The thromboembolism in COVID-19: the unsolved problem.

INTRODUCTION: The recent Sars-Cov-2 pandemic (COVID-19) has led to growing research to explain the poor clinical prognosis in some patients. EVIDENCE ACQUISITION: While early observational studies highlighted the role of the virus in lung failure, in a second moment thrombosis emerged as a possible explanation of the worse clinical course in some patients. Despite initial difficulties in management of such patients, the constant increase of literature in the field is to date clarifying some questions from clinicians. However, several other questions need answer. EVIDENCE SYNTHESIS: A novel disease (Covid-19) due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was responsible for thousands of hospitalizations for severe acute respiratory syndrome, with several cases of thrombotic complications due to excessive inflammation, platelet activation, endothelial dysfunction, and stasis. Covid-19 and hospitalizations for Covid-19 may carry several potential risk factors for thrombosis. Severe coagulation abnormalities may occur in almost all of the severe and critical ill COVID-19 cases. CONCLUSIONS: Despite a strong pathophysiological rationale, the evidences in literature are not enough to recommend an aggressive antithrombotic therapy in COVID- 19. However, it is our opinion that an early use, even at home at the beginning of the disease, could improve the clinical course.

Natural Course of COVID-19 and Independent Predictors of Mortality.

BACKGROUND: During the SARS-CoV-2 pandemic, several biomarkers were shown to be helpful in determining the prognosis of COVID-19 patients. The aim of our study was to evaluate the prognostic value of N-terminal pro-Brain Natriuretic Peptide (NT-pro-BNP) in a cohort of patients with COVID-19. METHODS: One-hundred and seven patients admitted to the Covid Hospital of Messina University between June 2022 and January 2023 were enrolled in our study. The demographic, clinical, biochemical, instrumental, and therapeutic parameters were recorded. The primary outcome was in-hospital mortality. A comparison between patients who recovered and were discharged and those who died during the hospitalization was performed. The independent parameters associated with in-hospital death were assessed by multivariable analysis and a stepwise regression logistic model. RESULTS: A total of 27 events with an in-hospital mortality rate of 25.2% occurred during our study. Those who died during hospitalization were older, with lower GCS and PaO2/FiO2 ratio, elevated D-dimer values, INR, creatinine values and shorter PT (prothrombin time). They had an increased frequency of diagnosis of heart failure (p < 0.0001) and higher NT-pro-BNP values. A multivariate logistic regression analysis showed that higher NT-pro-BNP values and lower PT and PaO2/FiO2 at admission were independent predictors of mortality during hospitalization. CONCLUSIONS: This study shows that NT-pro-BNP levels, PT, and PaO2/FiO2 ratio are independently associated with in-hospital mortality in subjects with COVID-19 pneumonia. Further longitudinal studies are warranted to confirm the results of this study.

The Impact of COVID-19 Pandemic on Hospitalization and Interventional Procedures for Cardiovascular Diseases during the First Wave in Italy.

Coronavirus disease 2019 (COVID-19) has been responsible for an epidemic of devastating proportion, and it has represented a challenge for worldwide healthcare systems with the need of resources reallocation in order to face epidemic spread. Italy was one of the hardest hit countries by COVID-19, and the Italian government adopted strict rules to contain the spread of the COVID-19 pandemic, such as national lockdown and home quarantine; moreover, the Italian healthcare system had to rapidly re-organize the diagnostic and therapeutic pathways, with a reallocation of health resources and hospital beds, in order to manage COVID-19 patients. The aim of the present review is to provide an overview of the effects of the first pandemic wave on cardiovascular assistance in Italy with the purpose of evaluating the strengths and weaknesses of the Italian health system.

Thromboembolic Complications in COVID-19 Patients Hospitalized in Italian Ordinary Wards: Data from the Multicenter Observational START-COVID Register.

