Evaluation of the Pneumonia Panel on laboratory samples from an Italian pediatric center: results from a monocentric study.

Lower respiratory tract infections (LRTI) are still burdened by considerable morbidity and mortality. Rapid and appropriate treatment imply knowledge of the underlying causative pathogen; while it is tempting to offer broad spectrum antibiotics, Antimicrobial Stewardship Practices invite a judicious use of the latter, especially when bacteria are not the cause. However, the epidemiology shifts to multidrug resistant (MDR) pathogens that require optimization of molecules in order to provide optimal treatment. Novel methods requiring direct sample result testing such as the Biofire Pneumonia (PN) panel have recently been made available on the market. Syndromic testing may hence provide support in the diagnosis of LRTI. There is paucity of data concerning experiences in high MDR settings, and even less concerning the performance of these panels in pediatric settings with moderate MDR prevalence. Our study highlights the optimal sensitivity and importance of support from such methods in settings burdened by MDR presence and where fast and appropriate therapy is mandatory.

Asymmetrical aortic root aneurism in patient with Filamin A mutation.

We report the case of a 28 years old woman with periventricular nodular heterotopia, due to Filamin A mutation. She had an asymmetrical aneurysm of the aortic root, involving, above all, noncoronary Valsalva sinus. She was asymptomatic and she had moderate aortic regurgitation. Reimplantation of the aortic valve with replacement of the aortic root was successfully accomplished. Filamin A is a protein that is encoded by the FLNA gene, which shows X-linked dominant inheritance. This protein is involved in neuronal migration, angiogenesis, cytoskeleton regulation, and cell signaling. Therefore, mutations of FLNA gene might result in brain, blood vessels, heart, and connective tissue disorders. A miscellany of cardiovascular abnormalities could be present in this subset of patients; cardiac symptoms may precede neurological manifestations. Aorta seems to be frequently affected. Consequently, in presence of FLNA gene mutations, cardiovascular evaluation should include vascular magnetic resonance imaging or computed tomography scan.

Arrhythmogenic potential of myocardial disarray in hypertrophic cardiomyopathy: genetic basis, functional consequences and relation to sudden cardiac death.

Myocardial disarray is defined as disorganized cardiomyocyte spatial distribution, with loss of physiological fibre alignment and orientation. Since the first pathological descriptions of hypertrophic cardiomyopathy (HCM), disarray appeared as a typical feature of this condition and sparked vivid debate regarding its specificity to the disease and clinical significance as a diagnostic marker and a risk factor for sudden death. Although much of the controversy surrounding its diagnostic value in HCM persists, it is increasingly recognized that myocardial disarray may be found in physiological contexts and in cardiac conditions different from HCM, raising the possibility that central focus should be placed on its quantity and distribution, rather than a mere presence. While further studies are needed to establish what amount of disarray should be considered as a hallmark of the disease, novel experimental approaches and emerging imaging techniques for the first time allow ex vivo and in vivo characterization of the myocardium to a molecular level. Such advances hold the promise of filling major gaps in our understanding of the functional consequences of myocardial disarray in HCM and specifically on arrhythmogenic propensity and as a risk factor for sudden death. Ultimately, these studies will clarify whether disarray represents a major determinant of the HCM clinical profile, and a potential therapeutic target, as opposed to an intriguing but largely innocent bystander.

Late acute aortic dissection following cardiac transplantation in lupus-affected donor aorta.

We report the case of a young woman who underwent cardiac transplantation from systemic lupus erythematosus affected donor and who developed a type A aortic dissection limited only to the graft aortic wall 9 years after.

Pathological features of COVID-19-associated myocardial injury: a multicentre cardiovascular pathology study.

