Biomarker candidates for progression and clinical management of COVID-19 associated pneumonia at time of admission

COVID-19 pathophysiology is currently not fully understood, reliable prognostic factors remain elusive, and few specific therapeutic strategies have been proposed. In this scenario, availability of biomarkers is a priority. MS-based Proteomics techniques were used to profile the proteome of 81 plasma samples extracted in four consecutive days from 23 hospitalized COVID-19 associated pneumonia patients. Samples from 10 subjects that reached a critical condition during their hospital stay and 10 matched non-severe controls were drawn before the administration of any COVID-19 specific treatment and used to identify potential biomarkers of COVID-19 prognosis. Additionally, we compared the proteome of five patients before and after glucocorticoids and tocilizumab treatment, to assess the changes induced by the therapy on our selected candidates. Forty-two proteins were differentially expressed between patients' evolution groups at 10% FDR. Twelve proteins showed lower levels in critical patients (fold-changes 1.20–3.58), of which OAS3 and COG5 found their expression increased after COVID-19 specific therapy. Most of the 30 proteins over-expressed in critical patients (fold-changes 1.17–4.43) were linked to inflammation, coagulation, lipids metabolism, complement or immunoglobulins, and a third of them decreased their expression after treatment. We propose a set of candidate proteins for biomarkers of COVID-19 prognosis at the time of hospital admission. The study design employed is distinctive from previous works and aimed to optimize the chances of the candidates to be validated in confirmatory studies and, eventually, to play a useful role in the clinical practice.

The Pulmonary Artery Catheter in the Perioperative Setting: Should It Still Be Used?

The pulmonary artery catheter (PAC) was introduced into clinical practice in the 1970s and was initially used to monitor patients with acute myocardial infarctions. The indications for using the PAC quickly expanded to critically ill patients in the intensive care unit as well as in the perioperative setting in patients undergoing major cardiac and noncardiac surgery. The utilization of the PAC is surrounded by multiple controversies, with literature claiming its benefits in the perioperative setting, and other publications showing no benefit. The right interpretation of the hemodynamic parameters measured by the PAC and its clinical implications are of the utmost essence in order to guide a specific therapy. Even though clinical trials have not shown a reduction in mortality with the use of the PAC, it still remains a valuable tool in a wide variety of clinical settings. In general, the right selection of the patient population (high-risk patients with or without hemodynamic instability undergoing high-risk procedures) as well as the right clinical setting (centers with experience and expertise) are essential in order for the patient to benefit most from PAC use.

Nephropathic Cystinosis: Pathogenic Roles of Inflammation and Potential for New Therapies

The activation of several inflammatory pathways has recently been documented in patients and different cellular and animal models of nephropathic cystinosis. Upregulated inflammatory signals interact with many pathogenic aspects of the disease, such as enhanced oxidative stress, abnormal autophagy, inflammatory cell recruitment, enhanced cell death, and tissue fibrosis. Cysteamine, the only approved specific therapy for cystinosis, ameliorates many but not all pathogenic aspects of the disease. In the current review, we summarize the inflammatory mechanisms involved in cystinosis and their potential impact on the disease pathogenesis and progression. We further elaborate on the crosstalk between inflammation, autophagy, and apoptosis, and discuss the potential of experimental drugs for suppressing the inflammatory signals in cystinosis.

L’omocistinuria classica in età pediatrica

Classical homocystinuria is an inborn error of methionin metabolism. It is characterized by an accumulation of homocysteine, due to a deficiency of the enzyme involved in its metabolism, namely cystathionine beta synthase. If not treated, the increase in homocysteine leads to a multisystem syndrome that involves connective tissue, nervous and vascular systems with a predisposition to thromboembolism and developmental delay in childhood. An early diagnosis allows the specific therapy to be promptly started and prevents the classical manifestations of the disease. Since 2016 in Italy homocystinuria detection has been included in the expanded newborn screening. However, it is important not to forget this disease, because of its severe consequences of an untreated condition on the quality and expectancy of life.

A Mathematical Model for Early HBV and -HDV Kinetics during Anti-HDV Treatment

Hepatitis delta virus (HDV) is an infectious subviral agent that can only propagate in people infected with hepatitis B virus (HBV). HDV/HBV infection is considered to be the most severe form of chronic viral hepatitis. In this contribution, a mathematical model for the interplay between HDV and HBV under anti-HDV treatment is presented. Previous models were not designed to account for the observation that HBV rises when HDV declines with HDV-specific therapy. In the simple model presented here, HDV and HBV kinetics are coupled, giving rise to an improved viral kinetic model that simulates the early interplay of HDV and HBV during anti-HDV therapy.

