Trends in pulmonary embolism in patients infected with HIV during the combination antiretroviral therapy era in Spain: A nationwide population-based study

Chronic infections are a major factor in the development of pulmonary embolism (PE). We aimed to evaluate the trends of PE-related hospitalizations and PE-related deaths in people living with HIV (PLWH) during the era of combination antiretroviral therapy (cART) through a retrospective study in Spain. Data were collected from the Minimum Basic Data Set (MBDS) between 1997 and 2013. The study period was fragmented into four calendar periods (1997-1999, 2000-2003, 2004-2007, and 2008-2013). The rate of PE-related hospitalizations remained stable in PLWH (P = 0.361). HIV-monoinfected patients had a higher incidence than HIV/HCV-coinfected patients during all follow-up [(98.7 (95%CI = 92.2; 105.1); P < 0.001], but PE incidence decreased in HIV-monoinfected patients (P < 0.001) and increased in HIV/HCV-coinfected patients (P < 0.001). Concretely, the rate of PE-related hospitalizations decreased significantly in patients monoinfected with HIV [from 203.6 (95%CI = 175.7; 231.6) events per 100,000 patient-years in 1997-1999 to 74.3 (95%CI = 66.1; 82.3) in 2008-2013; P < 0.001], while patients coinfected with HIV/HCV had a significant increase [from 16.3 (95%CI = 11; 21.6) in 1997-1999 to 53.3 (95%CI = 45.9; 60.6) in 2008-2013; P < 0.001]. The mortality rate of PE-related hospitalizations showed a similar trend as PE incidence. In conclusion, the epidemiological trends of PE in PLWH changed during the cART era, with decreases in incidence and mortality in HIV-monoinfected and increases in both variables in patients coinfected with HIV/HCV.We thank the National Centre for Epidemiology (Institute of Health Carlos III, ISCIII, Spain) for supplying the number of people living with HIV/AIDS in Spain. We also thank the Ministry of Health, Consumption and Social Welfare for providing the records of the Minimum Basic Data Set (MBDS). This work has been supported by a grant from “Instituto de Salud Carlos III” (grant numbers PI14/01094 and PI17/00657 to JB, and PI14CIII/00011 and PI17CIII/00003 to SR). The RD16CIII/0002/0002 and RD16/0025/0017 projects also funded the study as part of the Plan Nacional R + D + I and co-funded by ISCIII- Subdirección General de Evaluación y el Fondo Europeo de Desarrollo Regional (FEDER). JB is supported by the “Programa de Intensificación de la Actividad Investigadora en el Sistema Nacional de Salud (I3SNS)”, Refs INT15/00079 and INT16/00100.S

Epidemiological trends of deep venous thrombosis in HIV-infected subjects (1997-2013): A nationwide population-based study in Spain

Background: Chronic infections may be a triggering factor as well as a risk factor of deep venous thrombosis (DVT). The purpose of this study was to analyze the epidemiological trends of hospital admissions related to DVT in human immunodeficiency virus (HIV)-infected patients during the combination antiretroviral therapy (cART) era, in relation to hepatitis C virus (HCV) serological status. Methods: We performed a retrospective study using the Spanish Minimum Basic Data Set. We selected HIV-infected subjects over 15years old with a hospital admission and DVT diagnosis (ICD-9-CM codes: 453.4x and 453.8x) between 1997 and 2013. Patients were classified according to HCV serology. We estimated the incidence (events per 100,000 patient-years) in four calendar periods (1997-1999, 2000-2003, 2004-2007, and 2008-2013). Results: Overall, the incidence of DVT-related hospitalizations had a significant upward trend in all HIV-infected patients (P<0.001), with significant differences between 1997-1999 and 2008-2013 [49.5 vs. 88.1 (P<0.001)]. Moreover, the incidence was higher in HIV-monoinfected patients than in HIV/HCV-coinfected patients during the entire follow-up (P<0.001). However, the incidence had a significant downward trend in HIV-monoinfected patients (P=0.002) and a significant upward trend in HIV/HCV-coinfected patients (P<0.001). Specifically, the incidence of DVT-related hospitalizations in HIV-monoinfected patients significantly decreased from 1997-1999 to 2008-2013 [142.7 vs. 103.1 (P=0.006)], whereas in HIV/HCV-coinfected patients, the incidence increased from 8.4 (1997-1999) to 70.7 (2008-2013) (P<0.001). Conclusions: Our findings suggest that DVT is an emerging health problem among HIV-infected patients, with increasing incidence during the first 17years after the introduction of cART, particularly in HIV/HCV-coinfected patients.This work has been supported by a grant from “Instituto de Salud Carlos III” (grant numbers PI14/01094, PI14CIII/00011). The study was also funded by the RD16CIII/0002/0002 and RD16/0025/0017 projects as part of the Plan Nacional R + D + I and cofunded by ISCIII Subdirección General de Evaluación y el Fondo Europeo de Desarrollo Regional (FEDER). JB is an investigator from the Programa de Intensificación de la Ac tividad Investigadora en el Sistema Nacional de Salud (I3SNS), Refs INT15/00079 and INT16/00100.S

