K. Randall Young

A positive donor gram stain does not predict outcome following lung transplantation

BACKGROUND Many potential lung donors are excluded on the basis of a positive donor gram stain (DGS). We examined the association between a positive DGS and the probability of post-operative recipient pneumonia in the first 30 days. METHODS Ninety lung transplants (80 with a non-septic pre-transplant diagnosis) from 60 consecutive donors were evaluated for post-operative pneumonia (defined as a compatible clinical syndrome with fever, leukocytosis, chest X-ray abnormalities or histologic evidence obtained by transbronchial biopsy). DGS, white blood cell quantity, CXR and PaO(2)/FIO(2) (P/F) ratio were compared with immediate and 24-hour P/F ratio, length of mechanical ventilation and incidence of pneumonia. All recipients received standard prophylactic anti-bacterial coverage. Patients not surviving 30 days (n = 3) were excluded from this study, but none had evidence of pneumonia either by bronchoalveolar lavage (BAL), transbronchial biopsy or autopsy. RESULTS Fourteen (16%) of our 87 recipients developed pneumonia in the first 30 days after transplant. Of the 43 patients with a positive DGS, 5 (12%) developed pneumonia, compared to 9 of 44 (20%) with a negative DGS (p = 0.26). The mean post-operative P/F ratio (315 +/- 47 with a positive DGS, p = 0.3) and length of mechanical ventilation (2 days in each group) did not differ significantly between the negative and positive DGS groups. CONCLUSIONS In the current era of lung transplantation, DGS does not predict the development of early post-operative pneumonia and does not affect oxygenation or duration of mechanical ventilation; therefore, its role should be diminished when judging donor lung suitability.

Extensive surgical and comprehensive postoperative medical management for cystic fibrosis chronic rhinosinusitis

Background Chronic rhinosinusitis has a major impact on the quality of life of patients with cystic fibrosis (CF) and may contribute to progression of chronic lung disease. Despite multiple sinus surgeries, maxillary sinus involvement is a recurrent problem. The modified endoscopic medial maxillectomy (MEMM) permits debridement in the clinic, improves mucus clearance with nasal irrigations, and increases access for topical delivery of therapeutics. However, clinical outcomes of aggressive sinus surgery with regimented postoperative medical treatment have not been systematically evaluated. Methods CF patients completed the 22-Item Sinonasal Outcome Test questionnaires before sinus surgery (and bilateral MEMM) and at sequential postoperative visits. Objective measures included Lund-Kennedy endoscopic score and pulmonary function tests (forced expiratory volume at 1 second percent [FEV1%] predicted). Culture-directed antibiotic therapy, prednisone, and topical irrigations were initiated postoperatively. Results Twenty-two patients (mean age, 26.5 years; 4.9 prior sinus operations) underwent MEMM and sinus surgery. Symptom scores were significantly reduced at 60 days (primary outcome, 64.7 ± 18.4 presurgery versus 27.5 ± 15.3 postsurgery; p < 0.0001) and up to a year postoperatively (27.6 ± 12.6; p < 0.0001). Endoscopic scores were also reduced after surgery (10.4 ± 1.1 presurgery versus 5.7 ± 2.4 [30 days], 5.7 ± 1.4 [60 days], 5.8 ± 1.3 [120 days], and 6.0 ± 1.1 [1 year]; p < 0.0001)]. There were no differences in FEV1% predicted up to 1 year postoperatively, but hospital admissions secondary to pulmonary exacerbations significantly decreased (2.0 ± 1.4 versus 3.2 ± 2.4, respectively; p < 0.05). Conclusion Prospective evaluation indicates sinus surgery with MEMM is associated with marked improvement in sinus disease outcomes. Additional studies are necessary to confirm whether this treatment paradigm is associated with improved CF pulmonary disease.