Background Coronavirus disease 2019 (COVID-19) infection causes acute respiratory insufficiency with severe interstitial pneumonia and extrapulmonary complications; in particular, it may predispose to thromboembolic disease. The reported incidence of thromboembolic complications varies from 5 to 30% of cases. Aim We conducted a multicenter, Italian, retrospective, observational study on COVID-19 patients admitted to ordinary wards, to describe the clinical characteristics of patients at admission and bleeding and thrombotic events occurring during the hospital stay. Results The number of hospitalized patients included in the START-COVID-19 Register was 1,135, and the number of hospitalized patients in ordinary wards included in the study was 1,091, with 653 (59.9%) being males and 71 years (interquartile range 59-82 years) being the median age. During the observation, two (0.2%) patients had acute coronary syndrome episodes and one patient (0.1%) had an ischemic stroke; no other arterial thrombotic events were recorded. Fifty-nine patients had symptomatic venous thromboembolism (VTE) (5.4%) events, 18 (30.5%) deep vein thrombosis (DVT), 39 (66.1%) pulmonary embolism (PE), and 2 (3.4%) DVT+PE. Among patients with DVT, eight (44.4%) were isolated distal DVT and two cases were jugular thrombosis. Among patients with PE, seven (17.9%) events were limited to subsegmental arteries. No fatal PE was recorded. Major bleeding events occurred in nine (1.2%) patients and clinically relevant nonmajor bleeding events in nine (1.2%) patients. All bleeding events occurred among patients receiving thromboprophylaxis, more frequently when treated with subtherapeutic or therapeutic dosages. Conclusion Our findings confirm that patients admitted to ordinary wards for COVID-19 infection are at high risk for thromboembolic events. VTE recorded among these patients is mainly isolated PE, suggesting a peculiar characteristic of VTE in these patients.

Lesson Learnt by Covid-19: Going from Pandemic to Endemic Covid-19, should we Work for Diagnostic Criteria to Perform a Right Diagnosis of Covid-19 in the Future?

Patients with lung failure could be always easily identified because associated to typical signs and symptoms have anamnestic relevant data (e.g. immunocompromised patients or antivax people or non-responders to vaccines);yet also patients without recent clinical findings of lung failure may be found with interstitial pneumonia that should be investigated with a thorough differential diagnosis including also the research of SARS CoV2 on nasopharyngeal swab or bronchoalveolar lavage. Immunological tests as immunoglobulin's toward SARS CoV2 IG M or IG G have a positive clinical impact only if symptoms are longer than 5-6 days and in non-vaccinated people (in particular IG G). [...]in patients with high suspect of COVID-19radiological imaging of lung is always needed because the specific tropism of SARS CoV2 for respiratory system, in particular for the action of viral spike protein and its link with ACE2 protein present in high concentration on the surface of cells of respiratory tract. [...]these patients may induce clinical misunderstanding in daily clinical practice: they may refer a specific symptoms escaping each type of triage system, they may have a reduced or absent viral load so escaping real Time PCR at NPS and they may show not-extended interstitial pneumonia without recent infection and/or lung failure so inducing all of us to consider a thorough differential diagnosis with other causes of interstitial pneumonia. [...]after the exclusion of connettivitiis (e.g. rheumatoid arthritis, systemic erythematous lupus and so) [30] and hypersensitivity pneumonitis (e.g. drug intolerance, allergy and so on) [31, 32], an evaluation of infective causes should be performed and it should include the microbiological test to identify bacteria, pests or viruses (e.g. mycoplasma, legionellaspp, pneumocystis, influenza virus) [33, 34] and to include also the research of SARS CoV2 with NPS or bronchoalveolar lavage (BAL) with real time PCR (Table 1).

The pharmacology of anticoagulant drug treatment options in COVID-19 patients: reviewing real-world evidence in clinical practice.

INTRODUCTION: The optimal anticoagulation strategy for venous thromboembolism (VTE) prevention among COVID-19 patients, hospitalized or in the community setting, is still challenging and largely based on real-world evidence. AREAS COVERED: We analyzed real-world data regarding the safety and effectiveness of anticoagulant treatment, both parenteral and oral, for VTE prevention or atrial fibrillation (AF)/VTE treatment among COVID-19 patients. EXPERT OPINION: The efficacy of low-molecular-weight heparin (LMWH) doses for VTE prevention correlates with COVID-19 disease status. LMWH prophylactic dose may be useful in COVID-19 patients at the early stage of the disease. LMWH intermediate or therapeutic dose is recommended in COVID-19 patients with an advanced stage of the disease. COVID-19 patients on VKA therapy for atrial fibrillation (AF) and VTE should switch to NOACs in the community setting or LMWH in the hospital setting. No definitive data on de-novo starting of NOACs or VKA therapy for VTE prevention in COVID-19 outpatients are available. In patients at high risk discharged after hospitalization due to COVID-19, thromboprophylaxis with NOACs may be considered.

