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Background: COVID-19 causes significant morbidity and mortality, albeit with considerable heterogeneity among affected individuals. It remains unclear which host factors determine disease severity and survival. Given the propensity of clonal hematopoiesis (CH) to promote inflammation in healthy individuals, we investigated its effect on COVID-19 outcomes. Method(s): We performed a multi-omics interrogation of the genome, epigenome, transcriptome, and proteome of peripheral blood mononuclear cells from COVID-19 patients (n=227). We obtained clinical data, laboratory studies, and survival outcomes. We determined CH status and TET2-related DNA methylation. We performed single-cell proteogenomics to understand clonal composition in relation to cell phenotype. We interrogated single-cell gene expression in isolation and in conjunction with DNA accessibility. We integrated these multi-omics data to understand the effect of CH on clonal composition, gene expression, methylation of cis-regulatory elements, and lineage commitment in COVID-19 patients. We performed shRNA knockdowns to validate the effect of one candidate transcription factor in myeloid cell lines. Result(s): The presence of CH was strongly associated with COVID-19 severity and all-cause mortality, independent of age (HR 3.48, 95% CI 1.45-8.36, p=0.005). Differential methylation of promoters and enhancers was prevalent in TET2-mutant, but not DNMT3A-mutant CH. TET2- mutant CH was associated with enhanced classical/intermediate monocytosis and single-cell proteogenomics confirmed an enrichment of TET2 mutations in these cell types. We identified celltype specific gene expression changes associated with TET2 mutations in 102,072 single cells (n=34). Single-cell RNA-seq confirmed the skewing of hematopoiesis towards classical and intermediate monocytes and demonstrated the downregulation of EGR1 (a transcription factor important for monocyte differentiation) along with up-regulation of the lncRNA MALAT1 in monocytes. Combined scRNA-/scATAC-seq in 43,160 single cells (n=18) confirmed the skewing of hematopoiesis and up-regulation of MALAT1 in monocytes along with decreased accessibility of EGR1 motifs in known cis-regulatory elements. Using myeloid cell lines for functional validation, shRNA knockdowns of EGR1 confirmed the up-regulation of MALAT1 (in comparison to wildtype controls). Conclusion(s): CH is an independent prognostic factor in COVID-19 and skews hematopoiesis towards monocytosis. TET2-mutant CH is characterized by differential methylation and accessibility of enhancers binding myeloid transcriptions factors including EGR1. The ensuing loss of EGR1 expression in monocytes causes MALAT1 overexpression, a factor known to promote monocyte differentiation and inflammation. These data provide a mechanistic insight to the adverse prognostic impact of CH in COVID-19.
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Objectives: To investigate the factors influencing the clinical choice to change the current patients' therapies, and the impact of potential support of digital innovation and other knowledge assets, such as INTERCheckWEB information technology and/or guidelines, to optimize the prescription decision-making process in older and frailer patients, in polytherapy. Method(s): A narrative literature review was firstly conducted to define the main clinical and non-clinical factors, impacting on the propensity of the clinicians to change the patients' current therapies. Secondly, an observational study was developed involving 35 clinicians referring to the Internal Medicine wards, of five Italian medium size hospitals. Each clinician completed a questionnaire, aimed at evaluating 15 clinical cases of patients in polypharmacy and suffering from multiple diseases, thus defining if in case of specific information, they would have changed the patient's current therapy, during an Internal Medicine hospitalization. A hierarchical sequential linear regression model was implemented to define the predictors of the clinicians' choice to change the current therapy. Result(s): Inferential analysis demonstrated that younger patient's age (beta=-0.073, p-value=0.048), autonomy (beta=0.303, p-value=0.000) and body-max index (beta=0.505, p-value=0.000), as well as clinician's perception with regard to INTERCheckWEB ease of use (beta=0.298, p-value=0.043) and seniority (beta=0.087, p-value=0.009), number of drugs assumed by the patients (beta=0.541, p-value=0.000) and number of concomitant diseases (beta=0.302, p-value=0.000) are factors influencing a potential change in the current therapy. The above aspects explained the 53.7% of the clinician's choice variance, to modify the prescription, reducing the number of treatments to be administered to the patients. Conclusion(s): The findings provide insight into factors influencing clinical assessment decisions, that could highly be replicable in the COVID-19 era, since hospitalized COVID-19 patients are frequently older with comorbidities and receiving polypharmacy, thus strengthening the need for the clinicians to modify the therapy. Copyright © 2022