Efficacy of Live Attenuated Dengue Vaccines: CYD-TDV; TDV (TAK-003) and TV003/TV005

Highlight:Differences in the efficacy of CYD-TDV versus the other TAK-003 and TV003/TV005 were discussed.One licensed dengue vaccine is CYD-TDV (Dengvaxia). Abstract:Dengue fever is the most common tropical disease, but there still remains no specific therapy that can overcome it. Special attention needs to be paid to this disease, because there were large increases in incidence in the last decade. As an effective preventive strategy, finding a new vaccine for dengue fever with higher potentiation and efficacy is highly necessary to stop dengue transmission especially in the endemic area. Vaccine triggers an immune response, so that it can create a robust immune response when infected. Nowadays, there is only one licensed dengue vaccine that is CYD-TDV (Dengvaxia). However, this vaccine still has many weaknesses, namely its dependency on the serostatus of the recipient. There are also other dengue vaccines that are in ongoing clinical testing and have promising results, TDV (TAK-003) and TV003/TV005. These three vaccines are live attenuated vaccines with various results. This review discussed differences in the efficacy of CYD-TDV against the other TAK-003 and TV003/TV005; considering the known and unknown various factors.

400 Refractory pulmonary hypertension in a young woman

Aims Clinical case—Twenty-four years old Moroccan woman. Family history: parents and three siblings in good health. Methods and results Past medical history—In 2016, when she was 19 years old, she developed worsening exercise-induced dyspnoea. A right heart catheterization (RHC) was performed with evidence of increased median pulmonary artery pressure (mPAP 60 mmHg, wedge pressure 8 mmHg), cardiac index 2.27 l/min/m2. She was diagnosed with idiopathic pulmonary hypertension and combination therapy with sildenafil and macitentan was started with partial improvement. In August 2019, she became pregnant and vasodilatory therapy was suspended. The pregnancy was complicated by premature labor with foetal death. Specific therapy with sildenafil and macitentan was then restarted. Due to further clinical and haemodynamic impairment, triple combination therapy with selexipag was initiated. However, symptomatic deterioration progressed, and she was referred to a Pulmonary Hypertension Referral Center where HRTC of the chest showed centrilobular ground-glass opacities and interlobular septal thickening. Based on the imaging that was highly suspicious pulmonary veno-occlusive disease (PVOD), and the severe haemodynamic impairment (with pulmonary vascular resistance at RHC > 20 WU), assessment for lung transplantation was started. Recent medical history—she was transferred to our Center with Transplant Unit for lung transplant assessment. Pulmonary function testing demonstrated a restrictive disorder with severe reduction of DLCO (14%). At 6-min walking test, she could walk 100 m with desaturation up to 90% on O2 therapy. Evaluated by our multidisciplinary team, indications for lung transplantation were confirmed and she entered the transplant waiting list. At the end of February 2021: further clinical and haemodynamic deterioration with respiratory distress, reduction in urinary output and signs and symptoms of right-side heart failure; she was hospitalized in intensive care unit and required extra-corporeal membrane oxygenation (ECMO) circulatory support. Selexipag was suspended. On echocardiography: severe right ventricle hypertrophy and dilatation, tricuspid regurgitation velocity >4 m/s. Few days later, she underwent bilateral lung transplantation; anatomo-pathological evaluation of explanted organs confirmed PVOD. However, during post-operative monitoring, she suffered from two episodes of cardiac arrest on VT/VF which required multiple DC-shocks. Since no triggering causes were identified, an ICD was implanted for secondary prevention. Conclusions PVOD is a rare disease with clinical presentation and haemodynamic profile often similar to pulmonary arterial hypertension (and, therefore, the diagnosis is challenging) but the clinical course is more severe. The diagnosis requires clinical history and physical examination, together with multimodality imaging and functional testing. Bronchoalveolar lavage might be necessary. Patients do not usually respond satisfactorily to vasodilatory therapy but rather they are at high risk of drug-induced pulmonary oedema. Some case reports and case series have reported a slight benefit and/or clinical stabilization with vasodilatory therapy in selected patients; therefore, specific therapy can be used but cautiously and in experienced referral centres. Definitive therapy is lung transplantation (or heart-lung transplantation) and a multidisciplinary team is necessary for the appropriate management of these complicated patients. Ventricular arrhythmias are rare in patients with Group 1 pulmonary hypertension. In our specific clinical case, we suspect that ventricular arrhythmias might be related to the severely hypertrophic, and potentially fibrotic, right ventricle.

