Humoral/Cellular Immune Discordance in Stem Cell Donors: Impact on Cytomegalovirus-Specific Immune Reconstitution after Related Hematopoietic Transplantation.

Cytomegalovirus (CMV) reactivation is an important cause of complications after hematopoietic stem cell transplantation (HSCT). Discrepancies between serologic and cellular CMV-specific immune response have been reported. This study evaluated the impact of lack of CMV-specific CD8+ T cell response in seropositive donors (ie, discordant donors) on the reconstitution of CMV-specific cell-mediated immunity (CMI) after related HSCT in seropositive recipients. CMV-CMI was assessed in donors and recipients using the QuantiFERON-CMV assay (QF). CMV-CMI was prospectively assessed for 1 year in 81 CMV-seropositive HSCT recipients with a haploidentical or matched related donor. A Cox proportional hazard regression analysis was performed. Of the 67 CMV-seropositive donors, 54 (80.6%) were D+QFpos. The remaining 13 CMV-seropositive donors (19.4%) had a QFneg result and thus were classified as discordant donors (D+QFneg). We found that patients with D+QFneg had a significantly higher risk of impaired CMV-CMI reconstitution compared with patients with D+QFpos (log-rank test, P = .001) or D- donors (log-rank test, P = .023). In addition, the D+QFneg group had a higher incidence of single-episode reactivation compared with D+QFpos or D- donors (69.2% versus 44.4% and 28.6%, respectively) but a lower incidence of CMV recurrence compared with the D- group (7.7% versus 57.1%; P = .003). After adjusting for other relevant variables, immune discordance in donors was independently associated with impaired CMV-CMI reconstitution compared with D+QFpos donors (adjusted hazard ratio [HR], 0.18; 95% confidence interval [CI], .06 to .52; P = .001) and D- donors (adjusted HR, .17; 95% CI, .05 to .59; P = .005). Discordant donors were associated with undetectable CMV-CMI during the 12-month follow-up period using the QF assay. The inability of these patients to become QFpos persisted even after CMV reactivation. This might be related to the low frequency of CMV recurrence in this group. CMV-CMI assessment, in conjunction with CMV serostatus, can be of utility to better classify stem cell donors as well as the risk of impaired CMV-CMI reconstitution after HSCT.

Pretransplant CMV-Specific T-Cell Immunity But Not Dose of Antithymocyte Globulin Is Associated With Recovery of Specific Immunity After Kidney Transplantation.

BACKGROUND: This is a prospective, multicenter, observational study in cytomegalovirus (CMV)-seropositive kidney transplant recipients with pretransplant CMV-specific cell-mediated immunity (CMV-CMI) receiving antithymocyte globulin (ATG). We aimed to investigate posttransplant CMV-CMI over time and the impact of the dose-dependent ATG. METHODS: CMV-CMI was assessed at days +30, +45, +60, and +90 after transplantation with the QuantiFERON-CMV assay. A reactive result (interferon-γ [IFN-γ] ≥ 0.2 IU/mL) indicated a positive CMV-CMI. RESULTS: A total of 78 positive CMV-CMI patients were enrolled in the study, of which 59.5% had a positive CMV-CMI at day +30 and 82.7% at day +90. Multivariate logistic regression analysis showed that ATG dose was not associated with positive CMV-CMI at any point. However, pretransplant IFN-γ level (>12 IU/mL vs ≤12 IU/mL) was associated with positive CMV-CMI at day +30 (odds ratio, 12.9; 95% confidence interval, 3.1-53.3; P < .001). In addition, all the patients who did not recover CMV-CMI at day +90 had a pretransplant IFN-γ level ≤12 IU/mL. CONCLUSIONS: More than half of CMV-seropositive kidney transplant recipients receiving ATG recover (or maintain) CMV-CMI by the first month after transplantation. The pretransplant IFN-γ level, but not the ATG dose, shows a strong association with the kinetics of this recovery.

Analysis of spontaneous resolution of cytomegalovirus replication after transplantation in CMV-seropositive patients with pretransplant CD8+IFNG+ response.