Special Issue "COVID-19 and Thrombosis".

Since the pandemic began, an association among COVID-19 and venous thromboembolism has been reported, in particular for inpatients [...].

Correction: Di Micco et al. Clinical Differences between COVID-19 and a COVID-like Syndrome. J. Clin. Med. 2021, 10, 2519.

Incorrect Affiliation [...].

New-Onset Atrial Fibrillation and Early Mortality Rate in COVID-19 Patients: Association with IL-6 Serum Levels and Respiratory Distress.

Background and objectives: COVID-19 is associated with an aberrant inflammatory response that may trigger new-onset cardiac arrhythmias. The aim of this study was to assess the mortality risk in hospitalized COVID-19 patients according to IL-6 serum levels and new-onset atrial fibrillation (AF) according to PaO2/FiO2 stratification. Materials and Methods: 175 COVID-19 patients (25 new-onset AF, 22 other types of AF and 128 no-AF) were included in this single-center, retrospective study; clinical and demographic data, vital signs, electrocardiograms and laboratory results were collected and analyzed. The primary outcome of the study was to evaluate the mortality rate in new-onset AF patients according to IL-6 serum levels and PaO2/FiO2 stratification. Results: The incidence of new-onset AF in the study population was 14.2%. Compared to the no-AF group, new-onset AF patients were older with a positive history of chronic kidney disease and heart failure, had higher IL-6, creatinine and urea serum levels whereas their platelet count was reduced. After PaO2/FiO2 stratification, 5-days mortality rate was higher in new-onset AF patients compared to patients with other types of AF and no-AF patients, and mortality risk increases 5.3 fold compared to no-AF (p = 0.0014) and 4.8 fold compared to other forms of AF (p = 0.03). Conclusions: New-onset AF is common in COVID-19 patients and is associated with increased IL-6 serum levels and early mortality. Further studies are needed to support the use of IL-6 as an early molecular target for COVID-19 patients to reduce their high rate of mortality.

Clinical Outcome of Hospitalized COVID-19 Patients with History of Atrial Fibrillation.

Background and objectives: Pre-existing atrial fibrillation (AF) is a frequent comorbidity in hospitalized patients with COVID-19; however, little is still known about its prognostic role in infected patients. The aim of our study was to evaluate whether the pre-existing AF as comorbidity would contribute to increase the risk for severe forms of COVID-19, worse prognosis, or even higher mortality. Materials and Methods: We retrospectively evaluated all consecutive COVID-19 patients admitted to the emergency department of nine Italian Hospitals from 1 March to 30 April 2020.The prevalence and the type of pre-existing AF have been collected. The correlation between the history and type of AF and the development of severe ARDS and in-hospital mortality has been evaluated. Results: In total, 467 patients (66.88 ± 14.55 years; 63% males) with COVID-19 were included in the present study. The history of AF was noticed in 122 cases (26.1%), of which 12 (2.6%) with paroxysmal, 57 (12.2%) with persistent and 53 (11.3%) with permanent AF. Among our study population, COVID-19 patients with AF history were older compared to those without AF history (71.25 ± 12.39 vs. 65.34 ± 14.95 years; p < 0.001); however, they did not show a statistically significant difference in cardiovascular comorbidities or treatments. Pre-existing AF resulted in being independently associated with an increased risk of developing severe ARDS during the hospitalization; in contrast, it did not increase the risk of in-hospital mortality. Among patients with AF history, no significant differences were detected in severe ARDS and in-hospital mortality between patients with permanent and non-permanent AF history. Conclusions: Pre-existing AF is a frequent among COVID-19 patients admitted to hospital, accounting up to 25% of cases. It is independently associated with an increased risk of severe ARDS in hospitalized COVID-19 patients; in contrast, it did not affect the risk of death. The type of pre-existing AF (permanent or non-permanent) did not impact the clinical outcome.

Venous Thrombosis within 30 Days after Vaccination against SARS-CoV-2 in a Multinational Venous Thromboembolism Registry.