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As known after the Resolution N°IX/ 1479 sitting of 30/03/2011 (Lombardy Region Council) Regarding: Management determination of regional health services for the year 2011 - II° Measure of update in the health sector, approves Annex 1: clinical and organizational indications for the conduct of Sub Acute care activities. This is a taking charge, which takes place in a context of sheltered hospitalization, of patients suffering from the sequelae of an acute event or a clinically uncomplicated decompensation of a chronic disease aimed at achieving specific health objectives. Sub Acute cares require the formulation of a treatment plan for each patient that leads to the achievement of specific goals by qualified professionals. Sub Acute cares should not be confused with social-health activities in favor of dependent patients in rehabilitation departments. Enrollment criteria are necessary in addition to the evaluation of the patient's actual clinical condition. Known exclusion factors. In the year 2021 at the U.O. Cure Sub Acute of the Cuggiono Presidio Ospedaliero were admitted 256 patients, M:132, F:124. Noted AII. Evaluated with Braden Scale, Brass Scale and Conley Scale. Our data indicate: 45.3% discharged home, 8.2% deceased, 6.25% transferred to Hospice, 6.25% transferred to Rehabilitation Institute, 10.15% medical relapse and transferred back to medical area, 2.34% surgical relapse and transferred back to surgical area, 3 patients showed COVID-19 infection.
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Background and Aim of the study: Evidence suggests that most patients who recovered from COVID-19 carry residual respiratory symptoms. Aim of the study was to evaluate blood gas changes in post-COVID-19 patients. Materials and Methods: Hospitalized COVID-19 patients attending the outpatient clinic for post-COVID-19 patients in Magenta (Italy) were included in this retrospective study. They underwent blood draw (for inflammatory biomarkers and arterial blood gas analysis [ABG]) and chest high-resolution computed tomography (HRCT) scan. The primary endpoint was the assessment of blood gas exchanges after 3 months. Other endpoints included assessment of symptoms and chest HRCT scan abnormalities and changes in inflammatory biomarkers after 3 months from hospital discharge. Results: Eighty-eight patients (n=65 men) were included. Admission ABG showed hypoxia and hypocapnia and a PaO2/FiO2 of 271.4 (IQR 238-304.7) mmHg, that greatly improved after 3 months (426.19 [IQR 395.2-461.9] mmHg, p<0.001). Forty percent of patients were hypocapnic after 3 months, while inflammatory biomarkers improved. Fever, resting dyspnea, and cough were common at hospital admission and improved after 3 months, when dyspnea on exertion and arthralgias arose. On chest HRCT scan, more than half of individuals still presented interstitial involvement after 3 months. Conclusions: While inflammatory biomarkers normalized after 3 months, signs of lung damage persisted for a longer period, suggesting the need for an adequate follow-up of post-COVID- 19 patients.
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Background and Aims: COVID-19 caused a high influx of patientssuffering from respiratory complications showing a picture of cytokine perturbation with high levels of IL-6. Anti-IL6 drugstocilizumab and sarilumab are under investigation to understandtheir effectiveness.Materials and Methods: We retrospectively collected data about112 consecutive hospitalized in our center:50 (IL6 group) treatedwith tocilizumab or sarilumab and 62 treated with the standardof care (CONTROL group), with the aim to determine whether antiIL6 drugs are effective in improving prognosis and reducing hospitalization times and mortality. Results: To date 84% of IL6 group patients have been dischargedand only 2 are still recovered in Intensive Care. 6 patients died: 3due to severe respiratory failure within a framework of severeARDS, One suffered an acute myocardial infarction and one diedof massive pulmonary thromboembolism. There were no seriousadverse events or infectious complications. Compared to the CONTROL group they showed a lower mortality rate, same complications and days of hospitalization.Conclusions: Anti-IL6 drugs seem to be effective in treatment ofmedium to severe forms of COVID-19 pneumonia reducing the riskof mortality due to multi-organ failure, acting at the systemic leveland reducing inflammation and microvascular complications. However, it is essential to identify the best time for treatment, which,if delayed, is useless and counterproductive. Further studies andongoing clinical trials will help us to better define patients eligibleas candidates for more aggressive intervention.
