ABSTRACT
The SARS-CoV-2 is the betacoronavirus responsible for the coronavirus disease 2019 (COVID-19) pandemic. Severe COVID-19 affects approximately 10-15% of patients and results in prolonged morbidity and mortality. Little is known about the immunophenotypic changes of the lung parenchyma driven by the viral infection in patients who die of severe COVID-19. Ultrasound-guided lung biopsies (LB) were collected (IRB approval#1561/21) within few hours from death in 15 severe COVID-19 patients between November 2020 and January 2021, in two patients who underwent lung transplantation after COVID-19 and in one patient who had surgery for bacterial superinfection during COVID-19 disease. All samples underwent histologic and immunohistochemistry evaluation and molecular profiling using the nCounter Host Response and Coronavirus Panel plus. As controls, lungs from end-stage usual interstitial pneumonia (UIP;n=9) and from lobectomy for lung cancer (Norm;n=5) were used. Eleven lungs (61%) were positive for SARS-CoV-2 RNA. Signs of diffuse alveolar damage (DAD) were observed in 6 patients (30%). COVID-19 lungs showed a marked macrophage infiltration with M2 polarization compared with controls. Globally, COVID-19 lungs showed distinct molecular profiles from UIP or Norm lungs. Specifically, a marked upregulation of interferon-genes that was directly correlated with SARS-CoV-2 genes was seen in COVID-19 lungs. COVID-19-specific genes signatures (Log2FC >1.5;adj p<0.05) obtained using VENN diagram showed impairment of the STAT3-pathway accompanied by the upregulation of the NFkB signaling. Results herein provide new insights into lung alterations induced by severe COVID-19 and suggest novel potential targets for therapeutic intervention.
ABSTRACT
Introduction: The importance of movement iswidely confirmed in people with haemophilia. After the spread of SARS-CoV-2, though, and the subsequent pandemic and lockdown, several haemophilia centres started providing physiotherapy via tele medicine. The role of telerehabilitation in haemophilia patients remains unclear. We, therefore, studied the impact of a physiotherapy course with group sessions via Zoom platform (Zoom Video Communications, Inc.) on a group of severe haemophilia A patients. Method(s): We included patients with severe haemophilia A, who were undergoing prophylaxis with clotting factor concentrates or emicizumab and with at least one target joint;an exclusion criterion was a therapeutic switch during the year. A complete assessment of the patients was performed using the Hemophilia Joint Health Score (HJHS) and the quality-of-life questionnaire EQ-5D-5L before starting the physiotherapy course (T0) and at the end of the one-year-course (T1). During the course year, one exercise session per week was planned, led by a physiotherapist, and corrected by an observer physiotherapist. During the session, warm-up, global muscle strengthening, stretching, proprioception and coordination exercises were carried out. Result(s):We recruited 10 patients aged 29-54 years (mean: 42.6;standard deviation: 9.607). In this group, only two were already doing sports once a week - swim and nordic walking. Only one patient required additional treatment due to a post-fall hematoma on amountain hike. The mean HJHS was 10.8 at T0, decreased to 9.6 at T1. The HJHS-specific items relating to pain, muscle strength and muscle atrophy had all improved, while the parameters relating to joint damage were understandably unchanged. All the patients reported a feeling of well-being at the end of the course, and the mean of the global EQ-5D-5L score in T0 was 81, while at T1 was 85. Discussion/Conclusion: This experience highlights the role of telerehabilitation, an innovative tool that can give access to physical exercise to patients otherwise limited by the geographical distance or by the impossibility of reaching the treatment sites. However, further large studies are needed to fully explore its potential.
