Uriel Sandkovsky

What is the impact of hypogammaglobulinemia on the rate of infections and survival in solid organ transplantation? A meta-analysis.

Hypogammaglobulinemia has been described after solid organ transplantation and has been associated with increased risk of infections. The aim of the study was to evaluate the rate of severe hypogammaglobulinemia and its relationship with the risk of infections during the first year posttransplantation. Eighteen studies (1756 patients) that evaluated hypogammaglobulinemia and posttransplant infections were included. The data were pooled using the DerSimonian and Laird random‐effects model. Q statistic method was used to assess statistical heterogeneity. Within the first year posttransplantation, the rate of hypogammaglobulinemia (IgG < 700 mg/dL) was 45% (95% CI: 0.34–0.55; Q = 330.1, p < 0.0001), the rate of mild hypogammaglobulinemia (IgG = 400–700 mg/dL) was 39% (95% CI: 0.22–0.56; Q = 210.09, p < 0.0001) and the rate of severe hypogammaglobulinemia (IgG < 400 mg/dL) was 15% (95% CI: 0.08–0.22; Q = 50.15, p < 0.0001). The rate of hypogammaglobulinemia by allograft type: heart 49% (21%–78%; Q = 131.16, p < 0.0001); kidney 40% (30%–49%; Q = 24.55, p = 0.0002); liver 16% (0.001%–35%; Q = 14.31, p = 0.0002) and lung 63% (53%–74%; Q = 6.85, p = 0.08). The odds of respiratory infection (OR = 4.83; 95% CI: 1.66–14.05; p = 0.004; I2 = 0%), CMV (OR = 2.40; 95% CI: 1.16–4.96; p = 0.02; I2 = 26.66%), Aspergillus (OR = 8.19; 95% CI: 2.38–28.21; p = 0.0009; I2 = 17.02%) and other fungal infections (OR = 3.69; 95% CI: 1.11–12.33; p = 0.03; I2 = 0%) for patients with IgG <400 mg/dL were higher than the odds for patients with IgG >400 mg/dL. The odds for 1‐year all‐cause mortality for severe hypogammaglobulinemia group was 21.91 times higher than those for IgG >400 mg/dL group (95% CI: 2.49–192.55; p = 0.005; I2 = 0%). Severe hypogammaglobulinemia during the first year posttransplantation significantly increased the risk of CMV, fungal and respiratory infections, and was associated with higher 1‐year all‐cause mortality.

Adenovirus: Current Epidemiology and Emerging Approaches to Prevention and Treatment

Infections caused by adenoviruses are associated with significant morbidity and mortality in both hematopoietic stem cell and solid organ transplant recipients. The risk seems to be highest in allogeneic hematopoietic stem cell transplant recipients as well as heart, lung and small-bowel transplant recipients. Management of these infections may be difficult and includes reduction of immunosuppression whenever possible combined sometimes with antiviral therapy (mainly cidofovir). The currently available antiviral therapy is limited by the need for intravenous administration, potentially significant renal and hematologic toxicities. New emerging therapies such as brincidofovir and transfusion of adenovirus-specific T-lymphocytes may increase the available armamentarium for these potentially life-threatening infections.

Long-acting parenteral nanoformulated antiretroviral therapy: interest and attitudes of HIV-infected patients

AIM To gauge patient interest in receiving long-acting injectable nanoformulated antiretroviral therapy. METHODS Four hundred adult HIV-infected patients currently prescribed antiretroviral therapy were surveyed. χ(2) tests were used for comparisons of interest across groups. RESULTS Respondents were 68% male and 53% African-American, with a mean age of 47 years. Overall, 73% of patients indicated that they would definitely or probably try injectable nanoformulated antiretroviral therapy; 61% with weekly dosing; 72% every 2 weekly; and 84% monthly. In total, 48% indicated that they were very concerned about the possible side effects and 35% were very concerned about needle use. CONCLUSION The majority of respondents indicated that they definitely or probably would try parenteral nanoformulated antiretroviral therapy.