The Presence of a Matrix-Derived Neutrophil Chemoattractant in Bronchiolitis Obliterans Syndrome after Lung Transplantation

Lung transplantation is a therapeutic modality frequently used in end-stage lung disease. Unfortunately, lung transplant recipients have poor clinical outcomes, often due to the development of bronchiolitis obliterans syndrome (BOS). This process is often characterized by the pathologic findings of obliterative bronchiolitis: neutrophil influx and extracellular matrix remodeling leading to luminal obstruction and airway inflammation. The molecular mechanisms underlying BOS are poorly understood and disease-specific biomarkers are lacking. We report that in addition to increased levels of IL-8, the level of the neutrophil chemoattractant proline-glycine-proline (PGP) is elevated in BOS patient bronchoalveolar lavage (BAL) fluid. The enzymes responsible for generating PGP, matrix metalloproteases 8 and -9 and prolyl endopeptidase, are also elevated in these samples. Together, IL-8 and PGP account for most of the neutrophil chemoattractant capacity seen in BOS BAL fluid. Using specific neutralizing Abs to both IL-8 and PGP, we demonstrate that PGP is a prominent neutrophil chemoattractant found in BAL fluid from individuals at the time of diagnosis of BOS. These findings highlight the influence of a matrix-derived neutrophil chemoattractant in posttransplantation BOS and provide opportunities for the development of unique diagnostics and therapeutics to potentially improve disease outcomes.

Combination Prophylaxis with Ganciclovir and Cytomegalovirus (CMV) Immune Globulin After Lung Transplantation: Effective CMV Prevention Following Daclizumab Induction

Despite the serious direct and indirect deleterious effects caused by cytomegalovirus (CMV), the optimal prophylactic strategy remains unknown. We sought to determine whether combination prophylaxis using intravenous ganciclovir (GCV) and CMV‐IVIG reduced the incidence of CMV compared to GCV alone. Donor CMV positive/recipient negative (D+/R–) patients received GCV (6 weeks i.v. + 6 weeks oral) and CMV‐IVIG (every 2 weeks for 7 doses), while R+ patients received GCV (2 weeks i.v. + 4 weeks oral) and CMV‐IVIG (every 2 weeks for 3 doses). The group receiving combination prophylaxis (GpA) was compared to a historical, case‐controlled group receiving GCV alone (GpB). Groups were matched by CMV donor/recipient serology, pretransplant diagnosis, age, and sex in reverse chronological order. Cyclosporine, azathioprine, and prednisone were used in both groups. Additionally, GpA received daclizumab induction therapy. Groups were compared as to the incidence of CMV disease, CMV infection, and acute rejection (AR). In GpA, 38 patients were evaluable and matched to 48 patients in GpB. Three GpA patients (8%) (2 D+/R–) developed CMV disease vs. 16 patients (33%) in GpB, p = 0.0077, Fishers exact. There was also a trend toward a delay in CMV onset (148 days in GpA vs. 92 days in GpB, p = 0.07, Mann–Whitney). CMV infection did not occur in GpA, and one case occurred in GpB. There was no difference in the incidence of AR (66% in GpA vs. 79% in GpB, p = 0.22, Fishers exact) or the need for cytolytic therapy between groups. Despite the use of daclizumab induction therapy, combination prophylaxis with GCV and CMV‐IVIG reduced the incidence and probably delayed the onset of CMV infection compared to GCV alone. Longer follow‐up will be needed to evaluate the impact of combination therapy on the incidence of bronchiolitis obliterans syndrome (BOS).

The utility of open lung biopsy following lung transplantation.

BACKGROUND Most pulmonary complications associated with lung transplantation have non-specific clinical characteristics. Furthermore, common diagnostic modalities, including bronchoscopy with transbronchial biopsy (TBB), often do not render a definitive diagnosis. In this study, we reviewed our experience with open lung biopsy (OLB) following lung transplantation, specifically regarding its ability to safely provide clinically relevant information that affects therapeutic decisions. METHODS From October 1989 to March 2000, 202 patients underwent lung transplantation at our institution. We reviewed the clinical course of the 42 patients who received 48 OLBs. Of these patients, we determined the pre-operative clinical condition, preceding TBB histologic information, OLB histology, treatment changes, and procedural complications as a result of the OLB. RESULTS A new, clinically unsuspected diagnosis was made in 14 biopsies (29% of all OLB), and all of these resulted in therapy changes. Thirty-two biopsies (67% of all OLB) confirmed our clinical suspicions, and new therapy was initiated in 30 of these patients. Two patients (4% of all OLB) had non-diagnostic OLB. Four biopsies (8% of all OLB), including the 2 non-diagnostic OLBs, did not result in any therapy changes or initiation of new therapy. Complications occurred in 3 patients, all of whom had an air leak for >7 days. CONCLUSION Open lung biopsy in lung transplant patients renders a new, unsuspected diagnosis in nearly one third of patients and leads to specific, directed therapy in the vast majority of patients. Open-lung biopsy can be performed safely and should be considered when diagnosis is uncertain in clinically deteriorating patients.