This prospective study evaluates whether CMV-seropositive (R+) transplant patients with pretransplant CD8+IFNG+ T-cell response to cytomegalovirus (CMV) (CD8+IFNG+ response) can spontaneously clear the CMV viral load without requiring treatment. A total of 104 transplant patients (kidney/liver) with pretransplant CD8+IFNG+ response were evaluable. This response was determined using QuantiFERON-CMV assay. The incidence of CMV replication and disease was 45.2% (47/104) and 6.7% (7/104), respectively. Of the total patients, 77.9% (81/104) did not require antiviral treatment, either because they did not have CMV replication (n = 57) or because they had asymptomatic CMV replication that could be spontaneously cleared (n = 24). Both situations are likely related to the presence of CD8+IFNG+ response to CMV, which has a key role in controlling CMV infection. However, 22.1% of the patients (23/104) received antiviral treatment, although only 7 of them did so because they had symptomatic CMV replication. These patients developed symptoms in spite of having pretransplant CD8+IFNG+ response, thus suggesting that other immunological parameters might be involved, such as a dysfunctional CD4+ response or that they might have become QFNon-reactive due to the immunosuppression. In conclusion, around 80% of R+ patients with pretransplant CD8+IFNG+ response to CMV did not require antiviral treatment, although this percentage might be underestimated. Nevertheless, other strategies such as performing an additional CD8+IFNG+ response determination at posttransplant time might provide more reliable information regarding the patients who will be able to spontaneously clear the viremia.

Lack of evidence of association between IFNG and IL28B polymorphisms and QuantiFERON-CMV test results in seropositive transplant patients.

The aim of this study was to analyze the relationship between the IFNG +874 T/A and IL28B (rs12979860) C/T polymorphisms and the secretion of IFNG by CD8+ T cells after stimulation with cytomegalovirus (CMV) peptides, measured using QuantiFERON-CMV (QF-CMV) assay. A total of 184 CMV-seropositive solid organ transplant patients (108 kidney, 68 liver and 8 lung) were recruited. Of them, 151 patients were QF-CMV Reactive (IFNG ≥ 0.2 UI/mL) and 33 were Non-reactive. Genotype frequencies in the study population were TT (26.6%), AT (50.0%) and AA (23.4%) for IFNG +874 and CC (52.7%), CT (39.1%) and TT (8.2%) for IL28B (rs12979860). These frequencies did not significantly differ between QF-CMV Reactive and Non-reactive patients. Nor were any significant differences observed in the quantitative IFNG level among the genotypes in either the IFNG or the IL28 genes. When we analyzed whether these polymorphisms had any impact on the risk of CMV replication after transplantation, the adjusted analysis showed no association. In summary, our results showed that IFNG +874 T/A and IL28B (rs12979860) C/T polymorphisms are not associated with the IFNG response to CMV measured by the QuantiFERON-CMV assay, although these results should be confirmed with a higher number of patients.

Human Immunodeficiency Virus/Hepatits C Virus Coinfection in Spain: Elimination Is Feasible, but the Burden of Residual Cirrhosis Will Be Significant.

BACKGROUND: We assessed the prevalence of antibodies against hepatitis C virus (HCV-Abs) and active HCV infection in patients infected with human immunodeficiency virus (HIV) in Spain in 2016 and compared the results with those of similar studies performed in 2002, 2009, and 2015. METHODS: The study was performed in 43 centers during October-November 2016. The sample was estimated for an accuracy of 2% and selected by proportional allocation and simple random sampling. During 2016, criteria for therapy based on direct-acting antiviral agents (DAA) were at least significant liver fibrosis, severe extrahepatic manifestations of HCV, and high risk of HCV transmissibility. RESULTS: The reference population and the sample size were 38904 and 1588 patients, respectively. The prevalence of HCV-Abs in 2002, 2009, 2015, and 2016 was 60.8%, 50.2%, 37.7%, and 34.6%, respectively (P trend <.001, from 2002 to 2015). The prevalence of active HCV in 2002, 2009, 2015, and 2016 was 54.0%, 34.0%, 22.1%, and 11.7%, respectively (P trend <.001). The anti-HCV treatment uptake in 2002, 2009, 2015, and 2016 was 23.0%, 48.0%, 59.3%, and 74.7%, respectively (P trend <.001). In 2016, HCV-related cirrhosis was present in 7.6% of all HIV-infected individuals, 15.0% of patients with active HCV, and 31.5% of patients who cleared HCV after anti-HCV therapy. CONCLUSIONS: Our findings suggest that with universal access to DAA-based therapy and continued efforts in prevention and screening, it will be possible to eliminate active HCV among HIV-infected individuals in Spain in the short term. However, the burden of HCV-related cirrhosis will continue to be significant among HIV-infected individuals.