BACKGROUND: Venous thromboembolism (VTE)-including deep vein thrombosis, pulmonary embolism, and cerebral venous sinus thrombosis (CVST)-may occur early after vaccination against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We sought to describe the site, clinical characteristics, and outcomes of VTE after vaccination against SARS-CoV-2. METHODS: In a prospective study using the Registro Informatizado de Enfermedad TromboEmbólica (RIETE) platform, patients with VTE 4-30 days after vaccination against SARS-CoV-2 (1 February 2021 through 30 April 2021) were included. VTE patients recruited from the same centers into RIETE in the same months in 2018-2019 were selected as the reference group. All-cause mortality and major bleeding were the main study outcomes. RESULTS: As of 30 April 2020, 102 patients with post-vaccination VTEs had been identified (28 after adenovirus-based vaccination [ChAdOx1 nCov-19; AstraZeneca] and 74 after mRNA-based vaccination [mRNA-1273; Moderna, and BNT162b2; Pfizer]). Compared with 911 historical controls, patients with VTE after adenovirus-based vaccination more frequently had CVST (10.7% vs. 0.4%, p < 0.001) or thrombosis at multiple sites (17.9% vs. 1.3%, p < 0.001), more frequently had thrombocytopenia (40.7% vs. 14.7%, p < 0.001), and had higher 14-day mortality (14.3% vs. 0.7%; odds ratio [OR]: 25.1; 95% confidence interval [CI]: 6.7-94.9) and major bleeding rates (10.3% vs. 1.0%, OR: 12.03, 95% CI: 3.07-47.13). The site of thrombosis, accompanying thrombocytopenia, and 14-day mortality rates were not significantly different for patients with VTE after mRNA-based vaccination, compared with historical controls. CONCLUSIONS: Compared with historical controls, VTE after adenovirus-based vaccination against SARS-CoV-2 is accompanied by thrombocytopenia, occurs in unusual sites, and is associated with worse clinical outcomes.

Machine Learning to Calculate Heparin Dose in COVID-19 Patients with Active Cancer.

To realize a machine learning (ML) model to estimate the dose of low molecular weight heparin to be administered, preventing thromboembolism events in COVID-19 patients with active cancer. Methods: We used a dataset comprising 131 patients with active cancer and COVID-19. We considered five ML models: logistic regression, decision tree, random forest, support vector machine and Gaussian naive Bayes. We decided to implement the logistic regression model for our study. A model with 19 variables was analyzed. Data were randomly split into training (70%) and testing (30%) sets. Model performance was assessed by confusion matrix metrics on the testing data for each model as positive predictive value, sensitivity and F1-score. Results: We showed that the five selected models outperformed classical statistical methods of predictive validity and logistic regression was the most effective, being able to classify with an accuracy of 81%. The most relevant result was finding a patient-proof where python function was able to obtain the exact dose of low weight molecular heparin to be administered and thereby to prevent the occurrence of VTE. Conclusions: The world of machine learning and artificial intelligence is constantly developing. The identification of a specific LMWH dose for preventing VTE in very high-risk populations, such as the COVID-19 and active cancer population, might improve with the use of new training ML-based algorithms. Larger studies are needed to confirm our exploratory results.

Heparin and SARS-CoV-2: Multiple Pathophysiological Links.

Low molecular weight heparin, enoxaparin, has been one of most used drugs to fight the SARS-CoV-2 pandemic. Pharmacological properties of heparin recognize its specific ability, as with other oligosaccharides and glycosaminoglycan, to bind several types of viruses during their pass through the extracellular matrix of the respiratory tract, as well as its anticoagulant activity to prevent venous thromboembolism. Antithrombotic actions of enoxaparin have been testified both for inpatients with COVID-19 in regular ward and for inpatients in Intensive Care Units (ICUs). Prophylactic doses seem to be able to prevent venous thromboembolism (VTE) in inpatients in the regular ward, while intermediate or therapeutic doses have been frequently adopted for inpatients with COVID-19 in ICU. On the other hand, although we reported several useful actions of heparin for inpatients with COVID-19, an increased rate of bleeding has been recorded, and it may be related to several conditions such as underlying diseases with increased risks of bleeding, increased doses or prolonged administration of heparin, personal trend to bleed, and so on.

The COVID-19 Assessment for Survival at Admission (CASA) Index: A 12 Months Observational Study.