AIMS: Coronavirus disease 2019 (COVID-19) due to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has been associated with cardiovascular features of myocardial involvement including elevated serum troponin levels and acute heart failure with reduced ejection fraction. The cardiac pathological changes in these patients with COVID-19 have yet to be well described. METHODS AND RESULTS: In an international multicentre study, cardiac tissue from the autopsies of 21 consecutive COVID-19 patients was assessed by cardiovascular pathologists. The presence of myocarditis, as defined by the presence of multiple foci of inflammation with associated myocyte injury, was determined, and the inflammatory cell composition analysed by immunohistochemistry. Other forms of acute myocyte injury and inflammation were also described, as well as coronary artery, endocardium, and pericardium involvement. Lymphocytic myocarditis was present in 3 (14%) of the cases. In two of these cases, the T lymphocytes were CD4 predominant and in one case the T lymphocytes were CD8 predominant. Increased interstitial macrophage infiltration was present in 18 (86%) of the cases. A mild pericarditis was present in four cases. Acute myocyte injury in the right ventricle, most probably due to strain/overload, was present in four cases. There was a non-significant trend toward higher serum troponin levels in the patients with myocarditis compared with those without myocarditis. Disrupted coronary artery plaques, coronary artery aneurysms, and large pulmonary emboli were not identified. CONCLUSIONS: In SARS-CoV-2 there are increased interstitial macrophages in a majority of the cases and multifocal lymphocytic myocarditis in a small fraction of the cases. Other forms of myocardial injury are also present in these patients. The macrophage infiltration may reflect underlying diseases rather than COVID-19.

The XVth Banff Conference on Allograft Pathology the Banff Workshop Heart Report: Improving the diagnostic yield from endomyocardial biopsies and Quilty effect revisited.

The XVth Banff Conference on Allograft Pathology meeting was held on September 23-27, 2019, in Pittsburgh, Pennsylvania, USA. During this meeting, two main topics in cardiac transplant pathology were addressed: (a) Improvement of endomyocardial biopsy (EMB) accuracy for the diagnosis of rejection and other significant injury patterns, and (b) the orphaned lesion known as Quilty effect or nodular endocardial infiltrates. Molecular technologies have evolved in recent years, deciphering pathophysiology of cardiac rejection. Diagnostically, it is time to integrate the histopathology of EMBs and molecular data. The goal is to incorporate molecular pathology, performed on the same paraffin block as a companion test for histopathology, to yield more accurate and objective EMB interpretation. Application of digital image analysis from hematoxylin and eosin (H&E) stain to multiplex labeling is another means of extracting additional information from EMBs. New concepts have emerged exploring the multifaceted significance of myocardial injury, minimal rejection patterns supported by molecular profiles, and lesions of arteriolitis/vasculitis in the setting of T cell-mediated rejection (TCMR) and antibody-mediated rejection (AMR). The orphaned lesion known as Quilty effect or nodular endocardial infiltrates. A state-of-the-art session with historical aspects and current dilemmas was reviewed, and possible pathogenesis proposed, based on advances in immunology to explain conflicting data. The Quilty effect will be the subject of a multicenter project to explore whether it functions as a tertiary lymphoid organ.

Primary malignant pericardial tumour in Lynch syndrome.

BACKGROUND: This case represents the first report of malignant primary cardiac tumour in a patient with Lynch Syndrome associated with MSH2 pathogenic variant. CASE PRESENTATION: A 57-year-old woman with previous ovarian cystadenocarcinoma was admitted to the emergency room for hematic pericardial effusion. Multimodal diagnostic imaging revealed two solid pericardial vascularized masses. After pericardiectomy, the final histological diagnosis was poorly differentiated pleomorphic sarcomatoid carcinoma. During follow-up she developed an ampulla of Vater adenocarcinoma. Genetic analysis identified an MSH2 pathogenic variant. CONCLUSION: This case contributes to expand the tumour spectrum of Lynch syndrome, suggesting that MSH2 pathogenic variants cause a more complex multi-tumour cancer syndrome than the classic Lynch Syndrome. In MSH2 variant carriers, symptoms such as dyspnoea and chest discomfort might alert for rare tumours and a focused cardiac evaluation should be considered.

Post-mortem thermal angiography: a pilot study on swine coronary circulation.

