José M. Miró

Clinical Presentation, Etiology, and Outcome of Infective Endocarditis in the 21st Century: The International Collaboration on Endocarditis–Prospective Cohort Study

BACKGROUND We sought to provide a contemporary picture of the presentation, etiology, and outcome of infective endocarditis (IE) in a large patient cohort from multiple locations worldwide. METHODS Prospective cohort study of 2781 adults with definite IE who were admitted to 58 hospitals in 25 countries from June 1, 2000, through September 1, 2005. RESULTS The median age of the cohort was 57.9 (interquartile range, 43.2-71.8) years, and 72.1% had native valve IE. Most patients (77.0%) presented early in the disease (<30 days) with few of the classic clinical hallmarks of IE. Recent health care exposure was found in one-quarter of patients. Staphylococcus aureus was the most common pathogen (31.2%). The mitral (41.1%) and aortic (37.6%) valves were infected most commonly. The following complications were common: stroke (16.9%), embolization other than stroke (22.6%), heart failure (32.3%), and intracardiac abscess (14.4%). Surgical therapy was common (48.2%), and in-hospital mortality remained high (17.7%). Prosthetic valve involvement (odds ratio, 1.47; 95% confidence interval, 1.13-1.90), increasing age (1.30; 1.17-1.46 per 10-year interval), pulmonary edema (1.79; 1.39-2.30), S aureus infection (1.54; 1.14-2.08), coagulase-negative staphylococcal infection (1.50; 1.07-2.10), mitral valve vegetation (1.34; 1.06-1.68), and paravalvular complications (2.25; 1.64-3.09) were associated with an increased risk of in-hospital death, whereas viridans streptococcal infection (0.52; 0.33-0.81) and surgery (0.61; 0.44-0.83) were associated with a decreased risk. CONCLUSIONS In the early 21st century, IE is more often an acute disease, characterized by a high rate of S aureus infection. Mortality remains relatively high.

2015 ESC Guidelines for the management of infective endocarditis

3D : three-dimensional AIDS : acquired immune deficiency syndrome b.i.d. : bis in die (twice daily) BCNIE : blood culture-negative infective endocarditis CDRIE : cardiac device-related infective endocarditis CHD : congenital heart disease CIED : cardiac implantable electronic device

Timing of initiation of antiretroviral therapy in AIDS-free HIV-1-infected patients: a collaborative analysis of 18 HIV cohort studies

Summary Background The CD4 cell count at which combination antiretroviral therapy should be started is a central, unresolved issue in the care of HIV-1-infected patients. In the absence of randomised trials, we examined this question in prospective cohort studies. Methods We analysed data from 18 cohort studies of patients with HIV. Antiretroviral-naive patients from 15 of these studies were eligible for inclusion if they had started combination antiretroviral therapy (while AIDS-free, with a CD4 cell count less than 550 cells per μL, and with no history of injecting drug use) on or after Jan 1, 1998. We used data from patients followed up in seven of the cohorts in the era before the introduction of combination therapy (1989–95) to estimate distributions of lead times (from the first CD4 cell count measurement in an upper range to the upper threshold of a lower range) and unseen AIDS and death events (occurring before the upper threshold of a lower CD4 cell count range is reached) in the absence of treatment. These estimations were used to impute completed datasets in which lead times and unseen AIDS and death events were added to data for treated patients in deferred therapy groups. We compared the effect of deferred initiation of combination therapy with immediate initiation on rates of AIDS and death, and on death alone, in adjacent CD4 cell count ranges of width 100 cells per μL. Findings Data were obtained for 21 247 patients who were followed up during the era before the introduction of combination therapy and 24 444 patients who were followed up from the start of treatment. Deferring combination therapy until a CD4 cell count of 251–350 cells per μL was associated with higher rates of AIDS and death than starting therapy in the range 351–450 cells per μL (hazard ratio [HR] 1·28, 95% CI 1·04–1·57). The adverse effect of deferring treatment increased with decreasing CD4 cell count threshold. Deferred initiation of combination therapy was also associated with higher mortality rates, although effects on mortality were less marked than effects on AIDS and death (HR 1·13, 0·80–1·60, for deferred initiation of treatment at CD4 cell count 251–350 cells per μL compared with initiation at 351–450 cells per μL). Interpretation Our results suggest that 350 cells per μL should be the minimum threshold for initiation of antiretroviral therapy, and should help to guide physicians and patients in deciding when to start treatment. Funding UK Medical Research Council.