Objective: Coronavirus disease 2019 (COVID-19) is a disease with a high rate of progression to critical illness. However, the stratification of patients at risk of mortality is not well defined. In this study, we aimed to define a mortality risk index to allocate patients to the appropriate intensity of care. Methods: This is a 12 months observational longitudinal study designed to develop and validate a pragmatic mortality risk score to stratify COVID-19 patients aged ≥18 years and admitted to hospital between March 2020 and March 2021. Main outcome was in-hospital mortality. Results: 244 patients were included in the study (mortality rate 29.9%). The Covid-19 Assessment for Survival at Admission (CASA) index included seven variables readily available at admission: respiratory rate, troponin, albumin, CKD-EPI, white blood cell count, D-dimer, Pa02/Fi02. The CASA index showed high discrimination for mortality with an AUC of 0.91 (sensitivity 98.6%; specificity 69%) and a better performance compared to SOFA (AUC = 0.76), age (AUC = 0.76) and 4C mortality (AUC = 0.82). The cut-off identified (11.994) for CASA index showed a negative predictive value of 99.16% and a positive predictive value of 57.58%. Conclusions: A quick and readily available index has been identified to help clinicians stratify COVID-19 patients according to the appropriate intensity of care and minimize hospital admission to patients at high risk of mortality.

Pathophysiology of Vaccine-Induced Prothrombotic Immune Thrombocytopenia (VIPIT) and Vaccine-Induced Thrombocytopenic Thrombosis (VITT) and Their Diagnostic Approach in Emergency.

SARS-CoV-2 induced a pandemic that is reported to have started in Asia and was then extended to other countries in the world. Main clinical aspects of this viral infection have been lung injuries with severe pneumonia requiring prolonged hospitalization and associated morbidities such as venous thromboembolism and/or superinfection by bacteria, fungus or other pests. Immediately there was a need to develop a sustainable therapeutic strategy, such as vaccination. Vaccines against Covid-19, in fact, exert a protective action for common people and reduce viral diffusion. Yet, vaccination of a large number of people raises the question of a well-known complication of several types of vaccines; this complication is immune thrombocytopenia, which is sometimes associated with thrombosis as well. In this short review, we summarized mechanisms involved in the pathogenesis of vaccine-induced prothrombotic immune thrombocytopenia and vaccine-induced thrombocytopenic thrombosis.

The Impact of Risk-Adjusted Heparin Regimens on the Outcome of Patients with COVID-19 Infection. A Prospective Cohort Study.

BACKGROUND: According to recent guidelines, all hospitalized patients with COVID-19 should receive pharmacological prophylaxis for venous thromboembolism (VTE), unless there are specific contraindications. However, the optimal preventive strategy in terms of intensity of anticoagulation for these patients is not well established. OBJECTIVES: To investigate the impact of individualized regimens of enoxaparin on the development of VTE and on the risk of major bleeding complications during hospitalization in patients with COVID-19 infection. METHODS: All consecutive patients admitted to the medical wards of six Italian hospitals between 15 September and 15 October 2020 with COVID-19 infection of moderate severity were administered enoxaparin in subcutaneous daily doses adjusted to the Padua Prediction Score stratification model: No heparin in patients scoring less than 4, 4000 IU daily in those scoring 4, 6000 IU in those scoring 5, and 8000 in those scoring six or more. Objective tests were performed in patients developing clinical symptoms of deep vein thrombosis and/or pulmonary embolism. Bleeding complications were defined according to the ISTH classification. RESULTS: From the 154 eligible patients, enoxaparin was administered in all: 4000 IU in 73 patients, 6000 IU in 53, and 8000 IU in the remaining 28. During the course of hospitalization, 27 patients (17.5%) died. VTE developed in 14 of the 154 patients (9.1%; 95% CI, 4.6% to 13.6%), and was fatal in 1. Major bleeding complications developed in 35 patients (22.7%; 95% CI, 16.1% to 29.3%), and were fatal in 8. CONCLUSIONS: Despite the use of risk-adjusted doses of enoxaparin, the rate of VTE events was consistent with that reported in contemporary studies where fixed-dose low-molecular-weight heparin was used. The unexpectedly high risk of bleeding complications should induce caution in administering enoxaparin in doses higher than the conventional low ones.

