Todd L. Astor

Following Universal Prophylaxis with Intravenous Ganciclovir and Cytomegalovirus Immune Globulin, Valganciclovir is Safe and Effective for Prevention of CMV Infection Following Lung Transplantation

We prospectively determined the safety and efficacy of valganciclovir for prevention of cytomegalovirus (CMV) in at‐risk (donor positive/recipient negative [D+/R−] or R+) lung transplant recipients. We also determined the length of prophylaxis required to significantly decrease both CMV infection and disease. Consecutive lung transplant recipients surviving >30 days (n = 90) received combination prophylaxis with intravenous (i.v.) ganciclovir (GCV) 5 mg/kg/day and cytomegalovirus immune globulin (CMV‐IVIG) followed by valganciclovir (450 mg twice‐daily) to complete 180, 270 or 365 days of prophylaxis. This group was compared to a historical group (n = 140) who received high‐dose oral acyclovir following i.v. GCV and CMV‐IVIG. CMV disease was significantly lower in patients receiving valganciclovir compared to acyclovir (2.2% vs. 20%; p < 0.0001). Freedom from CMV infection and disease was significantly greater (p < 0.02) in patients receiving 180, 270 or 365 days of prophylaxis (90%, 95% and 90%, respectively) compared to those receiving 100–179 days (64%) or <100 days (59%). No patient receiving valganciclovir died during the study. Following prophylaxis with i.v. GCV and CMV‐IVIG, valganciclovir is safe and effective for prevention of CMV infection and disease in at‐risk lung transplant recipients. The required length of prophylaxis was at least 180 days.

Disseminated Ureaplasma infection as a cause of fatal hyperammonemia in humans.

Disseminated infection with Ureaplasma species causes fatal hyperammonemia syndrome in lung transplant recipients, likely by disrupting ammonia metabolism. The killer within Hyperammonemia, or abnormal buildup of ammonia, is an uncommon but generally fatal condition that affects immunosuppressed patients, particularly those who receive a lung transplant. Although there are treatments that can lower the blood concentration of ammonia, their effects are short-lived, and they are typically ineffective for this condition. Now, Bharat et al. identified Ureaplasma bacteria as the cause of this condition and demonstrated that it can be successfully treated with antibiotics. These findings suggest that patients with hyperammonemia should be screened for Ureaplasma species and treated with the appropriate antibiotics for this infection. Moreover, the authors found evidence of Ureaplasma species in one donor’s lung fluid sample, indicating that donors may need to be screened for it as well. Hyperammonemia syndrome is a fatal complication affecting immunosuppressed patients. Frequently refractory to treatment, it is characterized by progressive elevations in serum ammonia of unknown etiology, ultimately leading to cerebral edema and death. In mammals, ammonia produced during amino acid metabolism is primarily cleared through the hepatic production of urea, which is eliminated in the kidney. Ureaplasma species, commensals of the urogenital tract, are Mollicutes dependent on urea hydrolysis to ammonia and carbon dioxide for energy production. We hypothesized that systemic infection with Ureaplasma species might pose a unique challenge to human ammonia metabolism by liberating free ammonia resulting in the hyperammonemia syndrome. We used polymerase chain reaction, specialized culture, and molecular resistance profiling to identify systemic Ureaplasma infection in lung transplant recipients with hyperammonemia syndrome, but did not detect it in any lung transplant recipients with normal ammonia concentrations. Administration of Ureaplasma-directed antimicrobials to patients with hyperammonemia syndrome resulted in biochemical and clinical resolution of the disorder. Relapse in one patient was accompanied by recurrent Ureaplasma bacteremia with antimicrobial resistance. Our results provide evidence supporting a causal relationship between Ureaplasma infection and hyperammonemia, suggesting a need to test for this organism and provide empiric antimicrobial treatment while awaiting microbiological confirmation.