Efficiency of a self-administered outpatient parenteral antimicrobial therapy (s-opat) for infective endocarditis within the context of a shortened hospital admission based on hospital at home program.

OBJECTIVE: This study aimed to evaluate the efficiency of treatment of infectious endocarditis (IE) via Self-administered Outpatient Parenteral Antimicrobial Therapy (S-OPAT) supported by a shortening hospital admission program in a hospitalization-at-home unit (HAH), including a short review of the literature. METHODS: Ambispective cohort study of 57 episodes of IE in 54 patients treated in an HAH unit between 1988 and 2014 who receive S-OPAT after prior intra-hospital clinical stabilization. Characteristics of each episode of IE, safety and efficiency of the care model, were analyzed. RESULTS: Forty-three (76%) patients were males with a median age of 61 years (SD = 16.5). A total of 37 (65%) episodes affected the native valve (42% the aortic valve). In 75%, a micro-organism was isolated, of which 88% were Gram-positive bacteria. No deaths occurred during HAH program, clinical complications appeared in 30% of episodes, only 6 patients were re-admitted to hospital although no patient died. In the 12 months' follow-up 3 cases had a recurrence. The average cost of a day stay in HAH was €174 while in traditional cardiology hospitalization was €1100. The total average cost of treatment of each episode of IE managed entirely in hospital was calculated as €54,723. Application of the S-OPAT model based on HAH meant a cost reduction of 32.72%. CONCLUSIONS: In suitably selected patients, treatment of IE based on S-OPAT supported by a shortening hospital admission care program by means of referral to a HAH unit is a safe and efficient care model which entails a significant cost saving for the public healthcare system.

Self-administered outpatient parenteral antimicrobial therapy (S-OPAT) for infective endocarditis: a safe and effective model.

The safety and efficacy of treatment of infectious endocarditis (IE) was evaluated within a program of hospital-in-home (HIH) based on self-administered outpatient parenteral antimicrobial therapy (S-OPAT). IE episodes (n=48 in 45 patients; 71% middle-aged males) were recruited into the HIH program between 1998 and 2012. Following treatment stabilization at the hospital they returned home for HIH in which a physician and/or a nurse supervised the S-OPAT. Safety and efficacy were evaluated as mortality, re-occurrence, and unexpected re-admission to hospital. Of the episodes of IE, 83.3% had comorbidities with a mean score of 2.3 on the Charlson index and 1.5 on the Profund index; 60.4% had pre-existing valve disease (58.6% having had surgical intervention); 8.3% of patients had suffered a previous IE episode; 62.5% of all episodes affected a native valve; 45.8% being mitral; 70.8% of infection derived from the community. In 75% of the episodes there was micro-organism growth, of which 83.3% were Gram positive. Overall duration of antibiotic treatment was 4.8 weeks; 60.4% of this time corresponding to HIH. Re-admission occurred in 12.5% of episodes of which 33.3% returned to HIH to complete the S-OPAT. No deaths occurred during HIH. One year after discharge, 2 patients had recurrence and 5 patients died, in 2 of whom previous IE as cause-of-death could not be excluded. In conclusion, the S-OPAT schedule of hospital-in-home is safe and efficacious in selected patients with IE.

Valve surgery in active infective endocarditis: a simple score to predict in-hospital prognosis.