Thermal imaging (TI) allows the detection of thermal patterns emitted from objects as a function of their temperature in the long-infrared spectrum and produces visible images displaying temperature differences. The aim of this pilot study was to test TI to visualize the coronary circulation of swine hearts. Thirty swine hearts were prepared for ex situ coronarography, and thermal images were acquired through a FlirOne thermal camera (FLIR Systems®) paired with a Google Android Smartphone. Coronary arteries were cannulated, namely the anterior interventricular artery, the circumflex branch of the left coronary artery, and the right coronary artery. The heart was cooled, and contrast medium (CM) consisting of distilled water heated to 40 °C was injected in a coronary vessel, while thermal images were captured. These steps were repeated for each coronary vessel and under experimentally simulated coronary heart disease. Thermal imaging coronarography (TIC) allowed a clear representation of the morphology and course of the coronary vessels and of experimentally simulated coronary heart disease, moreover, demonstrated to be easy to perform during or after autopsies on ex situ hearts, non-destructive, reproducible, and cheap. On the basis of these preliminary results, TIC might allow a subsequent more focused and comprehensive cardiopathological examination of the heart, which remains mandatory for the definitive diagnosis of coronary heart disease. Although these preliminary results seem encouraging, further systematic studies on human hearts, both normal and pathological, are necessary for estimating the sensitivity and specificity of the proposed method and to draw any definitive conclusion.

A case report of IgG4-related disease: an insidious path to the diagnosis through kidney, heart and brain.

BACKGROUND: IgG4-related disease, described around the years 2000 as a form of autoimmune pancreatitis, is now increasingly accepted as a systemic syndrome. The diagnosis is based on both comprehensive and organ-specific criteria. For the kidney, Mayo clinic classification and the guidelines of the Japanese Nephrology Society are used. Ultimately, together with parameters that characterize every organ or apparatus involved, the key element is the confirmation of growing levels of IgG4 in blood or in tissues. CASE PRESENTATION: We describe a male patient with chronic renal failure associated to hypertension without proteinuria. IgG4-related disease was diagnosed through renal biopsy. After an initial positive response to steroids, he presented tinnitus, and histological assessment showed cerebral and subsequently cardiac damage, both IgG4-related. This case appears unique for the type of histologically documented cardiac and neurological parenchymal involvement, and at the same time, exemplifies the subtle and pernicious course of the disease. Frequently, blurred and non-specific signs prevail. Here, kidney damage was associated with minimal urinary findings, slowly progressive renal dysfunction and other factors that can be equivocated in the differential diagnosis. Neurological involvement was represented by tinnitus alone, while cardiac alterations were completely asymptomatic. CONCLUSIONS: This report is representative of the neurological and cardiac changes described in the literature for IgG4-related disease, which may be correlated or not with the renal form and highlights the need, in some cases, of targeted therapeutic approaches. In addition to glucocorticoids, as in this case, rituximab may be necessary.

Does the antibody mediated rejection grading scale have prognostic prediction? Yes, but the picture is still blurry.

PURPOSE OF REVIEW: Antibody-mediated rejection (ABMR) is a condition difficult to diagnose and treat, which may significantly impair the outcome of heart transplant recipients. In clinical practice, diagnosis is based on immunopathology grading of endomyocardial biopsies (EMB). Despite its value, the current diagnostic system has several pitfalls that have been addressed in recent literature. RECENT FINDINGS: Pathology grading of ABMR (pAMR) has a relevant prognostic factor. However, it does not capture several nuances, such as chronic vs. acute ABMR, mixed rejection or microvascular inflammation. Molecular biology-based assays are shedding new light on the mechanisms of ABMR, which could improve the precision of ABMR diagnosis. SUMMARY: These new findings have the potential to rearrange EMB grading system and to guide more precisely decision-making, but studies validating the therapeutic management based on molecular-pathology coupling are still missing.

Long-term Follow up of Patients with Acute Aortic Syndromes: Relevance of both Aortic and Non-aortic Events.

