Hepatitis B in Heart Transplant Donors and Recipients: A Systematic Review and Meta-Analysis.

INTRODUCTION: Expanding the heart donor pool to include patients with hepatitis B virus (HBV) could help ameliorate the organ shortage in heart transplantation. We performed a systematic review and meta-analysis to evaluate the management and recipient outcomes of D+/R- and D-/R+ heart transplants. METHODS: An electronic search was performed to identify all relevant studies published on heart transplants involving HBV+ donors and/or HBV+ recipients. A comparison was performed between two groups where heart transplants were performed a) D+/R- (n = 98) versus b) D-/R+ (n = 65). RESULTS: Overall, 13 studies were selected, comprising 163 patients. Mean patient age was 55 y (95% CI: 39, 78) and 79% (69, 86) were male. Active post-transplant HBV infection requiring antiviral treatment occurred in 11% (1, 69) of D+/R- recipients and 33% (9, 71) of D-/R+ recipients. Post-transplant antiviral therapy was given to 80% (6, 100) of D+/R- recipients compared to 72% (42, 90) of D-/R+ recipients (P = 0.84). Hepatitis-related mortality was observed in no D+/R- recipients and 7% (2, 27) of D-/R+ recipients. Survival 1-y post-transplant was comparable between both groups at 83% (83, 92) and 81% (61, 92) for D+/R- and D-/R+ transplants, respectively. CONCLUSIONS: Our review found that HBV D+/R- heart transplantation was associated with fewer active hepatitis infections and lower hepatitis-related mortality than D-/R+ transplantation, with comparable survival at 1 y. Additional studies utilizing HBV nucleic acid testing (NAT) to compare outcomes with HBsAg+ and anti-HBc+ donors are crucial to reach more definitive conclusions about the risk of donor-derived infections in this context.

Infective endocarditis following heart transplantation: A systematic review.

PURPOSE: Infective endocarditis (IE) is a rare but potentially fatal complication following heart transplantation (HTx). There is a lack of literature regarding the patterns and clinical course of IE development following HTx. We sought to pool the existing data in regards to defining characteristics, management options, and outcomes of IE following HTx. METHODS: An electronic search of Cochrane Central Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature, Ovid Medline, and the Scopus databases were performed to identify all articles in the English literature that report IE following HTx in adult patients. Patient-level data were extracted and analyzed. RESULTS: Systematic search yielded 57 patients from 32 articles. Median patient age was 52 [IQR 43, 59] and 75% of patients (43/57) were male. Median time to IE presentation post-HTx was 8.4 [IQR 3.0, 35.8] months. IE of the mitral valve was observed in 36.8% (21/57) of patients, followed by mural IE in 24.6% (14/57), and tricuspid valve IE in 21.1% (12/57). The most common organisms were Staphylococcus aureus in 26.3% (15/57), Aspergillus fumigatus in 19.3% (11/57), Enterococcus faecalis in 12.3% (7/57), and an undetermined or unspecified organism in 14.0% (8/57) patients. Overall case fatality was 44.6% (25/56). Fungal IE was associated with a significantly higher case fatality 75.0% (9/12) than that of bacterial IE 36.1% (13/36) (p = 0.02). Surgical management of post-HTx IE was observed in 35.1% (20/57) of patients. This included valve surgery for 70.0% (14/20), including the mitral valve in 50.0% (7/14), aortic valve in 35.7% (5/14), and the tricuspid valve in 14.3% (2/14) of patients. CONCLUSION: In addition to bacterial organisms, fungi also represent a frequent cause of IE in post-HTx patients. Overall HTx patient survival in the setting of IE is poor and may be worse if caused by A. fumigatus.

Continuous-flow left ventricular assist device systems infections: current outcomes and management strategies.

Left ventricular assisted devices (LVADs) are increasingly used for management of patients with advanced heart failure. However, infection remains one of the most commonly reported complications. Diagnosis, as well as treatment of LVAD infections is challenging. There are multiple diagnostic modalities that have been used to assist with accurate diagnosis of LVAD infections. Treatment of the infection can be especially challenging in these patients, given the presence of the implantable device that cannot be easily replaced or removed. There are no clinical trials assessing the best approach to diagnosis, treatment or long-term management of LVAD infections. In this article we review the most recent diagnostic modalities and treatment approaches, as well as offer our guidance on diagnosis and treatment of LVAD infections.

