Higher mortality risk from gynaecological neoplasms and non-Hodgkin's lymphoma in patients with systemic lupus erythematosus: an observational study from the Spanish National Registry.

OBJECTIVE: To evaluate the impact of the different types of neoplasms and lineages on mortality of patients with SLE. METHODS: Retrospective and observational comparison of the neoplasm-related deaths in patients with SLE and the general Spanish population reported in the Spanish Hospital Discharge Database. To determine the impact of SLE on the risk of dying from each neoplasm lineage, a binary logistic regression considering age, female sex, tobacco and alcohol consumption, was performed. RESULTS: During 2016-2019, 139 531 in-hospital deaths from neoplasms were certified in Spain (91 in patients with SLE). Patients with SLE presented a lower mortality rate from solid organ neoplasms, (80.2% vs 91.1%, OR 0.393), linked to their lower risk of colorectal carcinoma (1.1% vs 10.8%, OR 0.110). By contrast, gynaecological neoplasms presented a higher risk (8.8% vs 3%, OR 3.039) in the deceased patients with SLE, associated with the higher frequency of vulvar neoplasms (2% vs 0.2%, OR 14.767) and cervical carcinomas (3.3% vs 0.5%, OR 3.809). Haematological neoplasm-related deaths were also more prevalent in patients with SLE (19.8% vs 8.9%, OR 2.546), mostly attributable to the higher proportion of deaths due to non-Hodgkin's lymphoma (11% vs 2.9%, OR 4.060) of B cell lineage (9.9% vs 2.5%, OR 4.133). CONCLUSIONS: Patients with SLE present a higher risk of death from vulvar neoplasms, cervical carcinomas and B-cell non-Hodgkin's lymphoma in comparison with the general Spanish population. In addition to developing strategies that might help to attenuate their occurrence and impact, such as decreasing the immunosuppressive burden, specific early detection programmes for these conditions should be investigated and considered carefully.

Prospects for Controlling Hepatitis B Globally.

Infection with the hepatitis B virus (HBV) is highly prevalent globally. Over 250 million people suffer from chronic hepatitis B, and more than 800,000 patients die each year due to hepatitis B complications, including liver cancer. Although protective HBV vaccines are recommended for all newborns, global coverage is suboptimal. In adults, sexual transmission is by far the most frequent route of contagion. The WHO estimates that 1.5 million new HBV infections occur annually. Oral nucleos(t)ide analogues entecavir and tenofovir are the most frequent antivirals prescribed as HBV therapy. Almost all patients adherent to the medication achieve undetectable plasma viremia beyond 6 months of monotherapy. However, less than 5% achieve anti-HBs seroconversion, and viral rebound occurs following drug discontinuation. Therefore, nucleos(t)ide analogues need to be lifelong. New long-acting formulations of tenofovir and entecavir are being developed that will maximize treatment benefit and overcome adherence barriers. Furthermore, new antiviral agents are in development, including entry inhibitors, capside assembly modulators, and RNA interference molecules. The use of combination therapy pursues a functional HBV cure, meaning it is negative for both circulating HBV-DNA and HBsAg. Even when this goal is achieved, the cccDNA reservoir within infected hepatocytes remains a signal of past infection, and HBV can reactivate under immune suppression. Therefore, new gene therapies, including gene editing, are eagerly being pursued to silence or definitively disrupt HBV genomes within infected hepatocytes and, in this way, ultimately cure hepatitis B. At this time, three actions can be taken to push HBV eradication globally: (1) expand universal newborn HBV vaccination; (2) perform once-in-life testing of all adults to identify susceptible HBV persons that could be vaccinated (or re-vaccinated) and unveil asymptomatic carriers that could benefit from treatment; and (3) provide earlier antiviral therapy to chronic HBV carriers, as being aviremic reduces the risk of both clinical progression and transmission.

Trends in epidemiology, surgical management, and prognosis of infective endocarditis during the XXI century in Spain: A population-based nationwide study.