Multimodal neuroimaging evidence of alterations in cortical structure and function in HIV-infected older adults.

Combination antiretroviral therapy transformed human immunodefiency virus (HIV)‐infection from a terminal illness to a manageable condition, but these patients remain at a significantly elevated risk of developing cognitive impairments and the mechanisms are not understood. Some previous neuroimaging studies have found hyperactivation in frontoparietal networks of HIV‐infected patients, whereas others reported aberrations restricted to sensory cortices. In this study, we utilize high‐resolution structural and neurophysiological imaging to determine whether alterations in brain structure, function, or both contribute to HIV‐related cognitive impairments. HIV‐infected adults and individually matched controls completed 3‐Tesla structural magnetic resonance imaging (sMRI) and a mechanoreception task during magnetoencephalography (MEG). MEG data were examined using advanced beamforming methods, and sMRI data were analyzed using the latest voxel‐based morphometry methods with DARTEL. We found significantly reduced theta responses in the postcentral gyrus and increased alpha activity in the prefrontal cortices of HIV‐infected patients compared with controls. Patients also had reduced gray matter volume in the postcentral gyrus, parahippocampal gyrus, and other regions. Importantly, reduced gray matter volume in the left postcentral gyrus was spatially coincident with abnormal MEG responses in HIV‐infected patients. Finally, left prefrontal and postcentral gyrus activity was correlated with neuropsychological performance and, when used in conjunction, these two MEG findings had a sensitivity and specificity of over 87.5% for HIV‐associated cognitive impairment. This study is the first to demonstrate abnormally increased activity in association cortices with simultaneously decreased activity in sensory areas. These MEG findings had excellent sensitivity and specificity for HIV‐associated cognitive impairment, and may hold promise as a potential disease marker. Hum Brain Mapp 36:897–910, 2015.

Abnormal MEG Oscillatory Activity during Visual Processing in the Prefrontal Cortices and Frontal Eye-Fields of the Aging HIV Brain

Objective Shortly after infection, HIV enters the brain and causes widespread inflammation and neuronal damage, which ultimately leads to neuropsychological impairments. Despite a large body of neuroscience and imaging studies, the pathophysiology of these HIV-associated neurocognitive disorders (HAND) remains unresolved. Previous neuroimaging studies have shown greater activation in HIV-infected patients during strenuous tasks in frontal and parietal cortices, and less activation in the primary sensory cortices during rest and sensory stimulation. Methods High-density magnetoencephalography (MEG) was utilized to evaluate the basic neurophysiology underlying attentive, visual processing in older HIV-infected adults and a matched non-infected control group. Unlike other neuroimaging methods, MEG is a direct measure of neural activity that is not tied to brain metabolism or hemodynamic responses. During MEG, participants fixated on a centrally-presented crosshair while intermittent visual stimulation appeared in their top-right visual-field quadrant. All MEG data was imaged in the time-frequency domain using beamforming. Results Uninfected controls had increased neuronal synchronization in the 6–12 Hz range within the right dorsolateral prefrontal cortex, right frontal eye-fields, and the posterior cingulate. Conversely, HIV-infected patients exhibited decreased synchrony in these same neural regions, and the magnitude of these decreases was correlated with neuropsychological performance in several cortical association regions. Conclusions MEG-based imaging holds potential as a noninvasive biomarker for HIV-related neuronal dysfunction, and may help identify patients who have or may develop HAND. Reduced synchronization of neural populations in the association cortices was strongly linked to cognitive dysfunction, and likely reflects the impact of HIV on neuronal and neuropsychological health.

