Gianfranco Lauletta

Article: Hepatitis C virus-related autoimmunity before and after viral clearance: a single center, prospective, observational study - Minerva Medica 2024 Apr 24 - Minerva Medica - Journals

Introduction: Lung ultrasound (LUS) is widely used in clinical practice for identifying interstitial lung diseases (ILDs) and assessing their progression. Although high-resolution computed tomography (HRCT) remains the gold standard for evaluating the severity of ILDs, LUS can be performed as a screening method or as a follow-up tool post-HRCT. Minimum training is needed to better identify typical lesions, and the integration of innovative artificial intelligence (AI) automatic algorithms may enhance diagnostic efficiency. Aim: This study aims to assess the effectiveness of a novel AI algorithm in automatic ILD recognition and scoring in comparison to an expert LUS sonographer. The “SensUS Lung” device, equipped with an automatic algorithm, was employed for the automatic recognition of the typical ILD patterns and to calculate an index grading of the interstitial involvement. Methods: We selected 33 Caucasian patients in follow-up for ILDs exhibiting typical HRCT patterns (honeycombing, ground glass, fibrosis). An expert physician evaluated all patients with LUS on twelve segments (six per side). Next, blinded to the previous evaluation, an untrained operator, a non-expert in LUS, performed the exam with the SensUS device equipped with the automatic algorithm (“SensUS Lung”) using the same protocol. Pulmonary functional tests (PFT) and DLCO were conducted for all patients, categorizing them as having reduced or preserved DLCO. The SensUS device indicated different grades of interstitial involvement named Lung Staging that were scored from 0 (absent) to 4 (peak), which was compared to the Lung Ultrasound Score (LUS score) by dividing it by the number of segments evaluated. Statistical analyses were done with Wilcoxon tests for paired values or Mann–Whitney for unpaired samples, and correlations were performed using Spearman analysis; p < 0.05 was considered significant. Results: Lung Staging was non-inferior to LUS score in identifying the risk of ILDs (median SensUS 1 [0–2] vs. LUS 0.67 [0.25–1.54]; p = 0.84). Furthermore, the grade of interstitial pulmonary involvement detected with the SensUS device is directly related to the LUS score (r = 0.607, p = 0.002). Lung Staging values were inversely correlated with forced expiratory volume at first second (FEV1%, r = −0.40, p = 0.027), forced vital capacity (FVC%, r = −0.39, p = 0.03) and forced expiratory flow (FEF) at 25th percentile (FEF25%, r = −0.39, p = 0.02) while results directly correlated with FEF25–75% (r = 0.45, p = 0.04) and FEF75% (r = 0.43, p = 0.01). Finally, in patients with reduced DLCO, the Lung Staging was significantly higher, overlapping the LUS (reduced median 1 [1–2] vs. preserved 0 [0–1], p = 0.001), and overlapping the LUS (reduced median 18 [4–20] vs. preserved 5.5 [2–9], p = 0.035). Conclusions: Our data suggest that the considered AI automatic algorithm may assist non-expert physicians in LUS, resulting in non-inferior-to-expert LUS despite a tendency to overestimate ILD lesions. Therefore, the AI algorithm has the potential to support physicians, particularly non-expert LUS sonographers, in daily clinical practice to monitor patients with ILDs. The adopted device is user-friendly, offering a fully automatic real-time analysis. However, it needs proper training in basic skills.