BACKGROUND: Few population-based studies have evaluated the epidemiology of infective endocarditis (IE). Changes in population demographics and guidelines on IE may have affected both the incidence and outcomes of IE. Therefore, the aim of our study is to provide contemporary population-based epidemiological data of IE in Spain. METHODS: Retrospective nationwide observational study using data from the Spanish National Health System Discharge Database. We included all patients hospitalized with IE from January 2000 to December 2019. RESULTS: A total of 64,550 IE episodes were included. The incidence of IE rose from 5.25 cases/100,000 person-year in 2000 to 7.21 in 2019, with a 2% annual percentage change (95% CI 1.3-2.6). IE incidence was higher among those aged 85 or older (43.5 cases/100.000 person-years). Trends across the study period varied with sex and age. Patients with IE were progressively older (63.9 years in 2000-2004 to 70.0 in 2015-2019, p < 0.001) and had more frequent comorbidities and predispositions, including, previous valvular prosthesis (12.1% vs 20.9%, p < 0.001). After adjustment, a progressive reduction in mortality was noted including in 2015-2019 compared to 2010-2014 (adjusted odds ratio 0.93, 95% confident interval 0.88-0.99, p = 0.023)., which was associated with more frequent cardiac surgery in recent years (15.1% in 2010-2014 vs 19.9% in 2015-2019). CONCLUSIONS: In Spain, the incidence of IE has increased during the XXI century, with a more pronounced increase in elderly individuals. Adjusted-mortality decreased over the years, which could be related to a higher percentage of surgery. Our results highlight the changing epidemiology of IE.

Sarcoidosis and lymphoma mortality risk: An observational study from the Spanish National Registry.

Introduction: Patients with sarcoidosis have a lower survival rate than the general population, in part due to cardiovascular disease, infections and neoplasms. Our objective was to evaluate the impact of haematological neoplasms (HN) and lymphomas on sarcoidosis patient mortality in a nation-wide analysis conducted in Spain, a country with a population of 47 million. Methods: Retrospective and observational comparison of the HN related deaths in sarcoidosis patients and the general Spanish population reported in the Spanish Hospital Discharge Database. To determine the impact of sarcoidosis on the risk of dying from each HN lineage, a binary logistic regression considering age, female sex, tobacco and alcohol consumption, was performed. Results: In the period 2016 and 2019, 139,531 in-hospital deaths from neoplasms were certified in Spain (77 in patients with sarcoidosis). Patients with sarcoidosis died at younger age than the general Spanish population (72.9 vs 77.6, p<0.001). Sarcoidosis patients presented a higher mortality risk from HN (20.8% vs 8.9%, p=0.001, OR=2.64, 95% CI 1.52-4.59), attributable to the higher proportion of deaths from non-Hodgkin lymphoma (NHL), (9.2% vs 2.9%, p=0.006, OR= 3.33, 95% CI 1.53-7.25) from both B cell (6.6% vs 2.5%, p=0.044, OR= 2.62, 95% 1.06-6.5) and T/NK cell lineages (2.6% vs 0.3%, p=0.024, OR= 7.88, 95% CI 1.92-32.29) as well as HN with uncertain behavior and myeloproliferative disorders (2.6% vs 0.3%, p=0.018, OR= 11.88, 95% CI 2.88-49.02). The mean age of sarcoidosis patients who died from HN (63.6 vs 71.9, p=0.032) and non-Hodgkin lymphoma (56.9 vs 71, p=0.009) was lower than that of the general population. Conclusion: Patients with sarcoidosis present a higher risk of premature death from HN, including NHL from B, T/NK cell lineage and myeloproliferative disorders in comparison with the general Spanish population. In addition to developing strategies that might help to attenuate their occurrence and impact, such as decreasing the immunosuppressive burden, specific early-detection programs for these conditions should be investigated and considered carefully.

COVID-19 in hospitalized solid organ transplant recipients in a nationwide registry study.