Epidemiological trends of sepsis in the twenty-first century (2000-2013): an analysis of incidence, mortality, and associated costs in Spain

BACKGROUND: Sepsis has represented a substantial health care and economic burden worldwide during the previous several decades. Our aim was to analyze the epidemiological trends of hospital admissions, deaths, hospital resource expenditures, and associated costs related to sepsis during the twenty-first century in Spain. METHODS: We performed a retrospective study of all sepsis-related hospitalizations in Spanish public hospitals from 2000 to 2013. Data were obtained from records in the Minimum Basic Data Set. The outcome variables were sepsis, death, length of hospital stay (LOHS), and sepsis-associated costs. The study period was divided into three calendar periods (2000-2004, 2005-2009, and 2010-2013). RESULTS: Overall, 2,646,445 patients with sepsis were included, 485,685 of whom had died (18.4%). The incidence of sepsis (events per 1000 population) increased from 3.30 (2000-2004) to 4.28 (2005-2009) to 4.45 (2010-2013) (p < 0.001). The mortality rates from sepsis (deaths per 10,000 population) increased from 6.34 (2000-2004) to 7.88 (2005-2009) to 7.89 (2010-2013) (p < 0.001). The case fatality rate (CFR) or proportion of patients with sepsis who died decreased from 19.1% (2000-2004) to 18.4% (2005-2009) to 17.9% (2010-2013) (p < 0.001). The LOHS (days) decreased from 15.9 (2000-2004) to 15.7 (2005-2009) to 14.5 (2010-2013) (p < 0.001). Total and per patient hospital costs increased from 2000 to 2011, and then decreased by the impact of the economic crisis. CONCLUSIONS: Sepsis has caused an increasing burden in terms of hospital admission, deaths, and costs in the Spanish public health system during the twenty-first century, but the incidence and mortality seemed to stabilize in 2010-2013. Moreover, there was a significant decrease in LOHS in 2010-2013 and a decline in hospital costs after 2011.This research has been supported by Instituto de Salud Carlos III (grant numbers PI14CIII/00011 to SR, PI12/00019 to AAM, and PI15/01451 to ET), and “Gerencia de Salud, Consejería de Sanidad, Junta de Castilla y Leon” [grant number 773/A/13 to ET]. MAJS is supported by a contract of “Instituto de Salud Carlos III” (grant number CD13/00013).S

Prediction of hepatic fibrosis in patients coinfected with HIV and hepatitis C virus based on genetic markers

