An Update in Antimicrobial Therapies and Infection Prevention in Pediatric Lung Transplant Recipients.

Lung transplantation can offer life-prolonging therapy to children with otherwise terminal end-stage lung disease. However, infectious complications, like those experienced by their adult counterparts, are a significant cause of morbidity and mortality. These include bacteria, viruses, and fungi that infect the patient pretransplant and those that may be acquired from the donor or by the recipient in the months to years posttransplant. An understanding of the approach to the management of each potential infecting organism is required to ensure optimal outcomes. In particular, emphasis on aggressive preoperative management of infections in pediatric patients with cystic fibrosis is important. These include multidrug-resistant Gram-negative bacteria, fungi, and Mycobacterium abscessus, the posttransplant outcome of which depends on optimal pretransplant management, including vaccination and other preventive, antibiotic-sparing strategies. Similarly, increasing the transplant donor pool to meet rising transplant demands is an issue of critical importance. Expanded-criteria donors-those at increased risk of blood-borne viruses in particular-are increasingly being considered and transplants undertaken to meet the rising demand. There is growing evidence in the adult pool that these transplants are safe and associated with comparable outcomes. Pediatric transplanters are therefore likely to be presented with increased-risk donors for their patients. Finally, numerous novel antibiotic-sparing therapeutic approaches are on the horizon to help combat infections that currently compromise transplant outcomes.

ABO incompatible renal transplantation following lung transplantation.

We present management strategies utilised for the first case of an urgent live-donor ABO incompatible B blood group renal transplant, in a patient with a prior A blood group lung transplant for cystic fibrosis. Three years on, renal function is excellent and stable, whilst lung function has improved.

Invasive Scedosporium sternal osteomyelitis following lung transplant: Cured.

Scedosporium is an important pathogen in cystic fibrosis (CF) and post-transplant but rarely causes invasive infection. Treatment remains challenging, particularly due to inherent resistance to multiple antifungal agents. We present a young man with CF who developed invasive sternal and rib infection 10-months following lung transplant. The infection has been clinically and radiologically cured with extensive surgery and triazole therapy. This case highlights the importance of adjunctive surgery in addition to prolonged triazole treatment to manage invasive Scedosporium infections in immunosuppressed patients.

HLA Matching at the Eplet Level Protects Against Chronic Lung Allograft Dysfunction.

Donor selection in lung transplantation (LTx) is historically based upon clinical urgency, ABO compatibility, and donor size. HLA matching is not routinely considered; however, the presence or later development of anti-HLA antibodies is associated with poorer outcomes, particularly chronic lung allograft dysfunction (CLAD). Using eplet mismatches, we aimed to determine whether donor/recipient HLA incompatibility was a significant predictor of CLAD. One hundred seventy-five LTx undertaken at the Alfred Hospital between 2008 and 2012 met criteria. Post-LTx monitoring was continued for at least 12 months, or until patient death. HLA typing was performed by sequence-based typing and Luminex sequence-specific oligonucleotide. Using HLAMatchmaker, eplet mismatches between each donor/recipient pairing were analyzed and correlated against incidences of CLAD. HLA-DRB1/3/4/5+DQA/B eplet mismatch was a significant predictor of CLAD (hazard ratio [HR] 3.77, 95% confidence interval [CI]: 1.71-8.29 p < 0.001). When bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS) were analyzed independently, HLA-DRB1/3/4/5 + DQA/B eplet mismatch was shown to significantly predict RAS (HR 8.3, 95% CI: 2.46-27.97 p < 0.001) but not BOS (HR 1.92, 95% CI: 0.64-5.72, p = 0.237). HLA-A/B eplet mismatch was shown not to be a significant predictor when analyzed independently but did provide additional stratification of results. This study illustrates the importance of epitope immunogenicity in defining donor-recipient immune compatibility in LTx.

Comparative analysis of how immune sensitization is defined prior to lung transplantation.

BACKGROUND: Immune sensitization prior to lung transplantation may be associated with worse survival. Using solid phase assays to define sensitization, we assessed the relationship between PRA status, donor specific anti-HLA antibodies (DSA) pre-transplant, cytotoxic cross match results and the clinical outcomes following lung transplantation. METHODS: Luminex assays determined the presence of antibodies to class I and class II MHC molecules prior to lung transplantation. At the time of transplant, the PRA status, the presence of DSA and prospective cytotoxic cross match result were analysed in 195 patients undergoing lung transplantation between June 2008 and June 2012. Clinical outcomes analysed included acute cellular and antibody-mediated rejection, chronic lung allograft dysfunction (CLAD) and mortality. RESULTS: At the time of transplant, 45% of patients had a positive PRA and 29% had DSA. On univariate analysis, the presence of pre-transplant class I or II anti-HLA donor-specific antibodies was not associated with the development of chronic lung allograft dysfunction (CLAD) despite significant associations with PRA status and B-cell crossmatch. CONCLUSION: Defining sensitization using solid phase assays provide additional details regarding donor-specific sensitization but did not provide additional prognostic information to that provided by historically available cell-based cross-match assays.

Donation After Circulatory Determination of Death Lung Transplantation for Pulmonary Arterial Hypertension: Passing the Toughest Test.