Current features of infective endocarditis in elderly patients: Results of the international collaboration on endocarditis prospective cohort study

BACKGROUND Elderly patients are emerging as a population at high risk for infective endocarditis (IE). However, adequately sized prospective studies on the features of IE in elderly patients are lacking. METHODS In this multinational, prospective, observational cohort study within the International Collaboration on Endocarditis, 2759 consecutive patients were enrolled from June 15, 2000, to December 1, 2005; 1056 patients with IE 65 years or older were compared with 1703 patients younger than 65 years. Risk factors, predisposing conditions, origin, clinical features, course, and outcome of IE were comprehensively analyzed. RESULTS Elderly patients reported more frequently a hospitalization or an invasive procedure before IE onset. Diabetes mellitus and genitourinary and gastrointestinal cancer were the major predisposing conditions. Blood culture yield was higher among elderly patients with IE. The leading causative organism was Staphylococcus aureus, with a higher rate of methicillin resistance. Streptococcus bovis and enterococci were also significantly more prevalent. The clinical presentation of elderly patients with IE was remarkable for lower rates of embolism, immune-mediated phenomena, or septic complications. At both echocardiography and surgery, fewer vegetations and more abscesses were found, and the gain in the diagnostic yield of transesophageal echocardiography was significantly larger. Significantly fewer elderly patients underwent cardiac surgery (38.9% vs 53.5%; P < .001). Elderly patients with IE showed a higher rate of in-hospital death (24.9% vs 12.8%; P < .001), and age older than 65 years was an independent predictor of mortality. CONCLUSIONS In this large prospective study, increasing age emerges as a major determinant of the clinical characteristics of IE. Lower rates of surgical treatment and high mortality are the most prominent features of elderly patients with IE. Efforts should be made to prevent health care-associated acquisition and improve outcomes in this major subgroup of patients with IE.

The virological and immunological consequences of structured treatment interruptions in chronic HIV-1 infection

BackgroundSome individuals with chronic HIV-1 infection have discontinued their drug therapy with consequent plasma virus rebound. In a small number of patients, a delayed or absent rebound in plasma virus load has been noted after drug cessation, apparently associated with prior drug interruptions and autologous boosting of HIV-1 specific immune responses. We hypothesized that cyclic structured treatment interruptions structured treatment interruptions (STI) could augment HIV-1 specific immune responses in chronic HIV-1 infection, which might help to control HIV-1 replication off therapy. MethodsWe initiated an STI pilot study in 10 antiretroviral treatment-naive HIV-1 chronically infected subjects with baseline CD4 T-cell counts > 500 × 106 cells/l and plasma viral load > 5000 copies/ml who received highly active antiretroviral therapy (HAART) for 1 year with good response (plasma viral load < 20 copies/ml for at least 32 weeks). Three cycles of HAART interruption were performed. ResultsIn all of the patients viral load rebounded, but doubling times increased significantly between the first and third stops (P = 0.008), and by the third stop, six out of nine subjects had a virological set-point after a median 12 months off therapy that was lower than baseline before starting HAART (ranging from 0.6 log10 to 1.3 log10 lower than baseline) and in four it remained stable below 5000 copies/ml. Those subjects who controlled viral replication developed significantly stronger HIV-1 specific cellular immune responses than subjects lacking spontaneous decline (P < 0.05). During viral rebounds no genotypic or phenotypic changes conferring resistance to reverse trancriptase inhibitors or protease inhibitors was detected, but mean absolute CD4 T-cell counts declined significantly, although never below 450 × 106/l and the mean value at 12 months off therapy was significantly higher than the pre-treatment level (P = 0.004). ConclusionsOur findings suggest that STI in chronic HIV-1 infection might augment HIV-1-specific cellular immune responses associated with a spontaneous and sustained drop in plasma viral load in some subjects but at the potential cost of lower CD4 T-cell counts.