OBJECTIVES: Underlying immunodeficiency has been associated with worse clinical presentation and increased mortality in patients with COVID-19. We evaluated the mortality of solid organ transplant (SOT) recipients (SOTR) hospitalized in Spain due to COVID-19. METHODS: Nationwide, retrospective, observational analysis of all adults hospitalized because of COVID-19 in Spain during 2020. Stratification was made according to SOT status. The National Registry of Hospital Discharges was used, using the International Classification of Diseases, 10th revision coding list. RESULTS: Of the 117,694 adults hospitalized during this period, 491 were SOTR: kidney 390 (79.4%), liver 59 (12%), lung 27 (5.5%), and heart 19 (3.9%). Overall, the mortality of SOTR was 13.8%. After adjustment for baseline characteristics, SOTR was not associated with higher mortality risk (odds ratio [OR] = 0.79, 95% confidence interval [CI] 0.60-1.03). However, lung transplantation was an independent factor related to mortality (OR = 3.26, 95% CI 1.33-7.43), while kidney, liver, and heart transplantation were not. Being a lung transplant recipient was the strongest prognostic factor in SOT patients (OR = 5.12, 95% CI 1.88-13.98). CONCLUSION: This nationwide study supports that the COVID-19 mortality rate in SOTR in Spain during 2020 did not differ from the general population, except for lung transplant recipients, who presented worse outcomes. Efforts should be focused on the optimal management of lung transplant recipients with COVID-19.

Viral hepatitis in persons living with HIV in the post-COVID era.

Coinfection with hepatitis viruses A to E is frequent in persons living with HIV (PLWH) and causes significant morbidity and mortality. Oro-fecal transmissible hepatitis A and E mostly produce acute self-limited episodes in poor income regions and in non-vaccinated travelers. In high-income countries, outbreaks of hepatitis A occur in men having sex with men (MSM) and chronic hepatitis E is occasionally reported among PLWH with severe immunodeficiency. Chronic hepatitis B, C, and D are frequent in PLWH in highly endemic regions and globally in persons who inject drugs (PWID) and MSM. Progression to liver cirrhosis and development of hepatocellular carcinoma (HCC) is major clinical complications in coinfected patients. Current estimates for PLWH are of 38 million worldwide. Roughly 12% have chronic viral hepatitis (5 million). Coinfection figures are of 5-10% for HBV (2-4 million), 4% for HCV (1.5 million), and 15% of HBsAg+ for HDV (0.5 million). Oral direct-acting antivirals (DAA) cure almost all treated patients with hepatitis C. However, given that there is no protective HCV immunity, PLWH with high-risk behaviors may experience HCV reinfection episodes. Tenofovir is the drug of choice in PLWH with chronic hepatitis B, given its dual effect on HIV and HBV. Lifelong oral tenofovir suppresses HBV replication and ameliorate liver damage. However, the risk of HCC persists even in the absence of cirrhosis. Finally, HDV causes the worst of viral hepatitis with faster progression to cirrhosis and HCC. An entry inhibitor, bulevirtide, has recently been approved and another drug, lonafarnib, is completing Phase 3 trials. Combination antiviral therapy for hepatitis D could improve dramatically the poor prognosis of HIV-HDV coinfected patients. The resumption of good medical practices in PLWH after the big disruption caused by COVID-19 will reduce the burden of viral hepatitis coinfections. Renewed efforts on HAV and HBV vaccination of susceptible individuals and earlier and wider prescription of antiviral therapy for HBV, HCV, and/or HDV coinfection should be prioritized in PLWH. The benefits of innovative strategies for viral hepatitis, including pre-exposure prophylaxis or use of long-acting antivirals, warrant further consideration in PLWH.

Bulevirtide in the Treatment of Hepatitis Delta: Drug Discovery, Clinical Development and Place in Therapy.