ICP22 is required for wild-type composition and infectivity of herpes simplex virus type 1 virions

ABSTRACT The immediate-early regulatory protein ICP22 is required for efficient replication of herpes simplex virus type 1 in some cell types (permissive) but not in others (restrictive). In mice infected via the ocular route, the pathogenesis of an ICP22− virus, 22/n199, was altered relative to that of wild-type virus. Specifically, tear film titers of 22/n199-infected mice were significantly reduced at 3 h postinfection relative to those of mice infected with wild-type virus. Further, 22/n199 virus titers were below the level of detection in trigeminal ganglia (TG) during the first 9 days postinfection. On day 30 postinfection, TG from 22/n199-infected mice contained reduced viral genome loads and exhibited reduced expression of latency-associated transcripts and reduced reactivation efficiency relative to TG from wild-type virus-infected mice. Notably, the first detectable alteration in the pathogenesis of 22/n199 in these tests occurred in the eye prior to the onset of nascent virus production. Thus, ICP22− virions appeared to be degraded, cleared, or adsorbed more rapidly than wild-type virions, implying potential differences in the composition of the two virion types. Analysis of the protein composition of purified extracellular virions indicated that ICP22 is not a virion component and that 22/n199 virions sediment at a reduced density relative to wild-type virions. Although similar to wild-type virions morphologically, 22/n199 virions contain reduced amounts of two γ2 late proteins, US11 and gC, and increased amounts of two immediate-early proteins, ICP0 and ICP4, as well as protein species not detected in wild-type virions. Although ICP22− viruses replicate to near-wild-type levels in permissive cells, the virions produced in these cells are biochemically and physically different from wild-type virions. These virion-specific differences in ICP22− viruses add a new level of complexity to the functional analysis of this immediate-early viral regulatory protein.

Pulmonary Capillaritis as a Manifestation of Acute Humoral Allograft Rejection Following Infant Lung Transplantation

Pulmonary capillaritis has been described in adult lung transplant recipients, but has not been previously reported in pediatric recipients. We report a case of posttransplant pulmonary capillaritis in an 8‐month‐old infant, and demonstrate evidence of C4d deposition and B‐lymphocytes in the allograft, donor anti‐HLA antibodies in the serum and a clinical and immunohistochemical response to anti‐CD20 monoclonal antibody (rituximab) therapy. These findings strongly support the hypothesis that pulmonary capillaritis may represent a form of acute humoral rejection in the lung allograft that is less common than, and clinically and histologically distinct from, typical acute cellular rejection.

The Products of the Herpes Simplex Virus Type 1 Immediate-Early US1/US1.5 Genes Downregulate Levels of S-Phase-Specific Cyclins and Facilitate Virus Replication in S-Phase Vero Cells

ABSTRACT Herpes simplex virus type 1 ICP22−/US1.5− mutants initiate viral gene expression in all cells; however, in most cell types, the replication process stalls due to an inability to express γ2 late proteins. Although the function of ICP22/US1.5 has not been established, it has been suggested that these proteins activate, induce, or repress the activity of cellular proteins during infection. In this study, we hypothesized that cell cycle-associated proteins are targets of ICP22/US1.5. For this purpose, we first isolated and characterized an ICP22−/US1.5− mutant virus, 22/n199. Like other ICP22−/US1.5− mutants, 22/n199 replicates in a cell-type-specific manner and fails to induce efficient γ2 late gene expression in restrictive cells. Although synchronization of restrictive human embryonic lung cells in each phase of the cell cycle did not overcome the growth restrictions of 22/n199, synchronization of permissive Vero cells in S phase rendered them less able to support 22/n199 plaque formation and replication. Consistent with this finding, expression of cellular S-phase cyclins was altered in an ICP22/US1.5-dependent manner specifically when S-phase Vero cells were infected. Collectively, these observations support the notion that ICP22/US1.5 deregulates the cell cycle upon infection of S-phase permissive cells by altering expression of key cell cycle regulatory proteins either directly or indirectly.

Surveillance transbronchial biopsies in infant lung and heart–lung transplant recipients

There are limited published data on surveillance TBB for the identification of allograft rejection in infants after lung or heart‐lung transplantation. We performed a retrospective review of children under one yr of age who underwent lung or heart–lung transplant at our institution. Since 2005, four infants were transplanted (three heart–lung and one lung). The mean age (±s.d.) at the time of transplant was 5.5 ± 2.4 (range 3–8) months. A total of 16 surveillance TBB procedures were completed in both inpatient and outpatient settings, with a range of 3–7 performed per patient. A minimum of five acceptable tissue pieces with expanded alveoli were obtained in 81% (13/16) of TBB procedures and a minimum of three pieces in 88% (14/16). There was no evidence of acute allograft rejection in 88% (14/16) of TBB procedures. One TBB procedure yielded two tissue specimens demonstrating A2 acute allograft rejection. One TBB procedure failed to yield tissue with sufficient alveoli. Additionally, B‐grade assessment identified B0 in 50% (8/16), B1R in 12% (2/16), and BX (ungradeable or insufficient sample) in 38% (6/16) of biopsy procedures, respectively. In conclusion, TBB may be safely performed as an inpatient and outpatient procedure in infant lung and heart–lung transplant recipients and may provide adequate tissue for detecting acute allograft rejection and small airway inflammation.