COVID-19 in Solid Organ Transplantation: Disease Severity and Clinical Update.

BACKGROUND: Solid organ transplant (SOT) recipients are a complex, immunocompromised population in whom greater coronavirus disease 2019 (COVID-19) mortality has been reported compared with the general population. METHODS: We examined a retrospective cohort of 58 SOT recipients with first-wave COVID-19, comparing patients with severe and nonsevere illness. Additionally, SOT recipients are compared with general patients with first-wave COVID-19. RESULTS: Organs transplanted included 38 kidneys, 8 livers, 5 hearts, and 3 pancreases. Average SOT recipient age was 57.4 years; 62% were male; 46.6% were African American 36.2% were white. Comorbidities included hypertension (86%), chronic kidney disease (86%), diabetes mellitus (50%), coronary artery disease (26%), and chronic obstructive pulmonary disease (14%). Twenty patients had severe COVID-19 (34.5%) and 38 had nonsevere disease (65.5%). Severe disease was more common in older SOT recipients with comorbidities and was associated with cough, dyspnea, pneumonia, C-reactive protein >10 mg/L, and platelet count <150/µL. Sex, race, body mass index, time from transplant, baseline immunosuppression, and diagnosis month did not differ among those with severe and nonsevere COVID-19. Seventy percent of SOT recipients were hospitalized vs 27.2% of general patients with COVID-19 and inpatient SOT recipients had a higher mechanical ventilation rate. Though a trend toward longer length of stay, higher intensive care unit admission, and greater inpatient mortality was observed (19.5% vs 14.8%), these differences were not significant. CONCLUSIONS: The severe acute respiratory syndrome coronavirus 2 has greatly impacted SOT recipients. One-third of our SOT recipients seen during the first wave had severe illness with associated standard risk factors for poor outcome. Compared with general first-wave patients, more SOT recipients were hospitalized, although inpatient COVID-19 mortality did not significantly differ.

Management and outcomes of left ventricular assist device-associated endocarditis: a systematic review.

BACKGROUND: Left ventricular assist device (LVAD)-associated endocarditis remains poorly studied, especially in newer continuous-flow LVADs (CF-LVADs). The aim of this review was to assess outcomes of patients with LVAD-associated endocarditis, as stratified by CF-LVAD and pulsatile LVAD (P-LVAD) use as well as by different interventions and pathogen types. METHODS: An electronic search was performed to identify studies in the English literature on LVAD-associated endocarditis. RESULTS: Overall, 16 articles with 26 patients were included; seven had CF-LVADs and 19 had P-LVADs; time to development of endocarditis was 91 days (152 vs. 65 days, respectively, P=0.05). Eleven of 25 patients were treated with antibiotics only. Remaining 14 patients received antibiotics, however, they also underwent additional surgical intervention. One patient was treated with embolization alone for mycotic aneurysm and was therefore excluded. At a median follow-up time of 344 days post implant, there was no difference in overall mortality between CF-LVAD and P-LVAD-associated endocarditis patients (57.9% vs. 42.9%, P=0.81). Patients who underwent additional surgical intervention had higher overall survival compared to those treated with antibiotics alone (71.4% vs. 27.3%, P=0.07); with no difference in outcomes amongst those who underwent surgical device exchange as compared to heart transplantation (80.0% vs. 66.7%; P=0.23). CONCLUSIONS: Compared to patients with P-LVADs, CF-LVAD patients appeared to be resistant to early development of LVAD-associated endocarditis. There was a trend towards high survival observed amongst patients who underwent additional surgical intervention as compared to those treated with antibiotics alone, with no difference amongst surgical device exchange as compared to heart transplantation. Advantages of additional surgical intervention vs. medical therapy alone deserves further exploration to determine its applicability in CF-LVADs.

Single versus multi-drug antimicrobial surgical infection prophylaxis for left ventricular assist devices: A systematic review and meta-analysis.