AIMS: Surgery for infective endocarditis (IE) is associated with high mortality. Our objectives were to describe the experience with surgical treatment for IE in Spain, and to identify predictors of in-hospital mortality. METHODS: Prospective cohort of 1000 consecutive patients with IE. Data were collected in 26 Spanish hospitals. RESULTS: Surgery was performed in 437 patients (43.7%). Patients treated with surgery were younger and predominantly male. They presented fewer comorbid conditions and more often had negative blood cultures and heart failure. In-hospital mortality after surgery was lower than in the medical therapy group (24.3 vs 30.7%, p=0.02). In patients treated with surgery, endocarditis involved a native valve in 267 patients (61.1%), a prosthetic valve in 122 (27.9%), and a pacemaker lead with no clear further valve involvement in 48 (11.0%). The most common aetiologies were Staphylococcus (186, 42.6%), Streptococcus (97, 22.2%), and Enterococcus (49, 11.2%). The main indications for surgery were heart failure and severe valve regurgitation. A risk score for in-hospital mortality was developed using 7 prognostic variables with a similar predictive value (OR between 1.7 and 2.3): PALSUSE: prosthetic valve, age ≥ 70, large intracardiac destruction, Staphylococcus spp, urgent surgery, sex [female], EuroSCORE ≥ 10. In-hospital mortality ranged from 0% in patients with a PALSUSE score of 0 to 45.4% in patients with PALSUSE score >3. CONCLUSIONS: The prognosis of IE surgery is highly variable. The PALSUSE score could help to identify patients with higher in-hospital mortality.

Community-acquired pneumonia during the first post-pandemic influenza season: a prospective, multicentre cohort study.

OBJECTIVES: To determine the aetiology, clinical features and prognosis of CAP during the first post-pandemic influenza season. We also assessed the factors associated with severe disease and tested the ability of a scoring system for identifying influenza A (H1N1)pdm09-related pneumonia. METHODS: Prospective cohort study carried out at 10 tertiary hospitals of Spain. All adults hospitalised with CAP from December 01, 2010 to March 31, 2011 were analysed. RESULTS: A total of 747 adults with CAP required hospitalisation. The aetiology was determined in 315 (42.2%) patients, in whom 154 (21.9%) were due to bacteria, 125 (16.7%) were due to viruses and 36 (4.8%) were mixed (due to viruses and bacteria). The most frequently isolated bacteria were Streptococccus pneumoniae. Among patients with viral pneumonia, the most common organism identified were influenza A (H1N1)pdm09. Independent factors associated with severe disease were impaired consciousness, septic shock, tachypnea, hyponatremia, hypoxemia, influenza B, and influenza A (H1N1)pdm09. The scoring system evaluated did not differentiate reliably between patients with influenza A (H1N1)pdm09-related pneumonia and those with other aetiologies. CONCLUSIONS: The frequency of bacterial and viral pneumonia during the first post-pandemic influenza season was similar. The main identified virus was influenza A (H1N1)pdm09, which was associated with severe disease. Although certain presenting clinical features may allow recognition of influenza A (H1N1)pdm09-related pneumonia, it is difficult to express them in a reliable scoring system.

Effect of immunomodulatory therapies in patients with pandemic influenza A (H1N1) 2009 complicated by pneumonia.

OBJECTIVE: To determine the effect of immunomodulatory therapies on the development of severe disease in hospitalized adults with laboratory-confirmed pandemic influenza A (H1N1) 2009 complicated by pneumonia. METHODS: Observational, prospective cohort study at thirteen tertiary hospitals in Spain. The use of corticosteroids, macrolides and statins was recorded. The outcome of interest was severe disease, defined as the composite of intensive care unit admission or death after the first day of hospitalization. RESULTS: Of the 197 patients with pandemic influenza A (H1N1) 2009 complicated by pneumonia, 68 (34.5%) received some anti-inflammatory therapy since hospital admission (corticosteroids in 37, macrolides in 31 and statins in 12). Severe disease occurred in 29 (14.7%) patients. After adjustment for confounding factors, immunomodulatory therapies as a group were not associated with a lower risk for developing severe disease (odds ratio [OR] 0.64; 95% confidence interval [CI] 0.22-1.86). In a further a priori analysis, corticosteroids, macrolides and statins were included in a multivariate model. None of these therapies was found to be associated with a lower risk for developing severe disease. CONCLUSIONS: Immunomodulatory therapies use since hospital admission did not prevent the development of severe disease in adults with pandemic influenza A (H1N1) 2009 complicated by pneumonia.

Clinical presentation and prognosis of the 2009 H1N1 influenza A infection in HIV-1-infected patients: a Spanish multicenter study.

