José Manuel Pereira

Multicentre evaluation of multidisciplinary team meeting agreement on diagnosis in diffuse parenchymal lung disease: a case-cohort study

BACKGROUND Diffuse parenchymal lung disease represents a diverse and challenging group of pulmonary disorders. A consistent diagnostic approach to diffuse parenchymal lung disease is crucial if clinical trial data are to be applied to individual patients. We aimed to evaluate inter-multidisciplinary team agreement for the diagnosis of diffuse parenchymal lung disease. METHODS We did a multicentre evaluation of clinical data of patients who presented to the interstitial lung disease unit of the Royal Brompton and Harefield NHS Foundation Trust (London, UK; host institution) and required multidisciplinary team meeting (MDTM) characterisation between March 1, 2010, and Aug 31, 2010. Only patients whose baseline clinical, radiological, and, if biopsy was taken, pathological data were undertaken at the host institution were included. Seven MDTMs, consisting of at least one clinician, radiologist, and pathologist, from seven countries (Denmark, France, Italy, Japan, Netherlands, Portugal, and the UK) evaluated cases of diffuse parenchymal lung disease in a two-stage process between Jan 1, and Oct 15, 2015. First, the clinician, radiologist, and pathologist (if lung biopsy was completed) independently evaluated each case, selected up to five differential diagnoses from a choice of diffuse lung diseases, and chose likelihoods (censored at 5% and summing to 100% in each case) for each of their differential diagnoses, without inter-disciplinary consultation. Second, these specialists convened at an MDTM and reviewed all data, selected up to five differential diagnoses, and chose diagnosis likelihoods. We compared inter-observer and inter-MDTM agreements on patient first-choice diagnoses using Cohens kappa coefficient (κ). We then estimated inter-observer and inter-MDTM agreement on the probability of diagnosis using weighted kappa coefficient (κw). We compared inter-observer and inter-MDTM confidence of patient first-choice diagnosis. Finally, we evaluated the prognostic significance of a first-choice diagnosis of idiopathic pulmonary fibrosis (IPF) versus not IPF for MDTMs, clinicians, and radiologists, using univariate Cox regression analysis. FINDINGS 70 patients were included in the final study cohort. Clinicians, radiologists, pathologists, and the MDTMs assigned their patient diagnoses between Jan 1, and Oct 15, 2015. IPF made up 88 (18%) of all 490 MDTM first-choice diagnoses. Inter-MDTM agreement for first-choice diagnoses overall was moderate (κ=0·50). Inter-MDTM agreement on diagnostic likelihoods was good for IPF (κw=0·71 [IQR 0·64-0·77]) and connective tissue disease-related interstitial lung disease (κw=0·73 [0·68-0·78]); moderate for non-specific interstitial pneumonia (NSIP; κw=0·42 [0·37-0·49]); and fair for hypersensitivity pneumonitis (κw=0·29 [0·24-0·40]). High-confidence diagnoses (>65% likelihood) of IPF were given in 68 (77%) of 88 cases by MDTMs, 62 (65%) of 96 cases by clinicians, and in 57 (66%) of 86 cases by radiologists. Greater prognostic separation was shown for an MDTM diagnosis of IPF than compared with individual clinicians diagnosis of this disease in five of seven MDTMs, and radiologists diagnosis of IPF in four of seven MDTMs. INTERPRETATION Agreement between MDTMs for diagnosis in diffuse lung disease is acceptable and good for a diagnosis of IPF, as validated by the non-significant greater prognostic separation of an IPF diagnosis made by MDTMs than the separation of a diagnosis made by individual clinicians or radiologists. Furthermore, MDTMs made the diagnosis of IPF with higher confidence and more frequently than did clinicians or radiologists. This difference is of particular importance, because accurate and consistent diagnoses of IPF are needed if clinical outcomes are to be optimised. Inter-multidisciplinary team agreement for a diagnosis of hypersensitivity pneumonitis is low, highlighting an urgent need for standardised diagnostic guidelines for this disease. FUNDING National Institute of Health Research, Imperial College London.

New antifungal antibiotics.

Purpose of review The incidence of both invasive fungal infections and respiratory mould infections is increasing and they cause significant costs, morbidity and mortality. Non-Aspergillus moulds are increasing as cause of lung infections in specific populations and new problems of susceptibility and resistance are appearing. Recent findings The antifungal armamentarium has markedly improved in the past 10 years and some new drugs are in the pipeline. The use of these new agents is one of the drivers of the changes in fungal epidemiology. These new antifungal drugs are discussed in this article. Summary A good selection of the antifungal, taking into consideration the pathogen, the host and the pharmacokinetic/pharmacodynamics of the drug, is paramount for clinical success.