Infection remains the Achilles heel of left ventricular assist device (LVAD) therapy. However, an optimal antimicrobial surgical infection prophylaxis (SIP) regimen has not been established. This study evaluated the efficacy of a single-drug SIP compared to a multi-drug SIP on clinical outcomes in patients undergoing continuous-flow LVAD (CF-LVAD) and pulsatile LVAD (P-LVAD) implantation. An electronic search was performed to identify studies in the English literature on SIP regimens in patients undergoing LVAD implantation. Identified articles were assessed for inclusion and exclusion criteria. Fourteen articles with 1,311 (CF-LVAD: 888; P-LVAD: 423) patients were analyzed. Overall, 501 (38.0%) patients received single-drug SIP, whereas 810 (62.0%) received multi-drug SIP. Time to infection was comparable between groups. There was no significant difference in overall incidence of LVAD-specific infections [single-drug: 18.7% vs. multi-drug: 24.8%, P = 0.49] including driveline infections [single-drug: 14.1% vs. multi-drug: 20.8%, P = 0.37]. Compared to single-drug SIP, patients who received multi-drug SIP had a significantly lower survival rate [single-drug: 90.0% vs. multi-drug: 76.0%, P = 0.01] and infection-free survival rate [single-drug: 88.4% vs. multi-drug: 77.3%, P = 0.04] at 90 days. However, there were no significant differences in 1-year survival and 1-year infection-free survival between groups. No survival differences were observed in the CF-LVAD subset as well. This study demonstrated no additional advantage of a multi-drug compared to a single-drug regimen for SIP. Although there was a modest advantage in early survival among CF-LVAD and P-LVAD patients who received single-drug SIP, there were no significant differences in the 1-year survival and 1-year infection-free survival.

Single Versus Multidrug Regimen for Surgical Infection Prophylaxis in Left Ventricular Assist Device Implantation.

Infection is a serious complication of left ventricular assist device (LVAD) therapy. However, an optimal antimicrobial surgical infection prophylaxis (SIP) regimen for LVAD implantation is not well established. We retrospectively reviewed all adults who underwent continuous-flow LVAD implantation from February 2007 to March 2015 at Mayo Clinic Rochester. Left ventricular assist device infection (LVADI) was defined using criteria published by the International Society for Heart and Lung Transplant. Patients excluded from the analysis included those who did not have HeartMate II or HeartWare device, patients with incomplete documentation of SIP, and those with an actively treated infection at the time of LVAD implantation. We compared risk of LVAD-specific and LVAD-related infections and all-cause mortality between SIP regimens at postoperative day 90 and 1 year using Kaplan-Meier time-to-event analyses. During study period, 239 adults underwent continuous-flow LVAD implantation at our institution where 199 patients received single-drug and 40 received multidrug SIP regimen. Median patient age was 62 years. Left ventricular assist device infection occurred in three patients (1.5%) in the single-drug group versus two patients (5.0%) in the multidrug group at 90 days (p = 0.4). There was no difference in infection-free (p = 0.4) and overall survival (p = 0.9) between two groups at 1 year. In conclusion, there was no clear benefit of using multidrug regimen as it did not impact infection-free survival or all-cause mortality compared with single-drug regimen. Prospective clinical trials are needed to further define the optimal SIP regimen for LVAD implantation.

Postsurgical mediastinal aspergilloma masquerading as malignancy.

A 70-year-old man with non-ischaemic dilated cardiomyopathy presented with symptoms of fatigue, chills and unintentional weight loss over the past 2 months. Initial evaluation revealed anaemia, peripheral leucocytosis and elevated inflammatory markers. Results of an oesophagogastroduodenoscopy, colonoscopy, blood bacterial and fungal cultures and bone marrow biopsy were negative. An 18F-FDG positron-emission tomography-CT demonstrated an indeterminate, intensely FDG-avid 5 cm × 2 cm × 5.6 cm × 6.7 cm mass centred within the junction of the superior vena cava and right atrium, suggestive of probable malignancy versus an inflammatory thrombus. After multidisciplinary consideration, patient underwent a diagnostic minithoracotomy and a thick fibrotic mediastinal mass was visualised and evacuated. The encapsulated mass contained thick, white creamy liquid that appeared to be purulent/necrotic material. The biopsies of the capsule wall on frozen section demonstrated fungal elements consistent with Aspergillosis species. Fungal culture confirmed diagnosis of Aspergillus fumigatus.