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Background: Fever, cough, breathing difficulties, digestive issues and loss of smell and taste are commonest symptoms ofSARS-CoV2 infection but cutaneous manifestations have beenhighlighted by several dermatologists. We found this to be veryinteresting because it was underlined how COVID19 infectioninvolves cause inflammatory reactions, similar to those of vasculitis. Description of the cases: We documented 2 cases of skin involvement in young subjects with moderate to severe lung involvement and poor comorbidities. In one we saw a widespreadurticarial involving the thigh region and the perimalleolar area withspontaneous resolution in a few days. The other one, presenting asevere respiratory failure with ARDS framework, showed at first alegs vasculitic purpura then a fleeting erythematous rash. Itchingwas low and lesions healed in few days with steroid therapy. Skinmanifestations were similar to cutaneous involvement occurringduring autoimmune diseases. Conclusions: COVID-19 can feature signs of small blood vesselocclusion than can be petechiae or tiny bruises, and transient livedoid eruptions. There are few reports about the dermatologicalmanifestations of COVID-19;we need more experience to confirmand better understand skin involvement.
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Background and Aim of the study: To speculate on the role ofCD11/CD18 on inflammation and prothrombotic state inducedby COVID19.Patient sand Results: In a 65-year-old patient affected by COVID19 we studied the expression level of CD11b on peripheralblood CD14+ monocytes. At admission the expression of CD11bwas 8231 MFI (Mean Fluorescence Intensity) units. The patientwas treated with enoxaparin and tocilizumab.CD11b, expressionfell to 4582 MFI units over 7 days. In accordance with this, IL6values were also hyper - expressed (IL6 243,4 pg/mL;L<7pg/mL) while value after 8 days was 18 pg/mL, showing a reduction in value, congruent with the improvement of the patient.Conclusions: Physiological significance of factor X and fibrinogenbinding with activated CD11b/CD18 in vivo, is one of the possiblebridges between inflammation and thrombosis. The role of anti IL6drugs on the expression of CD11bCD/18 on monocytesmacrophages was previously studied in inflammation in atherosclerosis and in myocardial ischemia;our data seems to confirmthe hypothesis that the interaction between CD11b/CD18, endothelial cells platelets, factor X and fibrinogen plays a fundamental role in favoring inflammation and thrombosis. Overproductionof early response proinflammatory results in what has been described as an inflammatory storm. Advances in cytokine biologyand molecular biology have led to the development of novel immunologic approaches to the treatment of COVID19 lung injurythat target the cytokine. Increasing expression of CD11b/CD18induced by COVID19 play a key role in in bridging inflammationand thrombosis.
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Background: Although myocarditis can be a severe cardiac complication of COVID-19 patients, few data are available in the literature about the incidence and clinical significance in patientsaffected by SARS-CoV-2Methods: This study aims to investigate the incidence and theclinical-laboratory features of myocarditis in a cohort of patientshospitalized for COVID-19. We retrospectively evaluated all theconsecutive patients admitted for COVID-19 in our Medicine Department between March 4 to May 20, 2020. Age, sex, in-hospitaldeath, length of stay, comorbidities, serum cardiac markers, interleukin-6, electrocardiogram, echocardiogram and therapy wererecorded. Results: 1169 patients with COVID-19 were included in the studyperiod;no one was excluded. 12 patients (1%) had acute myocarditis;5 (41.7%) were men, mean age was 76 (SD 11.34);length of stay was 38 days on average (SD 8);3 (25%) patientsdied. 8 (66.7%) had a history of cardiac disease;7 (58.33%) patients had other comorbidities like diabetes, chronic obstructivepulmonary disease, or renal insufficiency.Conclusions: COVID-19 patients who experimented myocarditiswere older, had a higher frequency of previous cardiac diseaseand significantly more prolonged hospitalization and a lower valueof interleukin-6 than myocarditis patients without comorbidities.This is suggesting different myocarditis related pathogenetic mechanisms. Further studies, specifically designed on this issue, arewarranted.