Nebulization of antiinfective agents in invasively mechanically ventilated adults: a systematic review and meta-analysis

Background: Nebulization of antiinfective agents is a common but unstandardized practice in critically ill patients. Methods: A systematic review of 1,435 studies was performed in adults receiving invasive mechanical ventilation. Two different administration strategies (adjunctive and substitute) were considered clinically relevant. Inclusion was restricted to studies using jet, ultrasonic, and vibrating-mesh nebulizers. Studies involving children, colonized-but-not-infected adults, and cystic fibrosis patients were excluded. Results: Five of the 11 studies included had a small sample size (fewer than 50 patients), and only 6 were randomized. Diversity of case-mix, dosage, and devices are sources of bias. Only a few patients had severe hypoxemia. Aminoglycosides and colistin were the most common antibiotics, being safe regarding nephrotoxicity and neurotoxicity, but increased respiratory complications in 9% (95% CI, 0.01 to 0.18; I2 = 52%), particularly when administered to hypoxemic patients. For tracheobronchitis, a significant decrease in emergence of resistance was evidenced (risk ratio, 0.18; 95% CI, 0.05 to 0.64; I2 = 0%). Similar findings were observed in pneumonia by susceptible pathogens, without improvement in mortality or ventilation duration. In pneumonia caused by resistant pathogens, higher clinical resolution (odds ratio, 1.96; 95% CI, 1.30 to 2.96; I2 = 0%) was evidenced. These findings were not consistently evidenced in the assessment of efficacy against pneumonia caused by susceptible pathogens. Conclusions: Performance of randomized trials evaluating the impact of nebulized antibiotics with more homogeneous populations, standardized drug delivery, predetermined clinical efficacy, and safety outcomes is urgently required. Infections by resistant pathogens might potentially have higher benefit from nebulized antiinfective agents. Nebulization, without concomitant systemic administration of the drug, may reduce nephrotoxicity but may also be associated with higher risk of respiratory complications.

Use of nebulized antimicrobials for the treatment of respiratory infections in invasively mechanically ventilated adults: a position paper from the European Society of Clinical Microbiology and Infectious Diseases

With an established role in cystic fibrosis and bronchiectasis, nebulized antibiotics are increasingly being used to treat respiratory infections in critically ill invasively mechanically ventilated adult patients. Although there is limited evidence describing their efficacy and safety, in an era when there is a need for new strategies to enhance antibiotic effectiveness because of a shortage of new agents and increases in antibiotic resistance, the potential of nebulization of antibiotics to optimize therapy is considered of high interest, particularly in patients infected with multidrug-resistant pathogens. This Position Paper of the European Society of Clinical Microbiology and Infectious Diseases provides recommendations based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology regarding the use of nebulized antibiotics in invasively mechanically ventilated adults, based on a systematic review and meta-analysis of the existing literature (last search July 2016). Overall, the panel recommends avoiding the use of nebulized antibiotics in clinical practice, due to a weak level of evidence of their efficacy and the high potential for underestimated risks of adverse events (particularly, respiratory complications). Higher-quality evidence is urgently needed to inform clinical practice. Priorities of future research are detailed in the second part of the Position Paper as guidance for researchers in this field. In particular, the panel identified an urgent need for randomized clinical trials of nebulized antibiotic therapy as part of a substitution approach to treatment of pneumonia due to multidrug-resistant pathogens.

Severe sepsis in community-acquired pneumonia — Early recognition and treatment

Despite remarkable advances in its management, community-acquired pneumonia (CAP) remains an important cause of morbidity and mortality leading to significant consumption of health, social and economic resources. The assessment of CAP severity is a cornerstone in its management, facilitating selection of the most appropriate site of care and empirical antibiotic therapy. Several clinical scoring systems based on 30-day mortality have been developed to identify those patients with the highest risk of death. Although well validated in appropriate patient groups, each system has its own limitations and each exhibits different sensitivity and specificity values. These problems have increased interest in the use of biomarkers to predict CAP severity. Although so far no ideal solution has been identified, recent advances in bacterial genomic load quantification have made this tool very attractive. Early antibiotic therapy is essential to the reduction of CAP mortality and the selection of antibiotic treatment according to clinical guidelines is also associated with an improved outcome. In addition, the addition of a macrolide to standard empirical therapy seems to improve outcome in severe CAP although the mechanism of this is unclear. Finally, the role of adjuvant therapy has not yet been satisfactorily established. In this review we will present our opinion on current best practice in the assessment of severity and treatment of severe CAP.

Assessing severity of patients with community-acquired pneumonia.

Despite all advances in its management, community-acquired pneumonia (CAP) is still an important cause of morbidity and mortality requiring a great consumption of health, social, and economic resources. An early and adequate severity assessment is of paramount importance to provide optimized care to these patients. In the last 2 decades, this issue has been the subject of extensive research. Based on 30 day mortality, several prediction rules have been proposed to aid clinicians in deciding on the appropriate site of care. In spite of being well validated, their sensitivity and specificity vary, which limits their widespread use. The utility of biomarkers to overcome this problem has been investigated. At this moment, their full clinical value remains undetermined, and no single biomarker is consistently ideal for assessing CAP severity. Biomarkers should be seen as a complement rather than superseding clinical judgment or validated clinical scores. The search for a gold standard is not over, and new tools, like bacterial DNA load, are in the pipeline. Until then, CAP severity assessment should be based in three key points: a pneumonia-specific score, biomarkers, and clinical judgment.

Antimicrobial drug interactions in the critically ill patients.