Edoxaban for the treatment of pulmonary embolism in hospitalized COVID-19 patients.

PURPOSE: We aimed to investigate the clinical performance of edoxaban for the treatment of pulmonary embolism (PE) in hospitalized COVID-19 patients. METHODS: We conducted a retrospective analysis selecting hospitalized patients with COVID-19 admitted to our Institution from 20 May 2020 to 20 November 2020 with computer tomography (CT) detected PE at admission, treated with edoxaban after initial parenteral therapy. Clinical outcomes were compared between patients with and without ARDS at admission and between those with and without CT confirmed PE resolution. RESULTS: 50 patients were included. Mean follow-up was 42.5 ± 10 days. No baseline differences were found between patients with ARDS (30%) and those without ARDS at admission. Patients with PE resolution (84%) were younger (P = 0.03), had a shorter duration of fondaparinux therapy (9.9 ± 3.8 vs 15.8 ± 7.5 days; P = 0.0015) and length of hospitalization (36 ± 8 vs 46 ± 9 days: P = 0.0023) compared with those without PE resolution. 2 patients experienced major bleedings. At multivariate analysis the time to edoxaban switch was the only predictor of the PE resolution (HR: 0.92; 95% C.I. 0.86 to 0.99). CONCLUSION: Edoxaban was an effective and safe treatment for acute PE in COVID-19 setting.

Clinical Differences between COVID-19 and a COVID-Like Syndrome.

COVID-19 is an infection due to SARS-CoV-2; this virus has been identified as the cause of the present pandemic. Several typical characteristics are present in this infection, in particular pneumonia with possible lung failure, but atypical clinical presentations are being described daily by physicians around the world. Ground-glass opacities with pneumonia are the most common and dangerous presentations of the COVID-19 disease, and they are usually associated with positive nasopharyngeal swab (NPS) tests with detectable SARS-CoV-2 viral RNA. Compared to the general population, hospital workers have been at a greater risk of infection ever since the first patients were hospitalized. However, hospital workers have also been reported as having COVID-like symptoms despite repeated negative swab tests but having tested positive for SARS-CoV-2 antibodies with serological tests. We can postulate that a COVID-like syndrome is possible, in particular in hospital workers, that is characterized by symptoms similar to those of COVID-19, but with repeated negative nasopharyngeal swabs. These repeated negative NSPs make the difference in daily clinical management with people that experienced a single false negative nasopharyngeal swab; furthermore, a clear clinical differentiation of these situations is still lacking in the literature. For this reason, here, we report our main findings from a cohort of patients with a COVID-like syndrome compared to a similar group affected by typical COVID-19.

[ANMCO Position paper: Pulmonary circulation diseases and COVID-19]. / Position paper ANMCO: Malattie del circolo polmonare e COVID-19.

The new coronavirus disease 2019 (COVID-19), which is causing hundreds of thousands of deaths worldwide, is complex and can present with a multi-organ localization. One of its worst complications is an interstitial pneumonia with acute respiratory failure also known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which requires non-invasive or invasive ventilation. A severe coagulopathy with poor prognosis is found in 5-10% of cases. SARS-CoV-2 is manifesting as a multi-dimensional disease and, recently, unique co-existing pathophysiological and clinical aspects are being defined: (i) an increased immune and inflammatory response with the activation of a cytokine storm and consequent coagulopathy, which promote both venous thromboembolic events and in situ thrombosis localized in small arterioles and pulmonary alveolar capillaries; (ii) a high intrapulmonary shunt, which often accounts for the severity of respiratory failure, due to reduced hypoxic pulmonary vasoconstriction with pulmonary neo-angiogenetic phenomena. Furthermore, the high incidence of venous thromboembolism in COVID-19 patients admitted to the intensive care unit and the autoptic findings of in situ micro-thrombosis at the pulmonary vascular level, suggest that in this disease coagulopathy, unlike septic disseminated intravascular coagulation, is driven towards a hyper-thrombogenic state, giving rise to a debate (with ongoing studies) about the preventive use of anticoagulant doses of heparin to reduce mortality. The aim of this position paper from the Italian Association of Hospital Cardiologists (ANMCO) is to highlight the main implications that COVID-19 infection has on the pulmonary circulation from a pathophysiological, clinical and management point of view.