It has been ten years since the identification of NTCP as the cell surface receptor for HBV and HDV entry into hepatocytes. The search for molecules interfering with the binding of NTCP and HBV/HDV led to design bulevirtide (BLV). This large polypeptide mimics a region of the pre-S1 HBsAg and blocks viral entry by inhibitory competition. BLV was initially tested in cell cultures, animal models and more recently in Phase I-III human trials (called 'MYRS'). As monotherapy or in combination with peginterferon, BLV is well tolerated and exhibits potent antiviral activity. Plasma viremia significantly declines and/or becomes undetectable in more than 75% of patients treated for >24 weeks. However, serum HBsAg concentrations remain unchanged. No selection of BLV resistance in HBV/HDV has been reported in vivo to date. BLV is administered subcutaneously once daily at doses between 2 and 10 mg. BLV received conditional approval in Europe in 2020 to treat chronic hepatitis delta. The advent of peginterferon lambda or new specific anti-HDV antivirals (lonafarnib, etc.) will open the door for combination therapies with BLV. Since there is no stable reservoir for HDV-RNA within infected hepatocytes, viral clearance might be achieved using antivirals for a minimum timeframe. This is what happens in hepatitis C combining several antivirals, curing nearly all patients treated for 3 months. Clearance of HDV-RNA genomes may occur despite HBV persistence as cccDNA or chromosome integrated HBV-DNA within hepatocytes. This is supported by cases of HDV elimination using BLV despite persistence of serum HBsAg. Another path for HDV cure will derive from achieving HBsAg clearance, the goal of new promising anti-HBV gene therapies (bepirovirsen, etc.). In summary, the advent of BLV has triggered a renovated interest for antiviral therapy in hepatitis delta. We envision combination therapies that will lead to HDV cure in the near future.

Treatment of hepatitis delta and HIV infection.

Hepatitis delta virus (HDV) is a defective agent that only infects individuals with hepatitis B virus (HBV). Around 5-10% of chronic hepatitis B patients worldwide are superinfected with HDV, which means 15-25 million people. Hepatitis delta is the most severe of all chronic viral hepatitis, leading to cirrhosis, liver cancer and/or transplantation in most patients. Despite it, many HDV patients remain undiagnosed. The only treatment available until recently was peginterferon alfa, with poor results and significant side effects. The recent approval of bulevirtide, a lipopeptide that blocks HBV/HDV entry, has revolutionized the field. Another drug, lonafarnib, already approved to treat progeria, is expected to be available soon as HDV therapy. Since there is no cell reservoir for the HDV RNA genome, hypothetically viral clearance could be achieved if complete blocking of viral replication occurs for a minimum time frame. This is what happens in hepatitis C using direct-acting antivirals, with the achievement of cure in nearly all treated patients. We envision the cure of hepatitis delta using combination antiviral therapy. Given that sexual and parenteral transmission routes are the most frequent for the acquisition of HBV and HDV, shared with HIV infection and HBV/HDV and HIV coinfection. The clinical outcome of hepatitis delta is worst in the HIV setting, with more frequent liver complications. Since most persons infected with HIV are on regular health care follow-up, we propose that HIV-HDV patients should be prioritized for moving forward new and potentially curative treatments for hepatitis delta.

Red blood cell distribution width as a marker of hyperinflammation and mortality in COVID-19.

BACKGROUND: Red blood cell distribution width (RDW) could reflect interleukin-6 (IL-6) systemic activity since anisocytosis represents the inhibition of erythropoiesis, leaded by the hyperinflammatory background. Our objective was to analyze RDW performance to predict outcome in coronavirus disease 2019 (COVID-19) acute respiratory distress syndrome (ARDS). METHODS: Retrospective observational study including 173 patients with COVID-19-associated ARDS. Data was analyzed at hospital admission, inclusion in the TOCICOV Study (day 0), days 1, 3, 7 and 15 post-inclusion. RESULTS: Overall, 57% patients received tocilizumab. Overall mortality was 20.8%. RDW was higher in non-survivors compared to survivors at admission (13.53% vs. 14.35, P=0.0016), day 0 (13.60% vs. 14.42, P=0.026), day 3 (13.43% vs. 14.36, P<0.001) and day 7 (13.41% vs. 14.31, P=0.046), presenting better discrimination ability for mortality than other prognostic markers [area under the curve-receiver operating characteristic (AUC-ROC) =0.668 for admission RDW, 0.680 for day 0 RDW, 0.695 for day 3 RDW and 0.666 for day 7 RDW]. RDW values did not vary significantly according to tocilizumab treatment. When adjusted by hemoglobin and tocilizumab treatment, only RDW at admission, day 0, day 3 and C reactive protein (CRP) at day 0 and day 1 were associated with mortality (P<0.05). Only in non-tocilizumab treated patients, IL-6 levels at day 0 were correlated with day 3 RDW (r=0.733, P=0.004) and with day 3 CRP (r=0.727, P=0.022). Both parameters showed significant statistical correlation (r=0.255 for day 1 RDW and CRP in the overall cohort and r=0.358 for day 3 RDW and CRP in patients not treated with tocilizumab, P<0.015). CONCLUSIONS: RDW predicts COVID-19-associated ARDS mortality and reflects the hyperinflammatory background and the effects of cytokines such as IL-6, irrespective of tocilizumab treatment.