Objective: To assess the ability of the cirrhosis risk score (CRS) to predict liver fibrosis progression in HIV/hepatitis C virus (HCV)-coinfected patients. Design: Retrospective follow-up study. Methods: Based on a minimum follow-up time of 10 years with HCV infection, 190 HIV/HCV-coinfected patients were classified according to their METAVIR score: (1) 25 nonprogressor patients who did not develop fibrosis (F0) and (2) 165 progressor patients who developed fibrosis (F ≥ 1). Seven polymorphisms of CRS signature and IL28B genotype were performed using the GoldenGate assay. The CRS signature was calculated by naive Bayes formula as previously described. Results: Nonprogressors had CRS values significantly lower than progressors (0.61 versus 0.67; P = 0.043). Among the progressors, we observed similar CRS values through all the fibrosis stages (F1/F2/F3/F4). The percentage of patients with CRS > 0.70 (high risk of developing fibrosis) was higher in progressors than in nonprogressors; but the percentages with values between 0.50 and 0.70 (intermediate risk) and <0.50 (low risk) were quite similar for each of the fibrosis stages (P = 0.047). The area under the receiver-operating characteristic curve of CRS for discriminating nonprogressor versus progressor was 0.625 (P = 0.043). When clinical variables were considered (age at HCV infection, intravenous drug use, gender, IL28B, and HCV genotype), the area under the receiver-operating characteristic curve of CRS improved up to 0.739 (P < 0.001). Conclusions: CRS itself seems not to be a good marker for identifying HIV/HCV-coinfected patients who are at high risk of developing liver fibrosis. However, CRS score coupled with clinical factors might help to distinguish between nonprogressors and progressors patients.Supported by Fondo de Investigacion de Sanidad en España (FIS) (Spanish Health Founds for Research) Grants PI08/0738, PI11/00245; PI08/0928, and PI11/01556; Red Española de Investigación en SIDA (RIS) (AIDS Research Network) Grants RD12/0017/0024 and RD12/0017/0004; and “Fundación para la Investigación y la Prevención del Sida en España” (FIPSE) Grant 361020/10. A. F. R., M. G. F., P. G. B., and M. A. J. S. are supported by “Instituto de Salud Carlos III” Grants UIPY-1377/08, CM09/00031, FI12/00036, and CM10/00105, respectively.S

Th1 and Th17 hypercytokinemia as early host response signature in severe pandemic influenza

Abstract Introduction Human host immune response following infection with the new variant of A/H1N1 pandemic influenza virus (nvH1N1) is poorly understood. We utilize here systemic cytokine and antibody levels in evaluating differences in early immune response in both mild and severe patients infected with nvH1N1. Methods We profiled 29 cytokines and chemokines and evaluated the haemagglutination inhibition activity as quantitative and qualitative measurements of host immune responses in serum obtained during the first five days after symptoms onset, in two cohorts of nvH1N1 infected patients. Severe patients required hospitalization (n = 20), due to respiratory insufficiency (10 of them were admitted to the intensive care unit), while mild patients had exclusively flu-like symptoms (n = 15). A group of healthy donors was included as control (n = 15). Differences in levels of mediators between groups were assessed by using the non parametric U-Mann Whitney test. Association between variables was determined by calculating the Spearman correlation coefficient. Viral load was performed in serum by using real-time PCR targeting the neuraminidase gene. Results Increased levels of innate-immunity mediators (IP-10, MCP-1, MIP-1β), and the absence of anti-nvH1N1 antibodies, characterized the early response to nvH1N1 infection in both hospitalized and mild patients. High systemic levels of type-II interferon (IFN-γ) and also of a group of mediators involved in the development of T-helper 17 (IL-8, IL-9, IL-17, IL-6) and T-helper 1 (TNF-α, IL-15, IL-12p70) responses were exclusively found in hospitalized patients. IL-15, IL-12p70, IL-6 constituted a hallmark of critical illness in our study. A significant inverse association was found between IL-6, IL-8 and PaO2 in critical patients. Conclusions While infection with the nvH1N1 induces a typical innate response in both mild and severe patients, severe disease with respiratory involvement is characterized by early secretion of Th17 and Th1 cytokines usually associated with cell mediated immunity but also commonly linked to the pathogenesis of autoimmune/inflammatory diseases. The exact role of Th1 and Th17 mediators in the evolution of nvH1N1 mild and severe disease merits further investigation as to the detrimental or beneficial role these cytokines play in severe illness

Can serum hyaluronic acid replace simple non-invasive indexes to predict liver fibrosis in HIV/Hepatitis C coinfected patients?