Lung transplantation (LTx) is a therapeutic option for severe pulmonary arterial hypertension (PAH) patients failing optimal medical therapy. The use of donation after circulatory determination of death (DCDD) donor lungs for PAH LTx has rarely been reported, primarily reflecting concerns that DCDD lungs represent extended criteria donors, at risk of morbidity and mortality. A retrospective study of all Alfred Hospital DCDD and DNDD (donation after neurologic determination of death) PAH LTx was undertaken. Protocolized fluid/inotrope/ventilator and extracorporeal membrane oxygenation (ECMO) strategies were utilized. Since our first DCDD LTx in 2006, 512 LTx have been performed. Of 31 PAH recipients, 11 received DCDD lungs (11% of DCDD LTx) and 20 received DNDD lungs (5% of DNDD LTx) (p = 0.04). Only one PAH patient died on the LTx waiting list. Peri-LTx ECMO was utilized in 3/11 (27%) DCDD and 6/20 (30%) DNDD PAH LTx (p = 0.68). Primary graft dysfunction, intensive care, and overall stay were the same in both groups. Survival at 1 and 8 years was 100% and 80% for DCDD versus 100% and 70% for DNDD LTx (p = 0.88), respectively. In conclusion, excellent results can be achieved for PAH LTx. DCDD donor lungs are not extended lungs per se having passed the toughest test.

Cytomegalovirus replication within the lung allograft is associated with bronchiolitis obliterans syndrome.

Early studies reported cytomegalovirus (CMV) pneumonitis as a risk factor for development of bronchiolitis obliterans syndrome (BOS) following lung transplantation. While improvements in antiviral prophylaxis have resulted in a decreased incidence of CMV pneumonitis, molecular diagnostic techniques allow diagnosis of subclinical CMV replication in the allograft. We hypothesized that this subclinical CMV replication was associated with development of BOS. We retrospectively evaluated 192 lung transplant recipients (LTR) from a single center between 2001 and 2009. Quantitative (PCR) analysis of CMV viral load and histological evidence of CMV pneumonitis and acute cellular rejection was determined on 1749 bronchoalveolar lavage (BAL) specimens and 1536 transbronchial biopsies. CMV was detected in the BAL of 41% of LTR and was significantly associated with the development of BOS (HR 1.8 [1.1-2.8], p = 0.02). This association persisted when CMV was considered more accurately as a time-dependent variable (HR 2.1 [1.3-3.3], p = 0.003) and after adjustment for significant covariates in a multivariate model. CMV replication in the lung allograft is common following lung transplantation and is associated with increased risk of BOS. As antiviral prophylaxis adequately suppresses CMV longer prophylactic strategies may improve long-term outcome in lung transplantation.

The in vitro biological activity of selected South African Commiphora species.

Ten South African Commiphora (Burseraceae) species were investigated to validate their use in traditional healing rites. The leaf and stem extracts of each species were analysed for the anti-oxidant (ABTS and DPPH assays), antimicrobial (MIC and death kinetic assays), anti-inflammatory (5-LOX assay), anticancer (SRB assay) properties, as well as the cytotoxic effects (tetrazolium-based assay). The best anti-oxidant activity (ABTS assay) was observed for the stem extracts of Commiphora tenuipetiolata IC(50)=5.10 microg/ml), Commiphora neglecta (IC(50)=7.28 microg/ml) and Commiphora mollis (IC(50)=8.82 microg/ml). Extracts generally exhibited poor anti-oxidant activity in the DPPH assay, with the exception of Commiphora schimperi (stem), Commiphora neglecta (stem), Commiphora tenuipetiolata (stem and leaf), and Commiphora edulis (stem), with IC(50) values ranging between 7.31 and 10.81 microg/ml. The stem extracts exhibited moderate to good 5-LOX inhibitory activity with Commiphora pyracanthoides (stem) displaying the greatest inhibitory effect (IC(50)=27.86+/-4.45 microg/ml). For the antimicrobial (MIC) assay, a greater selectivity was exhibited by the extracts against the Gram-positive bacteria (0.01-8.00 mg/ml) and the yeasts (0.25-8.00 mg/ml) than against the Gram-negative bacteria (1.00-8.00 mg/ml). Using death kinetic studies (time-kill studies), the rate at which Commiphora marlothii (stem) kills Staphylococcus aureus over a 24h period was determined. Mostly, a concentration-dependent antibacterial activity was observed beginning after ca. 30 min. All concentrations exhibited antibacterial activity, with complete bactericidal effect achieved by the 24(th) hour. The most active Commiphora species against the HT-29 cells (SRB anticancer assay) were Commiphora glandulosa (leaf and stem) and Commiphora marlothii (leaf). The MCF-7 cells (SRB anticancer assay) exhibited the highest sensitivity to indigenous Commiphora species, with Commiphora edulis (leaf and stem), Commiphora glandulosa (leaf and stem), Commiphora marlothii (leaf), Commiphora pyracanthoides (leaf and stem), Commiphora schimperi (stem), and Commiphora viminea (stem) all possessing a percentage inhibition greater than 80% at 100 microg/ml. Commiphora glandulosa (leaf and stem) and Commiphora pyracanthoides (leaf and stem) were the two most active species against the SF-268 cells (SRB anticancer assay), with IC(50) values ranging between 68.55+/-2.01 and 71.45+/-1.24 microg/ml. The majority of the Commiphora extracts were largely non-cytotoxic against Graham human kidney epithelial cells when investigated in the MTT assay.