Serum cytokines to predict systemic lupus erythematosus clinical and serological activity.

We aimed to explore the role of interleukin (IL)-6, interferon-gamma (IFNγ), IL-10, and tumor necrosis factor (TNF) as predictors of systemic lupus erythematosus (SLE) clinical and serological activity, and their correlation with the treatment received. We performed a retrospective analysis of 77 patients with SLE according to the 2012 Systemic Lupus International Collaborative Clinics (SLICC) criteria. The outcomes were serological activity (SA), active disease (AD), complete remission (CR), the low-disease activity state (LDAS), and immunosuppressive treatment. SA was present in 17.1%, AD in 17.3%, CR in 13%, and LDAS in 64.9% of patients. IL-6 values were higher in patients in SA, in AD, in those receiving steroids alone, and in patients without CR or LDAS (p < 0.05). IFNγ was associated with anti-double stranded DNA (dsDNA) antibodies positivity and immunosuppression, whereas IL-10 values were higher in patients with CR (p < 0.05). The IL6-IFN product was able to predict anti-double stranded DNA (anti-dsDNA) antibodies positivity (area under the receiver operating characteristic curve [AUC-ROC] = 0.705, 95% confidence interval [CI] 0.563-0.847), SA (AUC-ROC = 0.720, 95% CI 0.542-0.899), AD (AUC-ROC = 0.701, 95% CI 0.520-0.882), steroid treatment (AUC-ROC = 0.751, 95% CI 0.622-0.879), and the absence of LDAS (AUC-ROC = 0.700, 95% CI 0.558-0.834). The IL6-IFN/IL10 ratio predicted AD (AUC-ROC = 0.742, 955 CI 0.540-0.944), steroid treatment (AUC-ROC = 0.721, 95% CI 0.572-0.870), and the absence of LDAS (AUC-ROC = 0.694, 95% CI 0.536-0.853). In conclusion, IL-6, IL-10, and IFNγ might help to assess SLE serological and clinical activity. Their combination in the IL-6-IFN product and the IL-6xIFN to IL-10 ratio results in novel tools to determine and predict SA, AD, and LDAS. Prompt detection of SLE activity might allow a rapid intervention to avoid established or chronic damage.

Impact of cardiovascular risk factors in antiphospholipid syndrome: an observational study from the Spanish national registry.

OBJECTIVES: To determine the burden and impact of cardiovascular risk factors (CRF) in antiphospholipid syndrome (APS) patients. METHODS: Analysis of the patients diagnosed with APS identified in the Spanish Hospital Discharge Database between 2016 and 2017. We analysed the admissions due to arterial (ATE) and venous thromboembolic events (VTE) and evaluated the incidence and the attributed risk of each CRF. RESULTS: 5424 admissions in patients diagnosed with APS were identified. 64.6% were women and the mean age was 54.6. The mortality rate was 3.1%. Overall, 35.8% of patients had hypertension, 14% were diabetic, 21.7% hypercholesterolaemic, 9.9% obese and 26.7% smokers. Thromboembolic events (67.9% arterial and 32.1% venous) accounted for 11.9% of admissions and 7.1% of deaths. Male sex (OR 1.83, 95% CI 1.41-2.21), cholesterol (OR 1.25, 95% CI 1.01-1.54) and smoking (OR 1.49, 95% CI 1.22-1.81) were independently associated with thromboembolic events. Meanwhile, patients with ATE were older (57 vs. 54.1 years p=0.033), and presented more secondary APS (17.1% vs. 10.6%, p=0.034), hypertension (47.7% vs. 33.5%, p=0.001), diabetes (16.9% vs. 9.6%, p=0.017), cholesterol (34.3% vs. 17.8%, p<0.001) and smoking habit (41.2% vs. 24%, p<0.001) when compared with VTE. Risk factors independently associated with ATE events were male sex (OR=1.61, 95% CI=1.30-2.03), hypertension (OR=1.30, 95% CI=1.03-1.64), cholesterol (OR=1.51, 95% CI=1.18-1.94) and smoking habit (OR=1.84, 95% CI=1.47-2.32), while VTE events were determined by male sex (OR=2.06, 95% CI=1.53-2.77) and obesity (OR=1.61, CI=1.02-2.52). CONCLUSIONS: Thromboembolic events in APS were in part determined by a high prevalence of CRF. The identification of distinct profiles may allow us to undertake a more personalised approach to reduce thromboembolic events and to individualise anticoagulant and antiplatelet therapy.