Management of congenital abnormalities of the donor lung

Congenital abnormalities were encountered in three donor lungs. A donor tracheal bronchus was incorporated into the right bronchial anastomosis. Anomalous pulmonary venous return of the right upper lobe to the superior vena cava and the left upper lobe to the innominate vein were managed by bridging the anomalous veins to the left atrial cuff with autologous pericardium and donor iliac vein, respectively.

The role of nitric oxide in lung innate immunity: modulation by surfactant protein-A.

Surfactant protein A (SP-A) and alveolar macrophages are essential components of lung innate immunity. Alveolar macrophages phagocytose and kill pathogens by the production of reactive oxygen and nitrogen species. In particular, peroxynitrite, the reaction product of superoxide and nitric oxide, appears to have potent antimicrobial effects. SP-A stimulates alveolar macrophages to phagocytose and kill pathogens and is important in host defense. However, SP-A has diverse effects on both innate and adaptive immunity, and may stimulate or inhibit immune function. SP-A appears to mediate toxic or protective effects depending on the immune status of the lung. In contrast to mouse or rat cells, it has been difficult to demonstrate nitric oxide production by human macrophages. We have recently demonstrated that human macrophages produce nitric oxide and use it to kill Klebsiella pneumoniae. SP-A either stimulates or inhibits this process, depending on the activation state of the macrophage. Given its diverse effects on immune function, SP-A may prove to be an effective therapy for both infectious and inflammatory diseases of the lung.

Genetic and Reproductive Knowledge Among Adolescents and Adults With Cystic Fibrosis

Studies1,2 have shown that cystic fibrosis (CF) patients have limited knowledge of the genetics of CF. Previously, there was limited need to communicate this information: few CF patients lived to adulthood, and most who did could not reproduce.1,2 Genetic counseling focused on the patient’s parents, who were counseled about the recurrence risk at the time of the diagnosis. Today, CF is a disease of adulthood.3 In 2002, 40% of CF patients in the United States were 18 years old; by 2010, it will be 50%. Together with advances in assisted reproductive technology, reproduction and recurrence risk are now important issues for adolescent and young adult CF patients.3–6 A 19-item questionnaire was developed from the results of prior semistructured interviews with 18 CF patients aged 16 to 25 years. Knowledge-based questions (medical issues, inheritance, and reproductive options/risks) as well as communication patterns (preferred resources for learning about CF and preferred people with whom to talk about reproductive issues) were addressed. Recruited from the University of Alabama CF clinic population, 51 patients aged 15 to 29 years (mean, 21 years), 24 male (47%) and 27 female (53%), completed the questionnaire. The study was approved by the University of Alabama Institutional Review Board. Regarding autosomal recessive inheritance, only 33% knew that two carriers have a 25% chance of having a child with CF, and 25% knew that two carriers have a 50% chance of having a child who is a carrier. However, 82% knew that two carriers could have a child who did not have CF, and 52% knew that two carriers could have a child who did not carry CF. On their own reproductive risks, 59% knew that a CF patient had a 0% chance of having a child with CF if their partner was not a carrier, but only 26% knew that all their children would be carriers even if their partner was not a carrier. In the scenario of a CF patient with a CF carrier partner, 44% knew that a child had a 50% chance of having CF, and 24% knew that a child had a 50% chance of being a CF carrier. Most patients knew about their reproductive potential, as 96% responded that CF patients are able to have children. However, when asked about whether the chance for having children was different for male and female patients with CF, 65% answered that it was more difficult for men, 8% that it was more difficult for women, and 27% answered “not sure.” While 62% reported that they knew that there were options for male CF patients who wanted to have children, only 26% knew of assisted reproductive technology. Despite widespread availability, the lack of knowledge of adolescents and young adults with CF about the genetics of their disease continues. Furthermore, these patients are unaware of both modern technologies that could enable them to have biological children and the risk of those children having CF. This study illustrates the changing needs of patient education as medical knowledge progresses. CF patients would benefit from further genetic knowledge and counseling to enable them to make informed decisions about reproduction as they mature into adulthood.