OBJECTIVE: The aim of the study was to describe the clinical presentation and prognosis in HIV-1-infected patients with hospital admission and pandemic influenza A 2009 (H1N1) confirmed, and compare this data with those of a general population. DESIGN: : This is a prospective study in nature. METHODS: All adult patients admitted to 13 hospitals in Spain with confirmed influenza A 2009(H1N1) virus infection by real-time reverse transcriptase PCR assay or culture from June 12 to November 10, 2009 were recruited and followed up until 1 month after discharge. In the HIV group risk factors for HIV infection, AIDS criteria, last CD4 cell count and viral load, and antiretroviral therapy and pneumococcal vaccines were collected. RESULTS: Five hundred and eighty-five patients were recruited, 26 with HIV-1 infection and 559 non-HIV. The HIV patients had a long-term well controlled infection with a median CD4 cell count 503 cells/µl and 84% with undetectable viral load, although more frequently they had chronic liver and chronic obstructive pulmonary disease. No significant differences were observed about reported symptoms and physical findings on hospital admission. About 50% of patients in both groups present radiological infiltrates and 30% present respiratory failures. Practically all the patients in both groups received influenza antiviral therapy and in each group 80% received antibacterial therapy. No differences were observed in clinical outcomes. CONCLUSION: In HIV patients, well controlled on HAART, the pandemic influenza virus AH1N1 had a similar clinical outcome and prognosis to that of non-HIV patients.

Endogenous ocular candidiasis: changes in epidemiology and factors associated with poor functional outcome.

The evolution of the incidence and the epidemiology of ocular candidiasis in our hospital during the past 12 y, as well as the factors associated with poor functional outcome were analysed. A retrospective study of all cases of ocular candidiasis admitted to a university hospital between 1993 and 2004 was performed. Epidemiological, clinical and final outcome data were recorded. 37 episodes of ocular candidiasis in 36 patients were studied. 28 (75%) episodes occurred between 1993 and 1998 (13.09 episodes/100,000 admissions/y), and all of these patients were intravenous drug users. In contrast, only 9 episodes of ocular candidiasis were recorded between 1999 and 2004 (4.42 episodes/100,000 admissions/y; p<.0001) and 3 (33%) patients were not drug users (p<0.01). 19 (57%) cases had final visual acuity <0.1. Treatment with conventional amphotericin B instead of other newer antifungal drugs was associated with poor visual prognosis in the univariate (p = 0.03) and multivariate (p = 0.03) analysis. In conclusion, the incidence of ocular candidiasis has decreased significantly in recent y and the epidemiology has changed. Currently, one-third of patients are immunocompromised non-drug users. Therapy with conventional amphotericin B instead of newer antifungal drugs appears to be associated with a poorer functional outcome.

[Aspergillus fumigatus endocarditis in a patient with a biventricular pacemaker]. / Endocarditis por Aspergillus fumigatus en un marcapasos bicameral.

Aspergillus fumigatus endocarditis is one of the rarest and severest complications in cardiological patients. We describe a patient with an intracardial pacemaker who was diagnosed as having Aspergillus fumigatus endocarditis. Postmortem examination showed a large, Aspergillus-infected thrombus encased in the right ventricle, pulmonary trunk and main pulmonary branches.

Endocarditis por Aspergillus fumigatus en un marcapasos bicameral / Aspergillus fumigatus endocarditis in a patient with a biventricular pacemaker

La endocarditis por Aspergillus fumigatus es una de las complicaciones más raras y severas que puede presentar un paciente cardiológico. Presentamos el caso de una paciente portadora de marcapasos endocavitario diagnosticada de endocarditis por Aspergillus. El estudio postmortem mostró un trombo infectado por Aspergillus que ocupaba el ventrículo derecho, así como la arteria y las ramas de la arteria pulmonar (AU)

Aspergillus fumigatus endocarditis is one of the rare stand severest complications in cardiological patients. We describe a patient with an intracardial pacemaker who was diagnosed as having Aspergillus fumigatus endocarditis .Postmortem examination showed a large, Aspergillus-infected thrombus encased in the right ventricle, pulmonary trunk and main pulmonary branches (AU)