BACKGROUND: The aim was to assess the long-term outcome of patients diagnosed with type A and type B acute aortic syndromes (AAS) and the mortality risk predictors. METHODS: A single centre retrospective observational study was performed on consecutive patients diagnosed with AAS and discharged between 2000 and 2016: 242 surgically treated type A, 87 uncomplicated, medically treated type B, and 80 complicated type B who received endovascular/surgical/hybrid treatment. Follow up of discharged patients (5 ± 3.9 years) was almost complete by the end of the study (December 2017). RESULTS: The mean age was 65.3 ± 12.5 years, and 70.2% were men. Long-term all cause mortality was 5.4 per 100 patients per year in surgically treated type A AAS patients and 6.7 per 100 patients per year in type B AAS patients (p = .236). The rates of major aorta related events were 6.1 per 100 patients per year and 13.4 per 100 patients per year, respectively (p < .001). Non-aorta related events during long-term follow up occurred in 18.2 per 100 patients per year in type A and 13.8 per 100 patients per year in type B (p = .055). At the end of follow up 279/409 (68.2%) patients (165/242 type A and 114/167 type B) experienced at least one event. CONCLUSIONS: Among patients with either type A or type B AAS surviving the acute phase, the risk of adverse aorta and non-aorta related events, including death, persists during follow up, so that eventually two thirds of patients will experience at least one event. Notably, all cause mortality after type B AAS exceeds that of type A AAS after three years.

Antibody-mediated rejection in heart transplantation: new developments and old uncertainties.

PURPOSE OF REVIEW: Antibody-mediated rejection (AMR) currently represents one of the main problems for clinical management of heart transplant because of its diagnostic complexity and poor evidences supporting treatments. RECENT FINDINGS: Disorder-based diagnosis is a cornerstone in defining AMR. The limitations of the current classification have been partially overcome by novel studies improving the description of the immune-pathological graft abnormalities, and by new molecular approaches allowing a better understanding of the mechanisms behind AMR and of its relationship with cellular rejection and chronic vasculopathy. In-depth characterization of donor-specific antibodies showed to provide additional prognostic information and guide for treatment. Clinical relevance of AMR is bound to appropriate detection of graft dysfunction. In addition to traditional longitudinal evaluation by echocardiogram, cardiac magnetic resonance and detection of cell-free DNA may represent novel sensitive markers for graft injury that could prompt treatment before dysfunction becomes clinically manifest. SUMMARY: Despite improvements in the diagnostic process, therapeutic strategies made little progress in addition to the consolidation of practices supported by limited evidences. Novel complement inhibitors appear promising in changing this scenario. Nevertheless, collaborative multicenter studies are needed to develop standardized approaches tailored to the highly variable clinical and laboratory features of AMR.

Sleep and cardiovascular phenotype in middle-aged hypocretin-deficient narcoleptic mice.

Narcolepsy with cataplexy (NC) is a lifelong disorder caused by loss of hypothalamic hypocretin/orexin (HCRT) neurones, often starting in childhood. NC patients show altered control of heart rate (HR) and a normotensive non-dipper blood pressure (BP) profile, but the natural history and prognostic significance of these alterations remain unclear. Similar alterations have been observed in HCRT-ataxin-3 transgenic (TG) NC mice lacking HCRT neurones, but studies have been limited to young adult individuals <4 months of age. Here we evaluated long-term effects of NC on derangements in the wake-sleep state and cardiovascular control by studying middle-aged TG. We chronically instrumented TG and wild-type mice aged 10-11 months with electrodes for sleep scoring and a telemetric transducer for BP and HR measurements. We then recorded mice in freely behaving conditions. TG showed a NC phenotype including fragmentation of wakefulness, reduced latency to rapid eye movement sleep (REMS) and cataplexy-like events. TG also showed blunted BP decline on entering non-rapid eye movement sleep (NREMS), enhanced BP increase on passing to REMS, increased HR, and blunted changes in HR upon arousal and awakening from NREMS. Histological and ultrastructural analysis of cardiovascular and renal tissue did not reveal evidence of subclinical hypertensive organ damage. These data indicate that HCRT neurone loss in TG causes alterations in wake-sleep behaviour and cardiovascular control that are not peculiar to the beginning of the disease but are maintained at least up to middle age. These alterations are similar to those in adult NC patients, but do not produce early subclinical damage to the heart and kidneys.

Medium-term outcome of recipients of marginal donor hearts selected with new stress-echocardiographic techniques over standard criteria.

