional data were presented as median and standard error of the median (SEM); due to small number of samples no statistical comparisons were performed between groups. RESULTS: From 833 pneumococcal CAP patients, 394 patients (47 %) were bacteremic. Bacteremic pneumococcal CAP were less likely to reach TCS with an adjusted hazard ratio (AHR) of 0.82 (95 % CI 0.69-0.97; p = 0.02) and had higher in-hospital mortality with an AHR of 1.63 (95 % CI 1.06-2.50, p = 0.026). Bacteremic pneumococcal CAP patients had a longer LOS than non-bacteremic pneumococcal CAP (p < 0.003). Higher plasma levels of CRP, PCT, and BNP were found in bacteremic than in non-bacteremic patients. The bacteremic group had consistently higher plasma levels of both pro- and anti-inflammatory cytokines. The blood neutrophil functional responses were similar in both groups of patients. CONCLUSIONS: Bacteremic pneumococcal CAP patients were significantly associated with higher in-hospital mortality, lower TCS, and longer LOS. HIV-infected patients showed a greater mortality which was not statistically significant. Bacteremic pneumococcal CAP patients had higher levels of biomarkers and systemic cytokines.

Flow cytometry significantly improves the diagnostic value of fine needle aspiration cytology of lymphoproliferative lesions of salivary glands.

OBJECTIVE: Lymphoid proliferations of the salivary glands can be either reactive or malignant. Diagnosis based solely on fine needle aspiration (FNA) cytology may be troublesome in view of the difficulty in distinguishing low-grade B-cell and mucosa-associated lymphoid tissue (MALT) lymphomas from reactive lymphoid proliferations. We report our experience with FNA cytology combined with flow cytometry (FC) immunophenotyping for the diagnosis of lymphoproliferative processes affecting the salivary glands. METHODS: Sixty-one FNA specimens, obtained from salivary glands over a 10-year period, were analysed by cytology and FC. The results were correlated with histological follow-up if available. RESULTS: A diagnosis of lymphoma was given in 37 of 61 (61%) specimens; 22 of 61 (36%) specimens were considered as benign/reactive or non-lymphomatous processes; two of 61 (3%) specimens were considered as suspicious for lymphoma on cytological analysis and negative on FC. Histological control was available in 23 malignant, four non-lymphomatous and one cytologically suspicious case. Data obtained by the combination of cytology and FC were confirmed in all but one case: the case suspicious on cytology received a histological diagnosis of carcinoma. Four of seven cases with small populations of clonal cells (less than 15%) were histologically confirmed as lymphoma, whereas two remain under surveillance and one was reactive. Correlation with histological data showed a sensitivity of 100% and a specificity of 83% for the combination of cytology and FC. CONCLUSIONS: FC is fundamental for the diagnosis of lymphoproliferative lesions of the salivary glands. It may solve cytologically suspicious cases and detect the presence of neoplastic B or T cells. This combined approach reduces the time to therapy and may prevent unnecessary surgical biopsies.

Diagnosis of deep-seated lymphomas by endoscopic ultrasound-guided fine needle aspiration combined with flow cytometry.

OBJECTIVE: Although endoscopic ultrasound combined with fine needle aspiration (EUS-FNA) is rapidly becoming the preferred diagnostic approach for the sampling and diagnosis of gastrointestinal and mediastinal malignancies, there are limited data as to its use in the diagnosis of lymphoproliferative disorders. Therefore, we carried out a retrospective evaluation of the performance of EUS-guided FNA combined with flow cytometry (FC) as a tool to improve overall sensitivity and specificity in the diagnosis of lymphoma. METHODS: Of 1560 patients having EUS-guided FNA during the period of the study, a total of 56 patients were evaluated by cytology with FC after EUS-FNA. There was adequate material to perform FC analysis for all but one case. RESULTS: EUS-FNA-FC gave a diagnosis of lymphoma in 11 cases and of reactive lymphadenopathy in 20. A specific histological type was defined by FC alone in eight cases. The remaining cases were diagnosed later by cytology and cell block sections: 13 carcinomas, nine granulomatous lymphadenopathies and one mediastinal extramedullary haematopoiesis. One case was considered only suspicious for lymphoma on cytology and FC but was not confirmed on molecular analysis and one had insufficient material for FC. CONCLUSIONS: Our results show that a combination of EUS-FNA-FC is a feasible and highly accurate method, which may be used for the diagnosis and subtyping of deep-seated lymphoma, providing a significant improvement to cytomorphology alone both for diagnosis and treatment planning, as long as immunocytochemistry is available for non-lymphoma cases.

Duration of antibiotic therapy in hospitalised patients with community-acquired pneumonia.