Obiettivo: l’epatopatia steatosica non alcolica o Nafld, deriva da alterazioni del metabolismo lipidico che comportano un incremento del deposito dei grassi a livello epatico risultando in un danno d’organo. Non ci sono dati chiari circa la connessione tra steatoepatite e malattia cardiaca, tuttavia, molti sono i fattori di rischio sovrapponibili per entrambe le patologie, pertanto, potremmo ritenere plausibile una possibile correlazione tra le due condizioni. Il nostro scopo è stato quello di valutare il rischio di malattia cardiovascolare in un cluster di pazienti affetti da NAFLD. Metodi: Abbiamo coinvolto nel nostro studio 41 pazienti (26 maschi, età media 58,71±13,56) affetti da NAFLD, diagnosticata rispettando i criteri indicati dalle linee guida internazionali e valutata tramite ecografia; abbiamo confrontato i nostri dati con quelli di un gruppo di controllo formato da 88 soggetti, non affetti da NAFLD (55M, età media 57,39±9,91). Abbiamo valutato la rigidità epatica come indicatore di fibrosi, misurandola tramite tecnica “Share Wave ultrasonography”. Per valutare la malattia cardiovascolare abbiamo calcolato per ogni paziente lo score di rischio tramite “ASCVD risk estimator” Risultati: nel gruppo NAFLD è stata riscontrata ipertensione arteriosa nel 58% dei pazienti (n.=24) e diabete mellito nel 34% dei pazienti (n.=14); nessuna differenza significativa, rispetto a questi fattori di rischio, è emersa dal gruppo di controllo. Tuttavia, i pazienti con NAFLD presentavano un aumento della fibrosi epatica (classe metavir 1 [IQR 1–3], p<0,05) ed un aumento del rischio cardiovascolare rispetto al gruppo di controllo (ASCVD–10–yr 17,21 ± 17,99% vs 7,93 ± 7,68, p<0,05). La fibrosi epatica mostrava, inoltre, una diretta correlazione con il rischio cardiovascolare (Spearman r 0,37, p<0,01). La stessa correlazione diretta è stata riscontrata tra ASCVD risk ed il dato relativo alla liver stiffness, misurata in valore assoluto, in kPa (Pearson r 0,39, p<0,05).

Purpose Mixed cryoglobulinemia syndrome (MCs) is a rare immunoproliferative systemic disorder with cutaneous and multiple organ involvement. Our multicenter survey study aimed to investigate the prevalence and outcome of COVID-19 and the safety and immunogenicity of COVID-19 vaccines in a large MCs series. Methods The survey included 430 unselected MCs patients (130 M, 300 F; mean age 70 ± 10.96 years) consecutively collected at 11 Italian referral centers. Disease classification, clinico-serological assessment, COVID-19 tests, and vaccination immunogenicity were carried out according to current methodologies. Results A significantly higher prevalence of COVID-19 was found in MCs patients compared to Italian general population (11.9% vs 8.0%, p < 0.005), and the use of immunomodulators was associated to a higher risk to get infected (p = 0.0166). Moreover, higher mortality rate was recorded in MCs with COVID-19 compared to those without (p < 0.01). Patients’ older age (≥ 60 years) correlated with worse COVID-19 outcomes. The 87% of patients underwent vaccination and 50% a booster dose. Of note, vaccine-related disease flares/worsening were significantly less frequent than those associated to COVID-19 (p = 0.0012). Impaired vaccination immunogenicity was observed in MCs patients compared to controls either after the first vaccination (p = 0.0039) and also after the booster dose (p = 0.05). Finally, some immunomodulators, namely, rituximab and glucocorticoids, hampered the vaccine-induced immunogenicity (p = 0.029). Conclusions The present survey revealed an increased prevalence and morbidity of COVID-19 in MCs patients, as well an impaired immunogenicity even after booster vaccination with high rate of no response. Therefore, MCs can be included among frail populations at high risk of infection and severe COVID-19 manifestations, suggesting the need of a close monitoring and specific preventive/therapeutical measures during the ongoing pandemic.