COVID-19-associated pulmonary aspergillosis (CAPA): Risk factors and development of a predictive score for critically ill COVID-19 patients.

BACKGROUND: COVID-19-associated pulmonary aspergillosis (CAPA) is a major complication of critically ill COVID-19 patients, with a high mortality rate and potentially preventable. Thus, identifying patients at high risk of CAPA would be of great interest. We intended to develop a clinical prediction score capable of stratifying patients according to the risk for CAPA at ICU admission. METHODS: Single centre retrospective case-control study. A case was defined as a patient diagnosed with CAPA according to 2020 ECMM/ISHAM consensus criteria. 2 controls were selected for each case among critically ill COVID-19 patients. RESULTS: 28 CAPA patients and 56-matched controls were included. Factors associated with CAPA included old age (68 years vs. 62, p = .033), active smoking (17.9% vs. 1.8%, p = .014), chronic respiratory diseases (48.1% vs. 26.3%, p = .043), chronic renal failure (25.0% vs. 3.6%, p = .005), chronic corticosteroid treatment (28.6% vs. 1.8%, p < .001), tocilizumab therapy (92.9% vs. 66.1%, p = .008) and high APACHE II at ICU admission (median 13 vs. 10 points, p = .026). A score was created including these variables, which showed an area under the receiver operator curve of 0.854 (95% CI 0.77-0.92). A punctuation below 6 had a negative predictive value of 99.6%. A punctuation of 10 or higher had a positive predictive value of 27.9%. CONCLUSION: We present a clinical prediction score that allowed to stratify critically ill COVID-19 patients according to the risk for developing CAPA. This CAPA score would allow to target preventive measures. Further evaluation of the score, as well as the utility of these targeted preventive measures, is needed.

Trends in Hospital Admissions and Death Causes in Patients with Systemic Lupus Erythematosus: Spanish National Registry.

BACKGROUND: the admission and death causes of SLE patients might have changed over the last years. METHODS: Analysis of the Spanish National Hospital Discharge database. All individuals admitted with SLE, according to ICD-9, were selected. The following five admission categories were considered: SLE, cardiovascular disease (CVD), neoplasm, infection, and venous-thromboembolic disease (VTED), along four periods of time (1997-2000, 2001-2005, 2006-2010, and 2011-2015). RESULTS: The admissions (99,859) from 43.432 patients with SLE were included. The absolute number of admissions increased from 15,807 in 1997-2000 to 31,977 in 2011-2015. SLE decreased as a cause of admission (from 47.1% to 20.8%, p < 0.001), while other categories increased over the time, as follows: 5% to 8.6% for CVD, 8.2% to 13% for infection, and 1.4% to 5.5% for neoplasm (p < 0.001 for all). The admission mortality rate rose from 2.22% to 3.06% (p < 0.001) and the causes of death evolved in parallel with the admission categories. A significant trend to older age was observed over time in the overall population and deceased patients (p < 0.001). CONCLUSIONS: Better control of SLE over the past two decades has led to a decrease in early admissions, and disease chronification. As a counterpart, CVD, infections, and neoplasm have become the main causes of admissions and mortality.