<p>Abstract</p> <p>Background</p> <p>Hyaluronic acid (HA) serum levels correlate with the histological stages of liver fibrosis in hepatitis C virus (HCV) monoinfected patients, and HA alone has shown very good diagnostic accuracy as a non-invasive assessment of fibrosis and cirrhosis. The aim of this study was to evaluate serum HA levels as a simple non-invasive diagnostic test to predict hepatic fibrosis in HIV/HCV-coinfected patients and to compare its diagnostic performance with other previously published simple non-invasive indexes consisting of routine parameters (HGM-1, HGM-2, Forns, APRI, and FIB-4).</p> <p>Methods</p> <p>We carried out a cross-sectional study on 201 patients who all underwent liver biopsies and had not previously received interferon therapy. Liver fibrosis was determined via METAVIR score. The diagnostic accuracy of HA was assessed by area under the receiver operating characteristic curves (AUROCs).</p> <p>Results</p> <p>The distribution of liver fibrosis in our cohort was 58.2% with significant fibrosis (F≥2), 31.8% with advanced fibrosis (F≥3), and 11.4% with cirrhosis (F4). Values for the AUROC of HA levels corresponding to significant fibrosis (F≥2), advanced fibrosis (F≥3) and cirrhosis (F4) were 0.676, 0.772, and 0.863, respectively. The AUROC values for HA were similar to those for HGM-1, HGM-2, FIB-4, APRI, and Forns indexes. The best diagnostic accuracy of HA was found for the diagnosis of cirrhosis (F4): the value of HA at the low cut-off (1182 ng/mL) excluded cirrhosis (F4) with a negative predictive value of 99% and at the high cut-off (2400 ng/mL) confirmed cirrhosis (F4) with a positive predictive value of 55%. By utilizing these low and high cut-off points for cirrhosis, biopsies could have theoretically been avoided in 52.2% (111/201) of the patients.</p> <p>Conclusions</p> <p>The diagnostic accuracy of serum HA levels increases gradually with the hepatic fibrosis stage. However, HA is better than other simple non-invasive indexes using parameters easily available in routine clinical practice only for the diagnosing of cirrhosis.</p

Viral RNA load in plasma is associated with critical illness and a dysregulated host response in COVID‑19