Background and Objectives: COVID-19 induces massive systemic inflammation. Researchers have spent much time and effort finding an excellent and rapid image tool to evaluate COVID-19 patients. Since the pandemic’s beginning, lung ultrasound (LUS) has been identified for this purpose. Monoclonal antibodies (mAb) were used to treat mild patients and prevent respiratory disease worsening. Materials and Methods: We evaluated 15 Caucasian patients with mild COVID-19 who did not require home oxygen, treated with Bamlanivimab and Etesevimab (Group 1). A molecular nose–throat swab test confirmed the diagnosis. All were office patients, and nobody was affected by respiratory failure. They were admitted to receive the single-day infusion of mAb treatment in agreement with the Italian Drug Agency (AIFA) rules for approval. LUS was performed before the drug administration (T0) and after three months (T1). We compared LUS at T1 in other outpatients who came for follow-up and were overlapping at the time of diagnosis for admittance criteria to receive mAb (Group 2). Results: Our COVID-19 outpatients reported no hospitalization in a follow-up visit after recovery. All patients became SARS-CoV-2 negative within one month since T0. LUS score at T0 was 8.23 ± 6.46. At T1 we found a significant decrease in Group 1 LUS score (5.18 ± 4.74; p < 0.05). We also found a significant decrease in the LUS score of Group 1 T1 compared to Group2 T1 (5.18 ± 4.74 vs 7.82 ± 5.21; p < 0.05). Conclusion: Early treatment of the SARS-CoV-2 virus effectively achieves a better recovery from disease and reduces lung involvement after three months as evaluated with LUS. Despite extrapolation to the general population may be done with caution, based on our data this ultrasound method is also effective for evaluating and following lung involvement in COVID-19 patients.

The term leishmaniasis includes multiple clinical syndromes: visceral, cutaneous, and mucosal leishmaniasis, resulting from an infection of macrophages throughout the reticuloendothelial system in the dermis and the naso-oropharyngeal mucosa, respectively. The clinical phenotype is mainly driven by the leishmania biologic characteristics and, ultimately, also by the host immune status. The disease is endemic in focal areas in the tropics, subtropics, and southern Europe, transmitted by the bite of female phlebotomine sandflies. Sandflies regurgitate the parasite’s flagellated promastigote stage into the host’s skin; promastigotes bind to receptors on macrophages are phagocytized and transformed within phagolysosomes into non-flagellated amastigotes which replicate and infect additional macrophages. Amastigotes ingested by sandflies transform back into infective promastigotes. Depending on the host’s innate and acquired immune status, systemic and visceral leishmaniasis can be characterized by irregular fever, weight loss, enlargement of the spleen and liver, and anaemia. We present a 42 year-old man with long-lasting type 1 autoimmune hepatitis under immunosuppressive treatment. In January 2017, the patient started to experience low-grade unresponsiveness to empiric antibiotic therapy. The patient developed severe anemia and progressive multilineage cytopenia accompanied by increased levels of inflammatory markers. FDG-PET revealed increased glucose uptake in the liver, spleen, and the whole bone marrow. The subsequently performed bone marrow biopsy evidenced Leishmania amastigotes inside macrophages, confirmed by serological positivity to anti-Leishmania antibody. Immunosuppressive therapy was suspended and replaced by treatment with amphotericin B at 4 mg/kg/day from day 1 to day 5, followed by a single infusion on days 10, 17, 24, 31, and 38. The bone marrow smear after treatment still evidenced few Leishmania amastigotes; in consideration of the patient’s immunosuppression status, two further doses of amphotericin B on days 45 and 52 were employed, leading to infection resolution. In real-life, as exemplified in this case, administering two additional doses of amphotericin B (concerning the guidelines) offered an additional therapeutic opportunity for a patient under long-term immunosuppressive treatment.