BACKGROUND: Heart transplantation is limited by severe donor organ shortage. Regardless of the changes made in the acceptance of marginal donors, any such mechanism cannot be considered successful unless recipient graft survival rates remain acceptable. A stress echo-driven selection of donors has proven successful in older donors with normal left ventricular resting function and in standard donors with reversible resting left ventricular dysfunction acutely improving during stress, or slowly improving (over hours) during intensive hormonal treatment. Aim of this study is to assess the medium-term outcome of recipients of marginal donor hearts selected with new echocardiographic techniques over standard criteria. METHODS AND RESULTS: We enrolled 43 recipients of marginal donor hearts: age > 55 years, or < 55 years but with concomitant risk factors, n = 32; acutely improving during stress, n = 3; or slowly improving during hormonal treatment, n = 8. At follow-up (median, 30 months; interquartile range, 21-52 months), 37 of the recipients were still alive. One-year survival was 93%. CONCLUSION: The strict use of new stress-echocardiographic techniques over standard criteria of marginal donor management, together with comprehensive monitoring of the donor, has the potential to substantially increase the number of donor hearts without adverse effects on recipient medium-term outcome.

Disease profile and differential diagnosis of hereditary transthyretin-related amyloidosis with exclusively cardiac phenotype: an Italian perspective.

AIMS: Hereditary transthyretin (TTR)-related amyloidosis (ATTR) is mainly considered a neurologic disease. We assessed the phenotypic and genotypic spectra of ATTR in a Caucasian area and evaluated the prevalence, genetic background, and disease profile of cases with an exclusively cardiac phenotype, highlighting possible hints for the differential diagnosis with hypertrophic cardiomyopathy (HCM) and senile systemic amyloidosis (SSA). METHODS AND RESULTS: In this Italian multicentre study, 186 patients with ATTR were characterized at presentation. Thirty patients with SSA and 30 age-gender-matched HCM patients were used for comparison. Phenotype was classified as exclusively cardiac (n = 31, 17%), exclusively neurologic (n = 46, 25%), and mixed cardiac/neurologic (n = 109, 58%). Among the eight different mutations responsible for an exclusively cardiac phenotype, Ile68Leu was the most frequent. Five patients with an exclusively cardiac phenotype developed mild abnormalities at neurological examination, but no symptoms during a 36-month follow-up (range: 14-50). Exclusively cardiac phenotype was characterized by male gender, age >65 years, heart failure symptoms, symmetric left ventricular (LV) 'hypertrophy', and moderately depressed LV ejection fraction. This profile was similar to SSA, but relatively distinct from HCM. Compared with patients with a mixed phenotype, patients with an exclusively cardiac phenotype showed a more pronounced cardiac involvement on both echocardiogram and electrocardiogram (ECG). CONCLUSION: A clinically relevant subset of Caucasian ATTR patients present with an exclusively cardiac phenotype, mimicking HCM or SSA. Echocardiographic and ECG findings are useful to differentiate ATTR from HCM but not from SSA. The role of liver transplantation in these patients should be reconsidered.

Myocardial perfusion in cardiac amyloidosis.

AIMS: Cardiac involvement is the main driver of clinical outcomes in systemic amyloidosis and preliminary studies support the hypothesis that myocardial ischaemia contributes to cellular damage. The aims of this study were to assess the presence and mechanisms of myocardial ischaemia using cardiovascular magnetic resonance (CMR) with multiparametric mapping and histopathological assessment. METHODS AND RESULTS: Ninety-three patients with cardiac amyloidosis (CA) (light-chain amyloidosis n = 42, transthyretin amyloidosis n = 51) and 97 without CA (three-vessel coronary disease [3VD] n = 47, unobstructed coronary arteries n = 26, healthy volunteers [HV] n = 24) underwent quantitative stress perfusion CMR with myocardial blood flow (MBF) mapping. Twenty-four myocardial biopsies and three explanted hearts with CA were analysed histopathologically. Stress MBF was severely reduced in patients with CA with lower values than patients with 3VD, unobstructed coronary arteries and HV (CA: 1.04 ± 0.51 ml/min/g, 3VD: 1.35 ± 0.50 ml/min/g, unobstructed coronary arteries: 2.92 ± 0.52 ml/min/g, HV: 2.91 ± 0.73 ml/min/g; CA vs. 3VD p = 0.011, CA vs. unobstructed coronary arteries p < 0.001, CA vs. HV p < 0.001). Myocardial perfusion abnormalities correlated with amyloid burden, systolic and diastolic function, structural parameters and blood biomarkers (p < 0.05). Biopsies demonstrated abnormal vascular endothelial growth factor staining in cardiomyocytes and endothelial cells, which may be related to hypoxia conditions. Amyloid infiltration in intramural arteries was associated with severe lumen reduction and severe reduction in capillary density. CONCLUSION: Cardiac amyloidosis is associated with severe inducible myocardial ischaemia demonstrable by histology and CMR stress perfusion mapping. Histological evaluation indicates a complex pathophysiology, where in addition to systolic and diastolic dysfunction, amyloid infiltration of the epicardial arteries and disruption and rarefaction of the capillaries play a role in contributing to myocardial ischaemia.