ABSTRACT
Background: Coronavirus disease-2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV- 2), has resulted in an ongoing world-wide pandemic. Vaccination is the key countermeasure of the COVID-19 pandemic. Data on the efficacy, safety and immunogenicity of COVID-19 vaccination in patients with hemophilia -and in particular in those with HIV -are still scarce. Aim(s): The aim of our study was to characterize the immunogenicity and biomarkers of coagulation and endothelial perturbation after mRNA-COVID- 19 vaccination in HIV-positive hemophilic patients. Method(s): We collected blood from 24 adult HIV-positive hemophilic patients followed at our centre (19 with hemophilia A, 5 with hemophilia B) before and two weeks after the administration of the complete vaccination schedule with mRNA-1273 (Moderna Biotech). Most patients had severe hemophilia (n = 21). We measured antibodies to SARS-CoV- 2 spike protein by Elecsys (Roche) to assess immunogenicity and we evaluated protein C, VWF, D-dimer plasma levels as biomarkers of coagulation and endothelial perturbation. Anti-Platelet Factor 4 (PF4) antibodies were also measured. Result(s): Before vaccination, three patients out of 24 showed anti-Spike IgG levels >0.8 U/ml (cut-off value). Two weeks after completing the vaccination schedule, all patients had high values of anti-Spike IgG (min-max 2,387-12,500 U/ml). Mean (standard deviation) basal values of protein C, VWF and D-dimer (106 +/- 21%, 171 +/- 45%, 593 +/- 692 ng/ml respectively) were not significantly different from values measured two weeks after the second dose of vaccine (103 +/- 20%, 162 +/- 43%, 583 +/- 531 ng/ml). Anti-PF4 antibodies were detected in three patients with no associated clinical manifestations. None of the patients reported bleeding in the site of inoculation nor serious adverse events after the vaccination. Conclusion(s): Since immune abnormalities can occur in HIV-positive patients, it is important to collect data on COVID-19 vaccination immunogenicity. We demonstrated that hemophilic HIV-positive patients have a normal antibody response against SARS-CoV- 2 spike protein. In addition, mRNA-1273 had no effect on coagulation and endothelial perturbation.
ABSTRACT
Background: Thrombotic thrombocytopenic purpura (TTP) has occasionally been described after vaccination. Since the availability of anti-SARS- CoV- 2 vaccines, 12 cases have been described on a possible association with TTP onset. Aim(s): This study aims to evaluate the relapse rates in patients affected by TTP undergoing anti-SARS- CoV- 2 vaccination. Method(s): All consecutive TTP patients undergoing anti-SARS- CoV- 2 vaccination from March to May 2021 were enrolled. Blood samples were collected before vaccination (T0), 2 weeks after the first (T1) and the second dose (T2) to evaluate ADAMTS13 activity and anti-ADAMTS13 antibody titer. Result(s): A total of 49 TTP patients were enrolled (48 acquired and 1 congenital), all vaccinated with an mRNA vaccine. No patients had a clinical TTP relapse, with an ADAMTS13 relapse rate of 1.36% per month. Mean levels of ADAMTS13 activity were stable among the three timepoints (Figure). In only two patients a significant drop in ADAMTS13 levels occurred after the first dose (from 28% to <3% and from 101% to 82%), and both remained stable after the second dose, with negative anti-ADAMTS13 antibodies. Due to a stable undetectable ADAMTS13, the first patient was treated with 4 doses of weekly 375 mg/m2 rituximab with a rapid ADAMTS13 response. One patient had positive basal anti-ADAMTS13 antibodies with a titer remaining stable after the two vaccine doses, while in another patient anti-ADAMTS13 antibodies became detectable after the first dose, with no corresponding drop in ADAMTS13 levels and a stable titer after the second dose. Conclusion(s): The result of our study prospectively evaluating the effect of anti-SARS- CoV- 2 vaccination on the risk of relapse in a large cohort of patients with TTP in Milan showed a lower than reported relapse rate (1.36% vs 2.6%) with an observed to expected incidence rate ratio of 0.52, confirming the safety of mRNA-based anti-SARS- CoV- 2 vaccination in TTP patients.