Severe Nucleoside-Associated Lactic Acidosis in Human Immunodeficiency Virus–Infected Patients: Report of 12 Cases and Review of the Literature

Lactic acidosis is a rare but often fatal complication reported in some human immunodeficiency virus (HIV)-infected patients treated with nucleoside-analogue reverse-transcriptase inhibitors. We report a series of 12 patients with HIV infection treated with nucleoside analogues who developed unexplained metabolic acidosis. We have also reviewed 60 additional published cases. The aim of the present study is to describe the clinical picture, prognostic factors, and final outcome for nucleoside-associated lactic acidosis. The mortality rate is high: 33% for our patients, and 57% for the patients described in the literature. In the multivariate analysis, a lactate serum level of >10 mM (odds ratio [OR], 13.23; 95% confidence interval [CI], 2.96-59.25) was the only factor associated with higher mortality. The administration of specific therapy with cofactors against acidosis was associated with a lower mortality (OR, 0.17; 95% CI, 0.04-0.73). We conclude that specific therapy with cofactors may improve the outcome for patients with this syndrome.

Health care-associated native valve endocarditis: importance of non-nosocomial acquisition.

BACKGROUND The clinical profile and outcome of nosocomial and non-nosocomial health care-associated native valve endocarditis are not well defined. OBJECTIVE To compare the characteristics and outcomes of community-associated and nosocomial and non-nosocomial health care-associated native valve endocarditis. DESIGN Prospective cohort study. SETTING 61 hospitals in 28 countries. PATIENTS Patients with definite native valve endocarditis and no history of injection drug use who were enrolled in the ICE-PCS (International Collaboration on Endocarditis Prospective Cohort Study) from June 2000 to August 2005. MEASUREMENTS Clinical and echocardiographic findings, microbiology, complications, and mortality. RESULTS Health care-associated native valve endocarditis was present in 557 (34%) of 1622 patients (303 with nosocomial infection [54%] and 254 with non-nosocomial infection [46%]). Staphylococcus aureus was the most common cause of health care-associated infection (nosocomial, 47%; non-nosocomial, 42%; P = 0.30); a high proportion of patients had methicillin-resistant S. aureus (nosocomial, 57%; non-nosocomial, 41%; P = 0.014). Fewer patients with health care-associated native valve endocarditis had cardiac surgery (41% vs. 51% of community-associated cases; P < 0.001), but more of the former patients died (25% vs. 13%; P < 0.001). Multivariable analysis confirmed greater mortality associated with health care-associated native valve endocarditis (incidence risk ratio, 1.28 [95% CI, 1.02 to 1.59]). LIMITATIONS Patients were treated at hospitals with cardiac surgery programs. The results may not be generalizable to patients receiving care in other types of facilities or to those with prosthetic valves or past injection drug use. CONCLUSION More than one third of cases of native valve endocarditis in non-injection drug users involve contact with health care, and non-nosocomial infection is common, especially in the United States. Clinicians should recognize that outpatients with extensive out-of-hospital health care contacts who develop endocarditis have clinical characteristics and outcomes similar to those of patients with nosocomial infection. PRIMARY FUNDING SOURCE None.

Long-term CD4+ T-cell response to highly active antiretroviral therapy according to baseline CD4+ T-cell count.

Current treatment guidelines for HIV infection recommend a relatively late initiation of highly active antiretroviral therapy (HAART). Nevertheless, there is still a concern that immune recovery may not be as complete once CD4+ T cells have decreased below a certain threshold. This study addressed the long-term response of CD4+ T-cell counts in patients on HAART and analyzed the influence of baseline CD4+ T-cell counts, baseline viral load, and age. An observational analysis of evolution of CD4+ T cells in 861 antiretroviral therapy–naive chronic HIV-1–infected patients who started treatment consisting of at least 3 drugs in or after 1996 was performed. Patients were classified in 4 groups according to baseline CD4+ T cells: <200 cells/mm3, 200–349 cells/mm3, 350–499 cells/mm3, and ≥500 cells/mm3. The main outcome measures were proportion of patients with CD4+ T cells <200/mm3 and >500/mm3 at last determination and rate of CD4+ T-cell recovery. Patients were followed-up for a median of 173 weeks (interquartile range [IQR], 100–234). There were no differences in follow-up between the 4 groups. CD4+ T cells increased in the whole cohort from a median of 214 cells/mm3 (IQR, 90–355) to 499 cells/mm3 (IQR, 312–733) (P < 0.001). Compared with the group with a baseline CD4+ T-cell count of ≥500/mm3, the relative risk of having a last determination of CD4+ T-cell counts >200 cells/mm3 was 0.79 (95% CI, 0.75–0.83), 0.92 (95% CI, 0.89–0.96) and 1 for baseline CD4+ T cells <200 cells/mm3, 200–349 cells/mm3, and 350–499 cells/mm3, respectively. The relative risk of having a last determination of CD4+ T-cell counts >500 cells/mm3 was 0.32 (95% CI, 0.27–0.39, P < 0.001), 0.69 (95% CI, 0.60–0.79, P < 0.001), and 0.94 (95% CI, 0.83–1.06, P = 0.38) for baseline CD4+ T-cell counts <200 cells/mm3, 200–349 cells/mm3, and 350–499 cells/mm3, respectively, compared with a baseline CD4+ T-cell count of ≥500 cells/mm3. The increase in CD4+ T cells from baseline was statistically significant and was maintained for up to 4 years of follow-up. This increase seemed to slow down after approximately 3 years and reached a plateau after 4–5 years of follow-up even in patients who achieved and maintained viral suppression in plasma. Long-term immune recovery is possible regardless of baseline CD4+ T-cell count. However, patients who start therapy with a CD4+ T-cell count <200 cells/mm3 have poorer immunologic outcome as measured by the proportion of patients with CD4+ T cells <200/mm3 or >500/mm3 at last determination. It seems that the immune recovery slows down after approximately 3 years of HAART and reaches a plateau after 4–5 years of HAART.