Transplant of stunned donor hearts rescued by pharmacological stress echocardiography: a "proof of concept" report.

BACKGROUND: Due to the shortage of donor hearts, the criteria for acceptance have been considerably expanded. Hearts with regional or global left ventricular dysfunction are excluded from donation, but stress echo might be useful to identify patients with reversible wall motion abnormalities, potentially eligible for donation. METHODS: Six marginal candidate donors (mean age, 40 ± 13 years; three men) were enrolled. Resting echocardiography showed in all subjects a LV ejection fraction ≥ 45% (mean 51 ± 5%), but multiple risk factors were present. All donors had either global or discrete wall motion abnormalities: Wall Motion Score Index (WMSI) rest = 1.33 ± 0.25. Stress echocardiography was performed with the dipyridamole high dose of 0.84 mg/kg given over 6 min. RESULTS: The stress echo results were abnormal in three donors (WMSI rest = 1.51 ± 0.19 vs peak = 1.41 ± 0.30). These hearts were excluded from donation and cardiac pathology verification was available in two cases of confirmed LV myocardial fibrosis and/or severe coronary stenosis. The remaining three hearts improved during stress (WMSI rest = 1.15 ± 0.13 vs peak = 1.04 ± 0.06) and were transplanted uneventfully. Recipients (three males, mean age 53 ± 4 years) underwent post-TX coronary angiography, IVUS and endomyocardial biopsies. No recipient had primary graft failure, and all showed normal coronary angiography and normal LV function (EF = 57 ± 6%; WMSI = 1 ± 0) at 1-month post-TX. The recipients were alive at 12-month median follow-up. CONCLUSIONS: Dipyridamole stress echo performed in brain-dead potential donors with LV resting global or discrete wall motion abnormalities identifies hearts with severe morphologic abnormalities excluded from donation (with fixed response during stress echo) from hearts eligible for donation, showing improvement in regional wall motion during stress (viability response) and normal function and coronary anatomy following transplantation.

Commentary on why implementing and standardizing histologic diagnosis of myocarditis is crucial for the clinical setting and patient care.

Histological examination of endomyocardial biopsy or myocardium at autopsy is key to the diagnosis of myocarditis. Among pathologists there is currently extensive variability in routine practice and criteria used to define, diagnose, and report myocarditis as well as to achieve consensus on cases. Two manuscripts emphasizing the need to standardize and implement histopathological diagnostic criteria for myocarditis are reviewed.

Sudden cardiac death related to left coronary artery anomalies including hypoplasia and anomalous origin with retro-aortic course.

Congenital anomalies of the coronary arteries are a rare condition with an incidence of 0.3-1.3% in the general population. Clinically, sometimes these anomalies increase the risk of myocardial ischemia, which can present with a wide spectrum of symptoms, from angina to sudden cardiac death (SCD). This case report is about the SCD of an 8-year-old male, in apparent good health, during a football training. Although basic life support maneuvers were performed timely from bystanders and medical staff, the automated external defibrillator (AED) was not used. Autopsy revealed multiple left coronary artery (LCA) anomalies: origin from a separate ostium in the right sinus of Valsalva, slit-like shape of the ostium, acute angle take-off of the LCA from the aorta, retro-aortic course and focal coronary hypoplasia of some branches of the LCA. Microscopic examination revealed diffuse ischemic consequences at a different stage of tissue repair and mild multifocal lymphocytic infiltration. No other significant elements were detected at post-mortem examination. We discuss the forensic evaluation about the cause and the manner of death, considering also the modality of the resuscitation attempts and the claimed malpractice, as often occurs in case of sudden unexpected death in young athletes.