Background. COVID-19 can course with respiratory and extrapulmonary disease. SARS-CoV-2 RNA is detected in respiratory samples but also in blood, stool and urine. Severe COVID-19 is characterized by a dysregulated host response to this virus. We studied whether viral RNAemia or viral RNA load in plasma is associated with severe COVID-19 and also to this dysregulated response. Methods. A total of 250 patients with COVID-19 were recruited (50 outpatients, 100 hospitalized ward patients and 100 critically ill). Viral RNA detection and quantification in plasma was performed using droplet digital PCR, targeting the N1 and N2 regions of the SARS-CoV-2 nucleoprotein gene. The association between SARS-CoV-2 RNAemia and viral RNA load in plasma with severity was evaluated by multivariate logistic regression. Correlations between viral RNA load and biomarkers evidencing dysregulation of host response were evaluated by calculating the Spearman correlation coefficients. Results. The frequency of viral RNAemia was higher in the critically ill patients (78%) compared to ward patients (27%) and outpatients (2%) (p < 0.001). Critical patients had higher viral RNA loads in plasma than non-critically ill patients, with non-survivors showing the highest values. When outpatients and ward patients were compared, viral RNAemia did not show significant associations in the multivariate analysis. In contrast, when ward patients were compared with ICU patients, both viral RNAemia and viral RNA load in plasma were associated with critical illness (OR [CI 95%], p): RNAemia (3.92 [1.183–12.968], 0.025), viral RNA load (N1) (1.962 [1.244–3.096], 0.004); viral RNA load (N2) (2.229 [1.382–3.595], 0.001). Viral RNA load in plasma correlated with higher levels of chemokines (CXCL10, CCL2), biomarkers indicative of a systemic inflammatory response (IL-6, CRP, ferritin), activation of NK cells (IL-15), endothelial dysfunction (VCAM-1, angiopoietin-2, ICAM-1), coagulation activation (D-Dimer and INR), tissue damage (LDH, GPT), neutrophil response (neutrophils counts, myeloperoxidase, GM-CSF) and immunodepression (PD-L1, IL-10, lymphopenia and monocytopenia). Conclusions. SARS-CoV-2 RNAemia and viral RNA load in plasma are associated with critical illness in COVID-19. Viral RNA load in plasma correlates with key signatures of dysregulated host responses, suggesting a major role of uncontrolled viral replication in the pathogenesis of this disease.This work was supported by awards from the Canadian Institutes of Health Research, the Canadian 2019 Novel Coronavirus (COVID-19) Rapid Research Funding initiative (CIHR OV2 – 170357), Research Nova Scotia (DJK), Atlantic Genome/Genome Canada (DJK), Li-Ka Shing Foundation (DJK), Dalhousie Medical Research Foundation (DJK), the “Subvenciones de concesión directa para proyectos y programas de investigación del virus SARS‐CoV2, causante del COVID‐19”, FONDO–COVID19, Instituto de Salud Carlos III (COV20/00110, CIBERES, 06/06/0028), (AT) and fnally by the “Convocatoria extraordinaria y urgente de la Gerencia Regional de Salud de Castilla y León, para la fnanciación de proyectos de investigación en enfermedad COVID-19” (GRS COVID 53/A/20) (CA). DJK is a recipient of the Canada Research Chair in Translational Vaccinology and Infammation. APT was funded by the Sara Borrell Research Grant CD018/0123 funded by Instituto de Salud Carlos III and co-fnanced by the European Development Regional Fund (A Way to Achieve Europe programme). The funding sources did not play any role neither in the design of the study and collection, not in the analysis, in the interpretation of data or in writing the manuscript

Trend of pneumonia incidence among children infected with HIV in the era of highly active antiretroviral therapy.

We performed a retrospective study using a cross-sectional design for each year from 1997 to 2008 to evaluate the trend in pneumonia rates among HIV-infected children in the highly active antiretroviral therapy (HAART) era in Spain. We found that rate of pneumonia decreased among HIV-Infected children in the highly active antiretroviral therapy era but still remained higher than in the general population. Non-AIDS-defining pneumonia remains a significant health problem for HIV-infected children.This work has beensupported by grants from Instituto de Salud Carlos III (Ref. PI08/0738 and PI11/00245) to SR.S

Rate of candidiasis among HIV-infected children in Spain in the era of highly active antiretroviral therapy (1997-2008)

BACKGROUND: Candidiasis is the most common opportunistic infection seen in human immunodeficiency virus (HIV)-infected individuals. The aim of our study was to estimate the candidiasis rate and evaluate its trend in HIV-infected children in Spain during the era of highly active antiretroviral therapy (HAART) compared to HIV-uninfected children. METHODS: We carried out a retrospective study. Data were obtained from the records of the Minimum Basic Data Set from hospitals in Spain. All HIV-infected children were under 17 years of age, and a group of HIV-uninfected children with hospital admissions matching the study group by gender and age were randomly selected. The follow-up period (1997-2008) was divided into three calendar periods: a) From 1997 to 1999 for early-period HAART; b) from 2000 to 2002 for mid-period HAART; and c) from 2003 to 2008 for late-period HAART. RESULTS: Among children with hospital admissions, HIV-infected children had much higher values than HIV-uninfected children during each of the three calendar periods for overall candidiasis rates (150.0 versus 6.1 events per 1,000 child hospital admissions/year (p < 0.001), 90.3 versus 3.1 (p < 0.001), and 79.3 versus 10.7 (p < 0.001), respectively) and for non-invasive Candida mycosis (ICM) rates (118.5 versus 3.8 (p < 0.001), 85.3 versus 2.3 (p < 0.001), and 80.6 versus 6.0 (p < 0.001), respectively). In addition, HIV-infected children also had higher values of ICM rates than HIV-uninfected children, except during the last calendar period when no significant difference was found (32.4 versus 1.2 (p < 0.001), 11.6 versus 0.4 (p < 0.001), and 4.6 versus 2.3 (p = 0.387), respectively). For all children living with HIV/AIDS, the overall candidiasis rate (events per 1,000 HIV-infected children/year) decreased from 1997-1999 to 2000-2002 (18.8 to 10.6; p < 0.001) and from 2000-2002 to 2003-2008 (10.6 to 5.7; p = 0.060). Within each category of candidiasis, both non-ICM and ICM rates experienced significant decreases from 1997-1999 to 2003-2008 (15.9 to 5.7 (p < 0.001) and 4.1 to 0.3 (p < 0.001), respectively). CONCLUSIONS: Although the candidiasis rate still remains higher than in the general population (from 1997 to 2008), candidiasis diagnoses have decreased among HIV-infected children throughout the HAART era, and it has ceased to be a major health problem among children with HIV infection.Financial support: This work has been supported by grants from Instituto de Salud Carlos III (Ref. PI08/0738 and PI11/00245 to SR and PI12/00019 to AAM).S