Short-course antiretroviral therapy in primary HIV infection.

BACKGROUND Short-course antiretroviral therapy (ART) in primary human immunodeficiency virus (HIV) infection may delay disease progression but has not been adequately evaluated. METHODS We randomly assigned adults with primary HIV infection to ART for 48 weeks, ART for 12 weeks, or no ART (standard of care), with treatment initiated within 6 months after seroconversion. The primary end point was a CD4+ count of less than 350 cells per cubic millimeter or long-term ART initiation. RESULTS A total of 366 participants (60% men) underwent randomization to 48-week ART (123 participants), 12-week ART (120), or standard care (123), with an average follow-up of 4.2 years. The primary end point was reached in 50% of the 48-week ART group, as compared with 61% in each of the 12-week ART and standard-care groups. The average hazard ratio was 0.63 (95% confidence interval [CI], 0.45 to 0.90; P=0.01) for 48-week ART as compared with standard care and was 0.93 (95% CI, 0.67 to 1.29; P=0.67) for 12-week ART as compared with standard care. The proportion of participants who had a CD4+ count of less than 350 cells per cubic millimeter was 28% in the 48-week ART group, 40% in the 12-week group, and 40% in the standard-care group. Corresponding values for long-term ART initiation were 22%, 21%, and 22%. The median time to the primary end point was 65 weeks (95% CI, 17 to 114) longer with 48-week ART than with standard care. Post hoc analysis identified a trend toward a greater interval between ART initiation and the primary end point the closer that ART was initiated to estimated seroconversion (P=0.09), and 48-week ART conferred a reduction in the HIV RNA level of 0.44 log(10) copies per milliliter (95% CI, 0.25 to 0.64) 36 weeks after the completion of short-course therapy. There were no significant between-group differences in the incidence of the acquired immunodeficiency syndrome, death, or serious adverse events. CONCLUSIONS A 48-week course of ART in patients with primary HIV infection delayed disease progression, although not significantly longer than the duration of the treatment. There was no evidence of adverse effects of ART interruption on the clinical outcome. (Funded by the Wellcome Trust; SPARTAC Controlled-Trials.com number, ISRCTN76742797, and EudraCT number, 2004-000446-20.).

Progressive multifocal leukoencephalopathy in HIV-1 infection

Progressive multifocal leukoencephalopathy is caused by the JC polyomavirus (JCV) and is one of the most feared complications of HIV-1 infection. Unlike other opportunistic infections, this disease can present when CD4 counts are higher than those associated with AIDS and when patients are receiving combined antiretroviral therapy, either shortly after starting or, more rarely, during long term successful treatment. Clinical suspicion of the disease is typically when MRI shows focal neurological deficits and associated demyelinating lesions; however, the identification of JCV in cerebrospinal fluid or brain tissue is needed for a definitive diagnosis. Although no specific treatment exists, the reversal of immunosuppression by combined antiretroviral therapy leads to clinical and MRI stabilisation in 50-60% of patients with the disease, and JCV clearance from cerebrospinal fluid. A substantial proportion of patients treated with combined antiretroviral therapy develop inflammatory lesions, which can be associated with either a favourable outcome or clinical worsening. The reasons for variability in the natural history of progressive multifocal leukoencephalopathy and treatment responses are largely undefined, and more specific and rational approaches to management are needed.