Antiretroviral medication prescribing errors are common with hospitalization of HIV-infected patients

OBJECTIVES Errors in prescribing antiretroviral therapy (ART) often occur with the hospitalization of HIV-infected patients. The rapid identification and prevention of errors may reduce patient harm and healthcare-associated costs. METHODS A retrospective review of hospitalized HIV-infected patients was carried out between 1 January 2009 and 31 December 2011. Errors were documented as omission, underdose, overdose, duplicate therapy, incorrect scheduling and/or incorrect therapy. The time to error correction was recorded. Relative risks (RRs) were computed to evaluate patient characteristics and error rates. RESULTS A total of 289 medication errors were identified in 146/416 admissions (35%). The most common was drug omission (69%). At an error rate of 31%, nucleoside reverse transcriptase inhibitors were associated with an increased risk of error when compared with protease inhibitors (RR 1.32; 95% CI 1.04-1.69) and co-formulated drugs (RR 1.59; 95% CI 1.19-2.09). Of the errors, 31% were corrected within the first 24 h, but over half (55%) were never remedied. Admissions with an omission error were 7.4 times more likely to have all errors corrected within 24 h than were admissions without an omission. Drug interactions with ART were detected on 51 occasions. For the study population (n = 177), an increased risk of admission error was observed for black (43%) compared with white (28%) individuals (RR 1.53; 95% CI 1.16-2.03) but no significant differences were observed between white patients and other minorities or between men and women. CONCLUSION Errors in inpatient ART were common, and the majority were never detected. The most common errors involved omission of medication, and nucleoside reverse transcriptase inhibitors had the highest rate of prescribing error. Interventions to prevent and correct errors are urgently needed.

Acceptable Plasma Concentrations of Raltegravir and Etravirine When Administered by Gastrostomy Tube in a Patient with Advanced Multidrug-Resistant Human Immunodeficiency Virus Infection

To determine whether the absorption of four antiretroviral agents—raltegravir, etravirine, emtricitabine, and tenofovir—is compromised when administered by gastrostomy tube.

The use and value of procalcitonin in solid organ transplantation

Procalcitonin (PCT) has been increasingly used as a biomarker of bacterial infection and as a tool to guide antimicrobial therapy, especially in lower respiratory tract and bloodstream infections. Despite its increased use, data in patients with solid organ transplants are limited. Even without the presence of infection, PCT increases as a result of surgical procedures during transplantation, implantation of devices, and use of induction immunosuppressive therapy. The risk of infection is also higher in solid organ transplant recipients when compared to the general population. Monitoring PCT in the early post‐transplant period seems to be a promising method for early detection of infectious complications. It has been shown that elevated PCT levels after one wk of transplantation are correlated with infectious complications. PCT may be a useful adjunctive biomarker that may improve early identification and guide appropriate treatment of infection or rejection, with the potential to further improve clinical outcomes. The use of serial PCT measurements may be more reliable than single values. It is important to recognize which factors may lead to PCT increases in the post‐transplantation period, which in turn will help understand the kinetics and utility of this biomarker in this important patient population.

Measurement of plasma and intracellular concentrations of raltegravir in patients with HIV infection

Paired plasma and intracellular samples were obtained from 12 HIV-infected adults taking raltegravir twice daily (b.i.d.), and after switching to once daily. With b.i.d. dosing, no plasma trough concentrations were below the IC95, in contrast to 33% for once daily dosing. Fifty percent of the once daily group had intracellular trough concentrations below the inhibitory concentration 95 (IC95), 25% in the b.i.d. group. Lower plasma and intracellular concentrations may contribute to inferior virologic suppression rates observed with once daily raltegravir dosing.

Fusobacterium necrophorum causing infective endocarditis and liver and splenic abscesses

A 25-year-old male without prior co-morbidities was admitted to hospital with Fusobacterium necrophorum bacteremia, where he was found to have liver and splenic abscesses. Further evaluation with echocardiography revealed a bicuspid aortic valve with severe insufficiency and a 1.68 x 0.86 cm vegetation. The patient required abscess drainage, intravenous antimicrobial therapy and aortic valve replacement. Complete resolution of the infection was achieved after valve replacement and a prolonged course of intravenous antimicrobial therapy. A brief analysis of the patients clinical course and review of the literature is presented.