Stopping conventional showering decreases Pseudomonas infections in left ventricular assist device patients.

BACKGROUND: Left ventricular assist device (LVAD) exit-site infections represent a major challenge in the era of modern LVADs. Infections caused by Pseudomonas are particularly difficult to treat due to limited antibiotic susceptibility. We hypothesized that keeping the LVAD exit site dry while bathing could result in reduced incidence of Pseudomonas infections. METHODS: Starting in April 2013, all patients who underwent placement of HeartMate II (HM II) LVAD were instructed not to take conventional showers and to keep the exit site dry while bathing. We retrospectively reviewed patients who underwent HeartMate II LVAD implantation at our institution. Overall and Pseudomonas exit-site infections were compared between two groups: Group 1 was implanted with an LVAD prior to intervention (4/1/2013) and Group 2 after the intervention. Both groups were subjected to cumulative hazard analysis and compared using log-rank test. RESULTS: From November 2006 to September 2015, 283 patients underwent HM II LVAD placement at a single institution (Group 1, 163 patients; Group 2, 120 patients). Median age was 59 years (interquartile range [IQR] 50-65), and 57 (20%) were female. Overall, driveline infection was noted in 86 (30%) patients. Pseudomonas was the causative or coexisting organism in 16 (6%) patients. Median days to infection were 347 (IQR, 162-568). Driveline infection was identified in 69 (42%) patients in Group 1 and 17 (14 %) in Group 2. Pseudomonas was an infectious organism in 15 (9%) patients of Group 1 and one (1%) patient of Group 2. The incidence of Pseudomonas exit-site infections (p = 0.077) decreased substantially after the intervention. CONCLUSIONS: Stopping conventional showering may reduce the rate of Pseudomonas LVAD exit-site infections. Additional, multi-institutional data are needed to further evaluate these findings.

Chronic tenosynovitis of the hand caused by Mycobacterium heraklionense.

Non-tuberculous mycobacteria are increasingly recognized as a cause of infection in both immunocompromised and immunocompetent hosts. Mycobacterium heraklionense is a recently described member of the Mycobacterium terrae complex. Herein we report a case of M. heraklionense chronic flexor tenosynovitis in the hand, managed with surgery and antibiotics.

Nucleo-cytoplasmic localization domains regulate Krüppel-like factor 6 (KLF6) protein stability and tumor suppressor function.

BACKGROUND: The tumor suppressor KLF6 and its oncogenic cytoplasmic splice variant KLF6-SV1 represent a paradigm in cancer biology in that their antagonistic cancer functions are encoded within the same gene. As a consequence of splicing, KLF6-SV1 loses both the C-terminus C2H2 three zinc finger (ZF) domain, which characterizes all KLF proteins, as well as the adjacent 5' basic region (5BR), a putative nuclear localization signal (NLS). It has been hypothesized that this NLS is a functional domain critical to direct the distinct subcellular localization of the tumor suppressor and its splice variant. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we demonstrate using EGFP fusion constructs that KLF6/KLF6-SV1 nucleo-cytoplasmic transport is not regulated by the 5' basic region but activated by a novel NLS encoded within the ZF domain, and a nuclear export signal (NES) located in the first 16 amino acids of the shared N-terminus sequence. We demonstrate KLF6 nuclear export to be Crm1-dependent. The dysregulation of nucleo-cytoplasmic transport when disrupting the KLF6 NLS using site-directed mutagenesis showed that its integrity is necessary for appropriate protein stability. Moreover, these mutations impaired transcriptional induction of two KLF6 well-characterized target genes, E-cadherin and p21, as shown by RT-PCR and luciferase promoter assays. The addition of the ZF domain to KLF6-SV1 results in its nuclear localization and a markedly decreased half-life similar to wild type KLF6. CONCLUSIONS/SIGNIFICANCE: We describe the domains that control KLF6 nucleo-cytoplasmic shuttling and how these domains play a role in KLF6 protein half-life and tumor suppressor function. The results begin to mechanistically explain, at least in part, the opposing functions of KLF6 and KLF6-SV1 in cancer.