590 ACE-I and ARBS do not influence the chest CT presentation and 1-year survival of COVID-19 patients: Italian multicentre registry

Aims A possible interference between ACE-i or ARBs with ACE-2 receptor and SARS-CoV-2 pathway has been raised. Despite data have shown no clinical impact of therapy with ACE-I or ARBs on COVID-19, these drugs are often discontinued upon hospitalization or diagnosis. To evaluate the effects of cardiovascular risk factors (CVRF) and prior outpatient therapy with RAAS inhibitors on the chest CT severity score performed within 24 h of diagnosis of SARS-CoV-2 infection (before stopping medications or starting specific therapy for COVID-19) and on 1-year survival. Methods and results This is a multicentre, prospective, observational study. All admitted patients diagnosed with SARS-CoV-2 infection who performed chest CT within 24 h of arrival were consecutively enrolled from 1 March to 1 June 2020. A severity score was attributed to Chest CT by two radiologists in blind to the patient’s clinical information and a cut-off value of 19.5 was considered to define severe radiological pneumonia. A 1-year telephone follow-up was performed in order to evaluate the determinants of 1-year survival. 590 patients with a mean age of 63 ± 14 years were included. Seventy-three (12.4%) patients were treated with ACE-I, 85 (14.4%) with ARBs and 62 (10.5%) with CCB. Cox regression analysis showed that male gender (OR: 1.4; 95% CI: from 1.02 to 2.07; P = 0.035), diabetes (OR: 1.6; 95% CI: from 1.03 to 2.7; P = 0.037), age (OR: 1.02; 95% CI: from 1.008 to 1.033; P = 0.001), and obesity (OR: 3.04; 95% CI: from 1.3 to 6.7; P < 0.001) were independently associated with a severe CT score. Of note, while prior outpatient therapy with ACE-I and ARBs was not independently associated with severe CT score, therapy with CCB was independently associated with a severe CT score (OR: 1.9, 95% CI: from 1.05 to 3.4, P = 0.033). Severe chest CT severity score (OR: 1.05; 95% CI: from 1.02 to 1.08; P < 0.001), P/F ratio (OR: 0.998; 95% CI: from 0.994 to 0.998; P < 0.001), and older age (OR: 1.06; 95% CI: from 1.03 to 1.1; P < 0.001) were independently associated with mortality at 1-year follow-up. Neither ACE-I, ARBs, and CCB were associated with mortality at 1 year follow-up. Conclusions ACE-I and ARBs do not influence the chest CT presentation of COVID-19 patients at the time of diagnosis. Furthermore, ACE-I and ARBs do not influence 1-year survival of COVID-19 survivors.

COVID-19 pandemic challenges: on the way to overcome obstacles in realization of PAH-specific therapy treatment goals

Our observation demonstrates a case of a 40-year-old female with idiopathic pulmonary arterial hypertension World Health Organization functional class III, who was admitted to NMRC of Cardiology repeatedly due to disease progression including dyspnea worsening and exercise tolerance decrease after previous COVID-19 infection on riociguat (7.5 mg daily), macitentan (10 mg daily) and selexipag (1600 mcg daily) therapy. Clinical examination demonstrated high-risk status according to the expected 1-year mortality. Due to unreleased treatment goals and high-risk status, we performed transition from selexipag to inhale iloprost. After therapy escalation the patient demonstrated a significant improvement in clinical condition, dyspnea reduction and exercise tolerance increase. The current treatment strategy for pulmonary arterial hypertension is based on regular multiparametric risk stratification approach in PAH patients. The impact of COVID-19 may become an important cause of clinical worsening in PAH patients during COVID-19 pandemic. Directed on vasodilatation and antiproliferation mechanisms of action of PAH-specific drugs are supposed to be protective in COVID-19 patients. However, the probability of clinical worsening in PAH patients despite PAH-specific therapy intake needs to be closely monitored to perform timely treatment correction in order to achieve low-risk status and to improve the prognosis of PAH patients.