Stroke in HIV-infected individuals with and without HCV coinfection in Spain in the combination antiretroviral therapy era

The incidence of stroke in human immunodeficiency virus (HIV)-infected individuals has been well analyzed in recent epidemiological studies. However, little is known about the specific contribution of hepatitis C virus (HCV) infection to stroke among HIV-infected individuals. The aims of this study were to analyze trends in the incidence rates of stroke in HIV-infected individuals during the combination antiretroviral (cART) era in Spain and to categorize them by the presence or absence of HCV coinfection. We analyzed hospital discharges with a diagnosis of stroke in Spain according to ICD-9-CM during 1997-2013. The study period was divided into four calendar periods (1997-1999, 2000-2003, 2004-2007, and 2008-2013). Patients were classified according to HCV serology. The number of HIV-infected patients was estimated based on data from the National Centre of Epidemiology. We calculated incidence rates (events per 10,000 patient-years) and in-hospital case fatality rates (CFR). The incidence of hemorrhagic stroke (HS) decreased in HIV-monoinfected patients (15.8 [1997-1999] to 6.5 [2008-2013]; P<0.001) and increased in HIV/HCV-coinfected patients (1.3 [1997-1999] to 5.5 [2008-2013]; P<0.001). The incidence of ischemic stroke (IS) decreased in HIV-monoinfected patients (27.4 [1997-1999] to 21.7 [2008-2013]; P = 0.005) and increased in HIV/HCV-coinfected patients (1.8 [1997-1999] to 11.9 [2008-2013]; P<0.001). The CFR was 3.3 times higher for HS than for IS for the whole study period. The CFR of HS in HIV-monoinfected patients decreased significantly (47.4% [1997-1999] to 30.6% [2008-2013]; P = 0.010) but did not change significantly among HIV/HCV-coinfected patients (41.4% [1997-1999] to 44.7% [2008-2013]; P = 0.784). The CFR of IS in the whole HIV-infected population decreased significantly (14.6% [1997-1999] to 10.9% [2008-2013]; P = 0.034), although no significant differences were found when each group was analyzed separately. In conclusion, after the introduction of cART, HS and IS rates decreased in HIV-monoinfected individuals, but increased steadily in HIV/HCV-coinfected individuals.This work was supported by grants from “Instituto de Salud Carlos III” (grant numbers PI14/01094, and PI14CIII/00011) and Red Española de Investigación en SIDA (RIS, AIDS Research Network; grant numbers RD16/0025/0017, and RD16CIII/0002/0002). This study was (partially) funded by the RD16/0025 project as part of the Plan Nacional R + D + I and cofunded by ISCIII- Subdirección General de Evaluación y el Fondo Europeo de Desarrollo Regional (FEDER). JB is an investigator of the Programa de Intensificación de la Actividad Investigadora en el Sistema Nacional de Salud (I3SNS) (Ref. INT15/00079).S