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Background : Several thrombotic manifestations have been reported with SARS-Cov-2 infection including liver vascular involvement. Aims : We present a dramatic case of acute liver necrosis in a 36-year-old SARS-Cov-2 positive Italian woman with no respiratory symptoms and triple positive antiphospholipid syndrome (APS). Methods : The patient was referred to our University Hospital for acute hypertransaminasemia and liver failure (Figure). She had systemic lupus erythematosus (positivity for: ANA, anti-dsDNA, complement activation, Coombs;thrombocytopenia, previous arthritis). Anti-phopspholipid antibodies (aPL) were detected for the first time in 2015 during routine pregnancy screening and chronically treated with aspirin. Apparently, no venous/arterial nor obstetric events were recorded up to the recent hospitalization. FIGURE 1 Results : At arrival, US-Doppler and CT-scan were consistent with signs of chronic liver disease and occlusion of the three hepatic veins defining a Budd-Chiari syndrome. We opted for a stepwise approach considering anticoagulation (clexane 100 UI/Kg b.i.d) the first line of therapy before any invasive intervention. Dexamethasone 6 mg/ day b.i.d., 6 sessions of plasma-exchange, i.v.-immunoglobulin were sequentially planned to revert the liver damage sustained by aPL. After 5-days, two hepatic-veins resulted recanalized in association with amelioration of liver-enzyme/function and aPL quantification. Then we performed hepatic vein catheterization and transjugular liver biopsy. The histology showed multiple areas of necrosis associated with liver cirrhosis. Unexpectedly, no signs of acute Budd-Chiari were observed (e.g. intraparenchymal hemorrhages, centrilobular congestion, sinusoidal dilation). Other etiologies were also excluded and we hypothesized the involvement of small arteries of the liver in a triple positive APS in a patients with SLE. We finally addressed the patient to a liver transplant program and a tight multispecialistic follow-up. Conclusions : Thrombosis of arterial/venous vessels or microcirculation causes liver damage in some patients with aPL. Our report suggests that SARS-Cov-2 can exacerbate this prothrombotic condition determining a life-threatening complication such as acute liver failure.
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Background : The novel coronavirus disease 2019 (COVID-19) presents an important and urgent threat to global health. Identifying strong predictors of mortality could assist medical staff in treating patients and allocating limited healthcare resources. Aims : The primary aim of this paper was to study the effect of ddimer levels at admission as a predictive marker for in-hospital mortality. Methods : This was a retrospective cohort study evaluating hospitalized patients (age > 18 years), who were positive for COVID-19 based on real-time PCR at one of nine COVID-19 units during the period of the first COVID-19 wave in Lombardy, Italy. The primary endpoint was in-hospital mortality. Information was obtained from patient records. Statistical analyses were performed using a Fine-Gray competing risk survival model. Predictive power was assessed using Harrell's C-index. Results : Out of 1049 patients that were admitted to the emergency department and subsequently hospitalized, 501 patients had evaluable data for d-dimer. Of these 501 patients, 96 did not survive. Cumulative incidence of in-hospital mortality within 30 days was 20%, and the majority of deaths occurred within the first 10 days. (Figure 1) When compared to patients in the lowest quartile of d-dimer blood concentration, the hazard ratio of in-hospital mortality for patients in the 2 nd , 3 rd and 4 th quartile was 3.9 (95CI: 1.5-10.0), 5.8 (95CI: 2.3-14.7), and 4.6 (95CI: 1.8-11.5) respectively, after multivariable adjustment for age, sex and number of comorbidities. The C-statistic of d-dimer for in-hospital mortality was 0.67 (95CI: 0.62-0.71). (Table 2) Conclusions : Higher d-dimer levels were strongly associated with inhospital mortality. However, the predictive power of d-dimer alone was not high enough to be useful as a risk prediction score. Future research should focus on the added value of d-dimer as part of a larger risk prediction score.