Recent guidelines suggest that duration of antibiotic therapy for hospitalized patients with community-acquired pneumonia (CAP) can be reduced by individualising treatment based on patient's clinical response. However, the degree of application of this principle in clinical practice is unknown. Duration of therapy was analysed in patients identified from the Community-Acquired Pneumonia Organization database and evaluated with respect to severity of the disease on admission and time to clinical stability (TCS). Among the 2,003 patients enrolled, mean duration of total antibiotic therapy was 11 days. Neither the pneumonia severity index (r(2) = 0.005) nor the CRB-65 (r(2) = 0.004) scores were related to total duration of therapy. Duration of intravenous antibiotic therapy was related to TCS (r(2) = 0.198). Conversely, TCS was not related to duration of either oral (r(2) = 0.014) or total (r(2) = 0.02) antibiotic therapy. Neither TCS nor other characteristics were found to be significantly associated with duration of total therapy by logistic regression analysis (r(2)<0.09). The individualised approach suggested by recent guidelines has not been adopted in current clinical practice. Duration of therapy is not influenced by either the severity of disease at the time of hospitalisation or the clinical response to therapy.

Non-invasive continuous positive airway pressure in monolateral lung transplant patient with pneumonia and IPF.

Patients who undergo lung transplantation are prone to develop lower respiratory tract infections, leading to severe acute respiratory failure (ARF). Endotracheal intubation may not be indicated in these patients in light of a higher rate of mortality due to infections. The application of non-invasive ventilation could play a role in bridging these patients through the episode of ARF waiting for medical treatment to have effect. We report the evidence of morphological and physiological effects of the application of non-invasive continuous positive airway pressure during ARF sustained by pneumonia in a patient who underwent left lung transplantation because of idiopathic pulmonary fibrosis (IPF). We studied the effects of the application of positive end-expiratory pressure on both the right native lung affected by IPF and the transplanted lung affected by pneumonia.

Balancing evidence and frontline experience in the early phases of the COVID-19 pandemic: current position of the Italian Society of Anti-infective Therapy (SITA) and the Italian Society of Pulmonology (SIP).

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19), which has rapidly become epidemic in Italy and other European countries. The disease spectrum ranges from asymptomatic/mildly symptomatic presentations to acute respiratory failure. At the present time the absolute number of severe cases requiring ventilator support is reaching or even surpassing the intensive care unit bed capacity in the most affected regions and countries. OBJECTIVES: To narratively summarize the available literature on the management of COVID-19 in order to combine current evidence and frontline opinions and to provide balanced answers to pressing clinical questions. SOURCES: Inductive PubMed search for publications relevant to the topic. CONTENT: The available literature and the authors' frontline-based opinion are summarized in brief narrative answers to selected clinical questions, with a conclusive statement provided for each answer. IMPLICATIONS: Many off-label antiviral and anti-inflammatory drugs are currently being administered to patients with COVID-19. Physicians must be aware that, as they are not supported by high-level evidence, these treatments may often be ethically justifiable only in those worsening patients unlikely to improve only with supportive care, and who cannot be enrolled onto randomized clinical trials. Access to well-designed randomized controlled trials should be expanded as much as possible because it is the most secure way to change for the better our approach to COVID-19 patients.

The role of neutropenia on outcomes of cancer patients with community-acquired pneumonia.

Although the presence of neutropenia may predispose cancer patients to develop community-acquired pneumonia, the role of neutropenia on their outcomes has not been investigated. The purpose of the present study was to compare clinical outcomes of cancer community-acquired pneumonia patients with and without neutropenia. Patients with cancer, identified in the Community-Acquired Pneumonia Organization database, were divided into two groups according to the type of cancer and the presence of neutropenia: patients with solid cancer without neutropenia versus those with functional or absolute neutropenia. Among the 3,106 community-acquired pneumonia patients enrolled, 135 had cancer without neutropenia and 75 had cancer with neutropenia. No significant difference was found between patients with and without neutropenia regarding mean time to clinical stability (5.4+/-2.7 versus 4.9+/-2.7 days, respectively), mean length of hospital stay (9.2+/-7.7 versus 9.9+/-9.6 days) and in-hospital mortality (18 versus 15%, respectively). Using a multiple logistic regression model, neutropenia was not associated with mortality in cancer patients when adjusting for significant covariates (odds ratio 1.30). Lack of neutropenia, during the initial evaluation of a cancer community-acquired pneumonia patient, should not be considered an indicator of better clinical outcome.

Knowledge and attitudes on influenza vaccination among Italian physicians specialized in respiratory infections: an Italian Respiratory Society (SIP/IRS) web-based survey.