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Background: COVID-19, the disease caused by SARS-CoV-2, ischaracterized by multiple lung infiltrates and extensive venous andarterial thromboembolism. Little is known about the natural historyof the disease, so we plan an outpatient clinic to follow COVID-19patients.Materials and Methods: All patients discharged alive who hasdeveloped respiratory insufficiency (i.e., arterial pO2 less than 60mmHg), or have needed mechanical ventilation for at least 72hours, or had lung infiltrates >40% of pulmonary parenchyma waseligible for the study. All those patients were re-evaluated at 1 and3 months after discharge with high-resolution CT (HRCT) of thechest, blood gases, blood chemistry, and Doppler color flow of theinvolved vessels.Results: Between February and May 2020, seventy-one COVID-19 patients were re-evaluated. Of these, with HRCT study, 12(17.14%) had pulmonary fibrosis, 19 (27,14%) had ground-glassopacities and 25 (35%) had multiple lesions;15 (21,43%) wasnormal;52 (73%) had persistent hypocapnia (mean pCO2 35.9;SD 3.26);14 had to start steroid therapy again;all patients hadcomplete vein recanalization at CUS. Conclusions: Our preliminary report showed that an outpatientclinic for patients convalescent from COVID-19 is highly advisableand may result in better knowledge of the natural history of thedisease and may help to clarify which patients will need in prolonged treatment and interventions. Furthermore, we speculatedthat a high incidence of persistent hypocapnia may result frompulmonary venous vessel microthrombosis.
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Background: Most studies on SARS-CoV-2 infection show thatpeople who have recovered from COVID-19 have antibodies to thevirus. No study has evaluated whether the presence of antibodiesto SARS-CoV-2 confers immunity to the infection relapse but however, to date, no human reinfections with SARS-CoV-2 have beenconfirmed.Materials and Methods: In our prospective, multicenter, cohortstudy we investigated within three months all patients, with confirmed COVID-19, discharged from two Hospitals (Legnano andMagenta Hospitals), in an area of Italy severely affected by the infection. Telephone follow-up at 1 and 2 months and clinical contact within 3 months was initiated;demographic, clinical,radiologic and laboratory data were recorded in electronic medicalrecords and updated.Results: Of 1081 patients involved, 804 (74.3%) were discharged alive. For all these patients we obtained follow-up data.In particular we reviewed the signs and symptoms of acute SARSCoV-2 infection, extending our attention also to the skin, the cardio-circulatory system, the gastro-enteric, psychic and nervousapparatus. At 1 and 2 months none has died and none has hadany signs of recurrence of infection at both telephone interviewand clinical visit.Conclusions: We are aware that our follow-up is still short, incomplete and lacking of the immunological data that will be investigated in the next months, but with our clinical observation we thinkwe have confirmed two basic points: the reinfection is very unlikelyand any antibody immunity protects against recurrence, at leastin the short term.
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Background and Aim of the study: Emergence of SARS-CoV-2required enormous effort to control the spread of infection andprotect the most fragile within society. This has generated an hospital focus on the threat of known and emerging infections likelyby loosening some infection control and antimicrobial management policies. The current pandemic appears to result in an increased risk of antibiotic resistance. Many patients receiveantibiotics to keep secondary bacterial infections under controland for the need to perform invasive procedures. The stressful conditions to which staff are subjected may reduce the effectivenessof antimicrobial stewardship programs, and the massive use ofteleconsultation may have caused overprescription of antibiotics.Materials and Methods: We assessed the consumption of antibiotics, and the class of antibiotics consumed, also in relation tothe documented positivity of the culture tests,in relation to thechange in the epidemiological situation on March and April 2020compared to the same period of 2019.Results: We have documented only an increased use ofmacrolides and cephalosporins but an overall reduction in the useof antibiotics in 2020 compared to the same period of 2019, evenmore evident if we consider some classes of antibiotics,in particular carbapenems.Conclusions: It is unclear whether the consequences of thesechanges will have a positive or negative net impact on antimicrobial resistance rates;attention must be paid to controlling this pandemic but sustained efforts to address the long-term global threatof antimicrobial resistance should not be overlooked.