Critically ill patients are typically polymedicated and therefore at a high risk for potential drug interactions. Clinical consequences of drugs interactions vary in severity from mild to lethal events. Since infection is an important issue in the Intensive Care Unit (ICU), a significant number of patients will receive an antimicrobial at some stage during their ICU admission. Therefore an adequate knowledge about possible interactions between antimicrobials and other drugs is necessary, since it may not only impact on the effectiveness of the antimicrobial but also in the incidence of drug adverse events. This review describes important drug interactions involving antimicrobials in the critically ill patient.

Mid-regional proadrenomedullin: An early marker of response in critically ill patients with severe community-acquired pneumonia?

BACKGROUND Mid-regional proadrenomedullin (MR-proADM) is a novel biomarker with potential prognostic utility in patients with community-acquired pneumonia (CAP). PURPOSE To evaluate the value of MR-proADM levels at ICU admission for further severity stratification and outcome prediction, and its kinetics as an early predictor of response in severe CAP (SCAP). MATERIALS AND METHODS Prospective, single-center, cohort study of 19 SCAP patients admitted to the ICU within 12h after the first antibiotic dose. RESULTS At ICU admission median MR-proADM was 3.58nmol/l (IQR: 2.83-10.00). No significant association was found between its serum levels at admission and severity assessed by SAPS II (Spearmans correlation=0.24, p=0.31) or SOFA score (SOFA<10: <3.45nmol/l vs. SOFA≥10: 3.90nmol/l, p=0.74). Hospital and one-year mortality were 26% and 32%, respectively. No significant difference in median MR-proADM serum levels was found between survivors and non-survivors and its accuracy to predict hospital mortality was bad (aROC 0.53). After 48h of antibiotic therapy, MR-proADM decreased in all but 5 patients (median -20%; IQR -56% to +0.1%). Its kinetics measured by the percent change from baseline was a good predictor of clinical response (aROC 0.80). The best discrimination was achieved by classifying patients according to whether MR-proADM decreased or not within 48h. No decrease in MR-proADM serum levels significantly increased the chances of dying independently of general severity (SAPS II-adjusted OR 174; 95% CI 2-15,422; p=0.024). CONCLUSIONS In SCAP patients, a decrease in MR-proADM serum levels in the first 48h after ICU admission was a good predictor of clinical response and better outcome.

Pleuroparenchymal fibroelastosis: role of high-resolution computed tomography (HRCT) and CT-guided transthoracic core lung biopsy

AbstractObjectivesPleuroparenchymal fibroelastosis (PPFE) is a rare idiopathic interstitial pneumonia (IIP) with variable clinical and radiological features. Diagnosis is based on histology obtained by surgical lung biopsy, which is associated with significant mortality and morbidity. This study aims to briefly review PPFE and discuss the role of CT-guided transthoracic core lung biopsy (TTB) in its diagnosis.Materials/MethodsFour cases of PPFE diagnosed at our institution with TTB are reported and discussed.ResultsClinical, radiological and histological features are in agreement with the previous literature cases. TTB provided the diagnosis in all cases. Iatrogenic pneumothorax was the main complication in all patients. Placement of a chest tube was needed in three patients. An overlap between PPFE and other interstitial lung diseases (ILD) was documented.ConclusionPPFE is an underdiagnosed IIP, so radiologist awareness of it needs to be widespread in patients with fibrosis with apical-caudal distribution. Coexistence of different lung diseases strengthens the idea of a predisposing factor. TTB proved to be a good diagnostic tool and can be considered the first choice for invasive assessment of these patients. PFFE has a variable course with no established therapeutic options; therefore a multidisciplinary team is crucial in the approach to patients with ILD.Main messages/Teaching Points• PPFE should be considered in the differential diagnosis of fibrosis with apical-caudal distribution. • CT-guided TTB can be considered the first choice for invasive assessment of PPFE. • Site of biopsy has to be chosen carefully in order not to miss PPFE. • Coexistence of different lung diseases strengthens the idea of a predisposing factor. • A multidisciplinary team is crucial in the approach to patients with ILD.

Fluoroquinolones: another line in the long list of their collateral damage record.

708 www.ccmjournal.org March 2015 • Volume 43 • Number 3 patients with some degree of neurological impairment were also included. And finally, HFNC is much easier to use than noninvasive ventilation, is probably cheaper and, as we just noted, it can also be used in patients with reduced levels of consciousness. In summary, HFNC is an easy-to-use supportive therapy that can be safely administered to prevent life-threatening hypoxemia during high-risk procedures in critically ill patients. However, although its presence is increasing every day in our ICUs, certain questions remain unanswered. Does the acute respiratory distress syndrome (ARDS) Berlin definition need to be expanded to consider HFNC patients as patients with mild ARDS? Which patients would benefit the most from HFNC therapy? How early can we predict the success of the technique in patients with ARF in order to avoid delayed intubation? Is HFNC therapy costeffective in different situations? It is clear that HFNC is a new therapeutic tool that is making its mark in respiratory critical care medicine and may well improve our daily practices. However, many issues still need to be investigated.