Late thrombus formation on the Helex septal occluder after double-lung transplant

Percutaneous device closure in patients with an atrial septal defect (ASD) or patent foramen ovale (PFO) has gained popularity because of the short learning curve, cosmetic advantage and relative safety compared with surgery. Device complications may include device embolism, erosion, pericardial tamponade or thrombus formation, and most complications occur early. Herein we describe the previously unreported finding of a late thrombus on a Helex device after PFO closure in a patient with cystic fibrosis and double-lung transplantation.

Comprehensive evaluation of lung allograft function in infants after lung and heart-lung transplantation

BACKGROUND Limited data exist on methods to evaluate allograft function in infant recipients of lung and heart-lung transplants. At our institution, we developed a procedural protocol in coordination with pediatric anesthesia where infants were sedated to perform infant pulmonary function testing, computed tomography imaging of the chest, and flexible fiberoptic bronchoscopy with transbronchial biopsies. METHODS A retrospective review was performed of children aged younger than 1 year who underwent lung or heart-lung transplantation at our institution to assess the effect of this procedural protocol in the evaluation of infant lung allografts. RESULTS Since 2005, 5 infants have undergone thoracic transplantation (3 heart-lung, 2 lung). At time of transplant, the mean ± standard deviation age was 7.2 ± 2.8 months (range, 3-11 months). Of 24 procedural sessions performed to evaluate lung allografts, 83% (20 of 24) were considered surveillance where the patients were completely asymptomatic. Of the surveillance procedures, 80% were performed as an outpatient, whereas 20% were done as inpatients during the lung or heart-lung transplant post-operative period before discharge home. Sedation was performed with propofol alone (23 of 24) or in addition to ketamine (1 of 24) infusion; mean sedation time was 141 ± 39 minutes (range, 70-214) minutes. Of the 16 outpatient procedures, patients were discharged after 14 (88%) on the same day, and after 2 (12%) were admitted for observation, with 1 being due to transportation issues and the other due to fever during the observation period. CONCLUSIONS A comprehensive procedural protocol to evaluate allograft function in infant lung and heart-lung transplant recipients was performed safely as an outpatient.

Domino Heart Transplantation Involving Infants

Domino heart transplantation has been well described in adults, but has not previously been reported in infant patients. We report the successful transplantation of a ‘domino’ heart from a 3‐month‐old infant with primary pulmonary hypertension undergoing heart–lung transplantation, into a 3‐month‐old infant with complex congenital heart disease. Both infants have survived past 1 year post‐transplant, and neither infant has experienced any clinically significant allograft‐related complications. Echocardiography and cardiac catheterization of the domino heart have consistently demonstrated stable hypertrophy of the right ventricle (RV) and interventricular septum, but good right and left ventricular function. Domino heart transplant surgery may be an effective way to provide ‘pre‐conditioned’ donor hearts to infants urgently in need of heart transplantation.

Bilateral Lung Transplantation in a Patient with Humoral Immune Deficiency: A Case Report with Review of the Literature

Humoral immune deficiencies have been associated with noninfectious disease complications including autoimmune cytopenias and pulmonary disease. Herein we present a patient who underwent splenectomy for autoimmune cytopenias and subsequently was diagnosed with humoral immune deficiency in the context of recurrent infections. Immunoglobulin analysis prior to initiation of intravenous immunoglobulin (IVIG) therapy was notable for low age-matched serum levels of IgA (11 mg/dL), IgG2 (14 mg/L), and IgG4 (5 mg/L) with a preserved total level of IgG. Flow cytometry was remarkable for B cell maturation arrest at the IgM+/IgD+ stage. Selective screening for known primary immune deficiency-causing genetic defects was negative. The disease course was uniquely complicated by the development of pulmonary arteriovenous malformations (AVMs), ultimately requiring bilateral lung transplantation in 2012. This is a patient with humoral immune deficiency that became apparent only after splenectomy, which argues for routine immunologic evaluation prior to vaccination and splenectomy. Lung transplantation is a rare therapeutic endpoint and to our knowledge has never before been described in a patient with humoral immune deficiency for the indication of pulmonary AVMs.