INTRODUCTION: Influenza epidemics are one of the main causes of morbidity and mortality worldwide. Influenza vaccination is considered the most important public health intervention to prevent seasonal influenza infection. European health authority policies focus on patient protection by vaccinating both these subjects and their care-givers, including health-care workers (HCWs). The aim of this survey is to investigate knowledge about influenza vaccination and intention to get vaccinated among Italian HCWs who take care patients with respiratory disease. METHODS: An anonymous web-based survey was addressed to members of the Italian Respiratory Society (IRS). RESULTS: Among the 1,776 IRS members who have been invited to the survey, 144 (8.1%) completed the survey (97 men; median age 59 years; 85.4% Respiratory Disease). The vast majority recommended vaccination to all their patients (81%). More than two thirds of respondents considered influenza vaccination safe for immunocompromised patients. More than 50% of respondents underwent seasonal influenza vaccination in 2015 and 68% declared the intention to undergo vaccination in 2016 epidemic season. Reasons for having vaccination mainly referred to 'protect oneself from influenza' (63%), 'protect patients' (31%) or household members' (6%). The main reasons for vaccination refusal were 'lack of time' (45%), 'concerns about side effects' (22%), 'do not get influenza easily and/or not afraid of influenza infection' (22%) and 'disagreement with indication of vaccination for HCWs' (9%). CONCLUSIONS: The promotion of better knowledge and attitude towards influenza vaccination among Italian specialists remains an unmet goal and should be addressed by appropriate multifaceted interventions.

Nosocomial transmission of carbapenem-resistant Klebsiella pneumoniae in an Italian university hospital: a molecular epidemiological study.

AIM: To describe the phenotypic and genotypic profiles of Klebsiella pneumoniae carbapenemase-producing K. pneumoniae (KPC-Kp) strains isolated from patients with invasive infections at an Italian university hospital in order to assess the epidemiological trend. METHODS: An observational prospective study was undertaken at the University Hospital of Sassari, Italy to detect KPC-Kp strains in patients with invasive bacteraemia. Isolates were identified phenotypically; carbapenemase production was assessed using phenotypic and genotypic methods. Sequencing of blaKPC genes, pulsed-field gel electrophoresis and multi-locus sequence typing were performed. RESULTS: During the period 2015-2017, 46 cases of invasive infection with K. pneumoniae were recorded. Two-thirds (67.4%) of the patients were male, and the mean age was 69.4 years. Most patients had at least one comorbidity (56.5%) and/or had been hospitalized previously (70.5%), 81.8% had current or recent medical device use, and 85.4% had recent antibiotic exposure. The mortality rate was 52.3%. A multi-drug-resistant pattern (including carbapenems, fluoroquinolones, third-/fourth-generation cephalosporins) was shown for all K. pneumoniae isolates. KPC-3 and -2 were produced by all strains. The most common sequence types were 512 (91.3%) and 101 (8.7%), grouped into three clusters (A, A1 and B). CONCLUSIONS: A high incidence of KPC-Kp in patients with invasive infections was recorded at an Italian university hospital compared with the incidence measured before 2015. This study confirmed the importance of the KPC-3 carbapenemase variant, as reported by other Italian studies. High mortality and comorbidity rates appear to be associated with KPC-Kp infection.

Response to melphalan in up-front investigational window therapy for patients with metastatic Ewing's family tumours.

The aim of the study was to determine the activity and toxicity of melphalan as a single agent given in up-front therapy for patients with newly-diagnosed Ewing's family tumours with bone/bone marrow metastases. Nineteen patients were enrolled from 2001 to 2004. The treatment consisted of up-front therapy with melphalan (two courses of 50 mg/m2, 3 weeks apart). The overall rate of response to melphalan (complete response+partial response, according to the RECIST criteria) was 78%. Transient grade 3-4 neutropenia, thrombocytopenia and anaemia were recorded in 97%, 81% and 28% of melphalan courses, respectively. No other relevant toxicities were recorded. Melphalan proved to be active in up-front treatment at non-myeloablative doses, and its toxicity was predictable and manageable. The schedule adopted did not interfere with any further intensive chemotherapy or myeloablative treatment in the majority of cases.

Selection of Candidates for Lung Transplantation: The First Italian Consensus Statement.

Lung transplantation is a well-established treatment for selected patients with advanced chronic respiratory insufficiency. Recognizing those patients with end-stage lung disease who might benefit from lung transplantation is a crucial task. Considering the presence of inadequate evidence-based practice, international and national scientific societies provided consensus opinions regarding the appropriate timing of listing. The Study Group for Thoracic Organs Transplantation (branch of the Italian Society for Organs Transplantation) promoted and realized a Delphi conference among the Italian lung transplantation centers to provide guidance to clinical practice based on international recommendations. The experts from the nine Italian centers completed two rounds of standardized questionnaires (answer rate, 100%): 42 statements received a consensus ≥80%. The selected statements presented in this article are intended to assist Italian clinicians in selecting patients for lung transplantation.

Allogeneic hemopoietic stem cell transplantation in solid tumors.

The existence of a graft versus tumor (GVT) effect of donor-derived T cells after allogeneic hematopoietic stem cell transplantation is well established as a critical component for the success of the procedure in several hematologic malignancies. Although it has been suggested that a GVT effect might also be generated in patients affected by refractory solid tumors, the morbidity of conventional allogeneic hematopoietic stem cell transplantation has limited its investigation in these diseases. Recently introduced allogeneic nonmyeloablative regimens have greatly decreased morbidity and mortality related to transplants which retain a powerful GVT. On this basis, it has become possible to explore the existence of alloreactivity toward solid tumors. The present article reviews the early clinical results of this novel immunotherapeutic approach for solid tumors.