Immunoglobulins that reversibly precipitate at temperatures below 37 °C are called cryoglobulins (CGs). Cryoglobulinemia often manifests as cryoglobulinemic vasculitis (CV), whose symptoms range in severity from purpuric eruptions to life-threatening features. The majority of CV patients are infected with hepatitis C virus (HCV), whereas lymphoproliferative disorders or connective tissue diseases (CTD) are commonly diagnosed among patients with CV of non-infectious origin. In the absence of detectable associated disease, cryoglobulinemia is classified as “essential” (EMC). All HCV-positive CV patients should be given direct-acting antiviral agents (DAAs) that are consistently able to induce a sustained virologic response (SVR). Glucocorticoids (GCs) can mitigate CV-associated vasculitis, but they have no role as maintenance therapy. Cyclophosphamide restrains the hyperactive phase(s) of the disease and the post-apheresis rebound of newly synthesized CGs. Its use has been largely replaced by rituximab (RTX) in patients unresponsive to DAAs, patients progressing to B-cell non-Hodgkin lymphoma (B-NHL) and patients in whom CV persists or reappears after clearance of HCV. Therapeutic apheresis is an emergency treatment for CV patients with hyperviscosity syndrome. HCV-positive CV patients are at an increased risk of developing NHL, but the achievement of SVR can effectively prevent HCV-related NHL or induce the remission of an already established lymphoma, even without chemotherapy. The treatment of patients with IgM or IgG monoclonal cryoglobulins and an underlying immunoproliferative disorder is based on the regimens adopted for patients with the same B-cell malignancies but without circulating CGs. For patients with CTD, GCs plus alkylating agents or RTX are similarly effective as first-line therapy and in the relapse/refractory setting. In patients with EMC, treatment should consist of GCs plus RTX, with the dose of GCs tapered as soon as possible to reduce the risk of infectious complications.

Coronavirus Disease 2019 (COVID-19) has been a pandemic challenge for the last year. Cardiovascular disease is the most described comorbidity in COVID-19 patients, and it is related to the disease severity and progression. COVID-19 induces direct damage on cardiovascular system, leading to arrhythmias and myocarditis, and indirect damage due to endothelial dysfunction and systemic inflammation with a high inflammatory burden. Indirect damage leads to myocarditis, coagulation abnormalities and venous thromboembolism, Takotsubo cardiomyopathy, Kawasaki-like disease and multisystem inflammatory syndrome in children. Imaging can support the management, assessment and prognostic evaluation of these patients. Ultrasound is the most reliable and easy to use in emergency setting and in the ICU as a first approach. The focused approach is useful in management of these patients due its ability to obtain quick and focused results. This tool is useful to evaluate cardiovascular disease and its interplay with lungs. However, a detailed echocardiography evaluation is necessary in a complete assessment of cardiovascular involvement. Computerized tomography is highly sensitive, but it might not always be available. Cardiovascular magnetic resonance and nuclear imaging may be helpful to evaluate COVID-19-related myocardial injury, but further studies are needed. This review deals with different modalities of imaging evaluation in the management of cardiovascular non-ischaemic manifestations of COVID-19, comparing their use in emergency and in intensive care.

Background Genetic variants of IFNL4 and PDCD1 genes have been shown to influence the spontaneous clearance of hepatitis C virus (HCV) infection. We investigated the IFNL4 rs12979860 and the PDCD1 polymorphisms in 734 HCV‐positive patients, including 461 cases with liver disease of varying severity and 273 patients with lymphoproliferative disorders to determine association of these genes with patient’s outcome. Methods Expression levels of PDCD1 mRNA encoded by haplotypes were investigated by quantitative PCR in hepatocellular carcinoma (HCC) tissue and peripheral blood mononuclear cells. Flow cytometry was used to detect PD‐1 and its ligand PD‐L1. Results The frequency of IFNL4 rs12979860 C/T or T/T genotypes was significantly higher in patients with HCV‐related diseases than blood donors (PPDCD1 mRNA levels in HCC tissue were significantly higher in cases carrying the PD‐1.3 A or the PD‐1.7 G allele (P=0.0025 and P=0.0167). Linkage disequilibrium (LD) between PD‐1.3 and IFNL4 was found in patients with mixed cryoglobulinemia (MC) only (LD=0 in HCC; LD=72 in MC). PBMCs of MC patients expressed low levels of PD‐L1 in CD19+IgM+ B cells and of PD‐1 in CD4+ T cells suggesting the involvement of regulatory B‐T cell interaction to the pathogenesis of MC. Conclusion Collectively, our data indicate an important contribution of IFNλ4 expression to the development of HCV‐related HCC and an epistatic contribution of IFNL4 and PDCD1 in MC.