First Report of Clivus Osteomyelitis Caused by Nocardia veterana in a Lung Transplant Recipient.

Nocardia species have been implicated as a cause of pulmonary, cutaneous, ocular, and disseminated central nervous system disease. Dissemination to the bones, commonly the spine, has also been described in the literature. However, isolated osteomyelitis of the skull base is rare. Additionally, advances in the use of molecular techniques have identified many new Nocardia species, including Nocardia veterana that was thought to be clinically insignificant when it was first identified. Here, we report the clinical features and treatment approach for a lung transplant patient who developed N. veterana clivus osteomyelitis secondary to sphenoid sinusitis. It is the first case of skull base osteomyelitis caused by this rare species of Nocardia.

Hepatitis C virus and kidney transplantation: Recent trends and paradigm shifts.

The management of HCV infection in kidney transplantation presents significant challenges. HCV, left untreated, worsens patient and graft survival after kidney transplantation through multiple mechanisms. The field has evolved significantly in recent years, due to the ability to effectively eliminate the virus with direct-acting antivirals. Limited data suggest that current HCV treatment improves outcomes of infected kidney transplant patients. Along with the ability to successfully treat HCV, the increased HCV prevalence among donors has led to transplantation of kidneys from HCV-viremic donors into uninfected recipients. The practice has become increasingly common, but optimization of protocols to guide this practice is currently under debate. We have searched the literature on HCV and kidney transplantation, and review here the epidemiology, clinical outcomes, HCV treatment, and studies on transplantation from positive donor to negative recipient. We also discuss the evolving clinical management paradigms and address unresolved questions, highlighting the need for additional data with longer follow up.

Retrograde Parotid Gland Infusion through Stensen's Duct in a Non-Human Primate for Vectored Gene Delivery.

Salivary glands are an attractive tissue target for gene therapy with promising results already leading to human trials. They are inherently capable of secreting proteins into the bloodstream and are easily accessible, making them potentially superior tissue sites for replacement hormone production or vaccination by gene transfer. Suggested methods for gene delivery include transcutaneous injection and retrograde infusion through salivary ducts. We demonstrate how to perform Retrograde Salivary Gland Infusion (RSGI) in non-human primates. We describe the important anatomic landmarks including identification of the parotid papilla, an atraumatic method of cannulating and sealing Stensen's Duct utilizing basic dental tools, polyethylene tubing, and cyanoacrylate, and the appropriate rate of infusion. While this is the least traumatic method of delivery, the method is still limited by the volume able to be delivered (<0.5 mL) and the potential for trauma to the duct and gland. We demonstrate using fluoroscopy that an infusate can be fully delivered into the gland, and further demonstrate by immunohistochemistry the transduction of a typical vector and expression of the delivered gene.

Staphylococcus pseudintermedius Bacteremia in a Lung Transplant Recipient Exposed to Domestic Pets.

Staphylococcus pseudintermedius commonly colonizes companion animals, including canines. This microbe is a major opportunistic pathogen responsible for pyogenic and necrotizing skin and soft tissue infection in canines. Infection with S. pseudintermedius is increasingly being recognized in humans, especially in those who are immunocompromised. This microbe is quite similar to Staphylococcus aureus, expressing several analogous virulence factors and a variety of toxins. Furthermore, S. pseudintermedius has variants that display multi-drug resistance comparable to methicillin-resistant S. aureus. We report a 50-year-old female with bilateral lung transplant on immunosuppression who presents with signs of sepsis and pneumonia. Initial blood cultures grew Gram-positive cocci that were not initially identified via molecular diagnostics as Staphylococcus species but were later confirmed as S. pseudintermedius through mass spectrometry. Antimicrobial susceptibility testing demonstrated multi-drug resistance, including methicillin. Despite aggressive medical and antimicrobial treatment, our patients succumbed to the infection. The source of infection likely came from her companion canine at home as no other source could be identified; however, cultures were unable to be obtained from the companion canine. Those who are immunosuppressed, such as with solid organ transplants, should take caution with exposure to companion animals due to the potential for S. pseudintermedius infection.

Absolute lymphocyte count as marker of cytomegalovirus and allograft rejection: Is there a "Safe Corridor" after kidney transplantation?

The contrasting outcomes of lymphocyte manipulation after solid organ transplantation are allograft rejection and infections, commonly with cytomegalovirus (CMV). Peripheral blood absolute lymphocyte count (ALC) may serve as a predictive marker for these outcomes. Using a retrospective review of clinical and laboratory dataset, we aimed to determine whether a range of ALC (termed "safe ALC corridor") exists where CMV infection and rejection outcomes are minimal in a cohort of 381 kidney transplant recipients. In an extended Cox model using a time-dependent covariate for peripheral blood ALC, a value below the cut-off of 610 cells/uL was associated with the development of CMV infection both in the overall cohort (Hazard Ratio [HR] 2.25 (95% confidence internal [CI] 1.02-4.96; P = .043) and the subgroup of high-risk CMV D+/R- mismatch patients (HR 2.91 [95% CI 1.09-7.77]; P = .033). In contrast, a time-dependent Cox analysis did not show any significant association between ALC and rejection (per IQR decrease, HR 1.2 [95% CI: 0.76-1.9]; P = .434). Accordingly, a "safe ALC corridor" could not be defined. In conclusion, a low peripheral blood ALC (ie, threshold of 610 cells/uL) can be used to stratify the risk of CMV disease after kidney transplantation.

Tetravalent dengue DNA vaccine is not immunogenic when delivered by retrograde infusion into salivary glands.

INTRODUCTION AND BACKGROUND: A tetravalent DNA vaccine for Dengue virus is under development but has not yet achieved optimal immunogenicity. Salivary glands vaccination has been reported efficacious in rodents and dogs. We report on a pilot study testing the salivary gland as a platform for a Dengue DNA vaccine in a non-human primate model. MATERIALS AND METHODS: Four cynomolgus macaques were used in this study. Each macaque was pre-medicated with atropine and sedated with ketamine. Stensen's duct papilla was cannulated with a P10 polyethylene tube, linked to a 500ul syringe. On the first two infusions, all macaques were infused with 300ul of TVDV mixed with 2 mg of zinc. For the 3rd infusion, to increase transfection into salivary tissue, two animals received 100uL TVDV mixed with 400uL polyethylenimine 1µg/ml (PEI) and the other two animals received 500uL TVDV with zinc. Antibody titers were assessed 4 weeks following the second and third infusion. RESULTS AND CONCLUSIONS: SGRI through Stensen's duct is a well-tolerated, simple and easy to reproduce procedure. TVDV infused into macaques salivary glands elicited a significantly weaker antibody response than with different delivery methods.

Safety considerations with current and emerging antiviral therapies for cytomegalovirus infection in transplantation.

Introduction: Human cytomegalovirus (HCMV) is a major contributor of morbidity and mortality, and its management is essential for the successful outcome of solid organ and hematopoietic stem cell transplantation. Areas covered: This review discusses the safety profiles of currently available and emerging antiviral drugs and the other strategies for HCMV prevention and treatment after transplantation. Expert opinion: Strategies for management of HCMV rely largely on the use of antiviral agents that inhibit viral DNA polymerase (ganciclovir/valganciclovir, foscarnet, and cidofovir/brincidofovir) and viral terminase complex (letermovir), with different types and degrees of adverse effects. An investigational agent, maribavir, exerts its anti-CMV effect through UL97 inhibition, and its safety profile is under clinical evaluation. In choosing the antiviral medication to use, it is important to consider these safety profiles in addition to overall efficacy. In addition to antiviral drugs, reduction of immunosuppression is often generally needed in the management of HCMV infection, but with a potential risk of allograft rejection or graft-versus-host disease. The use of HCMV-specific or non-specific intravenous immunoglobulins remains debated, while adoptive HCMV-specific T cell therapy remains investigational, and associated with unique set of adverse effects.

Cryptococcus neoformans pericarditis in a lung transplant recipient: Case report, literature review and pearls.

A 68-year-old man presented for outpatient evaluation of dyspnea and new-onset atrial fibrillation 9 months after undergoing bilateral lung transplantation. Echocardiography prior to cardioversion raised concern for tamponade. Therapeutic pericardiocentesis returned fluid containing 1875 wbc/mcl (68% pmn) and yielded Cryptococcus neoformans in culture. Cryptococcal antigen was detected in serum at a titer of 1:20. Cerebrospinal (CSF) fluid was without evidence of inflammation and without detectable cryptococcal antigen. There was no radiographic evidence of pulmonary cryptococcosis. Cultures of blood and CSF were without growth. Liposomal amphotericin B (3 mg/kg/day) was administered for 15 days. Oral fluconazole was added on day seven of amphotericin, and the patient was discharged to home 3 days later. Daily dosages of prednisone (10 mg), mycophenolate (500 mg), and tacrolimus (3 mg) at discharge were the same as at hospital admission. He was readmitted 12 days later with dyspnea and with re-accumulation and loculation of pericardial fluid. A pericardial window was created. Pericardial fluid contained 722 wbc/mcl (35% pmn); Cryptococcus was not identified on direct examinations or cultures of pericardial fluid or tissue. Cryptococcus antigen was present in serum at 1:160. Liposomal amphotericin B was resumed and continued for 2 weeks followed by resumption of fluconazole. Mycophenolate was stopped. Prednisone and tacrolimus were continued. Restrictive pericarditis was evident 3 weeks after window creation. Colchicine was initiated, prednisone increased to 15 mg daily and pericardiectomy planned. We aim to raise awareness to Cryptococcus as a potential etiology for pericarditis in solid organ transplant recipients.

Letermovir for the prevention of cytomegalovirus infection and disease in transplant recipients: an evidence-based review.

Cytomegalovirus (CMV) is a leading opportunistic infection in immune compromised patients, including allogeneic hematopoietic stem cell (HSCT) or solid organ transplant (SOT) recipients, where primary infection or reactivation is associated with increased morbidity and mortality. Antiviral drugs are the mainstay for the prevention of CMV infection and disease, most commonly with valganciclovir. However, valganciclovir use is often associated with adverse drug reactions, most notably leukopenia and neutropenia, and its widespread use has led to emergence of antiviral resistance. Foscarnet and cidofovir, however, are associated with nephrotoxicity. Letermovir, a novel CMV viral terminase inhibitor drug, was recently approved for CMV prophylaxis in allogeneic HSCT recipients. It has a favorable pharmacokinetic and tolerability profile. The aim of this paper is to review the evidence supporting the use of letermovir in allogeneic HSCT recipients, and how the drug impacts our contemporary clinical practice. In addition, we discuss the ongoing clinical trial of letermovir for the prevention of CMV in SOT recipients. The use of letermovir for treatment of CMV infection and disease is not yet approved. However, because of a unique mechanism of activity, we provide our perspective on the potential role of letermovir in the treatment of ganciclovir-resistant CMV infection and disease. Furthermore, drug-resistant CMV has emerged during use of letermovir for prophylaxis and treatment. Caution is advised on its use in order to preserve its therapeutic lifespan.

Double invasive fungal infection due to dematiaceous moulds in a renal transplant patient.

Alternaria and Verruconis are two dematiaceous moulds that occasionally cause disease in immunocompromised hosts. We present the case of a 58-year-old man with history of deceased donor renal transplantation 14 months prior, who presented with fevers and cough. He was found to have right upper lobe pneumonia and a non-healing eschar of his right knee. Dematiaceous fungi grew from bronchoalveolar lavage (BAL) and was sent to reference lab for identification. Meanwhile, the eschar on his right knee was biopsied and grew Alternaria spp. Pathology was consistent with invasive mould infection and he was treated as having disseminated Alternaria infection with voriconazole and amphotericin B lipid complex. Later on, the dematiaceous mould from a BAL specimen was identified as Verruconis gallopava The patient was discharged on voriconazole awaiting minimal inhibitory concentrations for V. gallopava but was readmitted 2 days later with high fevers and died from acute respiratory failure.

Candida pararugosa: First Reported Bloodstream Infection in an Adult.

Candida pararugosa is a yeast that has been previously isolated in various human specimens. The first reported isolation was from human feces in 1998, with subsequent reports of positive cultures from the oral cavity where it was thought to represent colonization rather than true infection. Though it has been isolated from other human sites, its clinical significance and manifestations are poorly characterized. We report the case of a 39-year-old woman on parenteral hyperalimentation who developed post abdominal surgery sepsis and surgical wound necrotizing fasciitis. Candida pararugosa was isolated from two different blood cultures and the patient's clinical status improved after initiation of therapy with micafungin. Though it was not clear whether sepsis was driven by the candidemia or the necrotizing fasciitis or both, this report appears to be the first case of Candida pararugosa bloodstream infection described in an adult.