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 [FEV(1)%] 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 FEV(1)% 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.

Safety and preliminary clinical activity of a novel pancreatic enzyme preparation in pancreatic insufficient cystic fibrosis patients.

OBJECTIVES: Currently available pancreatic enzyme products are crude porcine products with few data available regarding their efficacy, safety, and manufacture. We conducted a phase 1 study of a novel pancreatic enzyme product, TheraCLEC-Total (TCT), a proprietary formulation of microbial-derived lipase, protease, and amylase, to determine its safety and preliminary efficacy in cystic fibrosis. METHODS: We conducted an open-label, dose-ranging study in 23 subjects diagnosed with pancreatic insufficiency with cystic fibrosis. The subjects received TCT containing lipase dose of 100, 500, 1000, 2500, or 5000 USP U/kg per meal with each meal or snack for 3 days. The clinical and laboratory parameters and adverse events (AEs) were monitored. RESULTS: There were no serious AEs. Most AEs were mild, although gastrointestinal complaints were common. TCT increased the coefficient of fat and nitrogen absorption in all groups except in the low-dose group. At the other dosing levels, the mean coefficient of fat and nitrogen absorption increases were 19.1% +/- 24.9% and 17.8% +/- 13.6%, respectively, whereas the mean stool weight decreased by 517 +/- 362 g. CONCLUSIONS: TCT was well tolerated in this short-term exposure study. The preliminary efficacy data demonstrate lipase and protease activity with little difference seen with lipase doses greater than 500 USP U/kg per meal. These data support a larger randomized phase 2 trial.

Increased frequency of HLA-B44 in recurrent sinopulmonary infections (RESPI).

To test whether MHC alleles associated with common variable immune deficiency (CVID) might also be over-represented in patients with normal serum immunoglobulin levels who suffer with recurrent sinopulmonary infections (RESPI), we identified 62 consecutive RESPI patients and compared their HLA-B and HLA-DR antigen frequencies to those of 60 consecutive patients with CVID, 1627 Alabama Caucasian bone marrow donors, and 997,230 published US Caucasians. Either HLA-B44, -B8, -DR3(17), or -DR7 was present in 74% of the RESPI and 85% of the CVID patients. HLA-B44 prevalence in particular proved identical between RESPI and CVID. When compared to US Caucasians, the increased prevalence of the four HLA alleles proved significant at P < 0.0001, P < 0.0001, P = 0.0005, and P = 0.02, respectively. When compared to Alabama Caucasians, only the increased prevalence of HLA-B44 achieved statistical significance (P = 0.0001). Inheritance of HLA-B44 may yield susceptibility to recurrent sinopulmonary infection even in the presence of normal serum immunoglobulin levels.

Multi-organ transplantation: is there a protective effect against acute and chronic rejection?

BACKGROUND: Heart-lung transplantation (Tx) is known to offer a protective effect against acute cardiac rejection. This study was undertaken to evaluate acute and chronic heart and/or lung rejection in the setting of multiple-transplanted organs from the same donor compared with single-organ transplantation. METHODS: Acute (treated rejection episodes of heart or lungs) and chronic (allograft vasculopathy in hearts and bronchiolitis obliterans syndrome [BOS] in lungs) rejection events were analyzed in 348 heart transplant (H) recipients, 24 heart-lung (HL) recipients, 82 double-lung (L) recipients and 8 heart-kidney (HK) recipients >18 years of age, who were transplanted between 1990 and 2002. RESULTS: Survival at 3 years differed among groups as follows: HK, 100%; H, 82%; HL, 74%; and L, 70%. The probability of acute rejection within the first 3 months was higher in H recipients than in HL (81% vs 22%; p < 0.0001) or HK (81% vs 12%; p = 0.00009) recipients. Acute cardiac rejection occurred more frequently during the first 2 years in isolated H recipients compared with HL (2.8 vs 0.27 episodes; p < 0.0001) and HK (2.8 vs 0.54; p < 0.001) recipients. Acute lung rejection occurred more frequently in the first 2 years in L than HL (2.4 vs 1.0 episodes; p = 0.02) recipients. Chronic cardiac rejection (allograft vasculopathy) was more likely within 3 years after H compared with HL (32% vs 16%; p = 0.04) or HK (32% vs 0%; p = 0.14). The onset of chronic lung rejection (BOS) within 3 years was similar in HL and L recipients (39% vs 40%; p = 0.9). CONCLUSIONS: Recipients of multiple organs from a single donor undergo less acute rejection of the heart or lungs compared with isolated heart or lung transplant recipients. Cardiac allograft vasculopathy is decreased significantly when cardiac transplantation is combined with a lung allograft. A lower incidence of cardiac allograft vasculopathy is observed when cardiac transplantation is combined with a renal allograft, and may prove statistically significant when more cases have been accumulated. These phenomena may result from immune modulation of the recipient by simultaneous transplant of disparate tissues or introduction of immune-modulating hematopoietic elements.

The intensive care unit oxygen challenge should not be used for donor lung function decision-making.

BACKGROUND: The intensive care unit oxygen challenge is a routine screening test for donor lung function. An arterial PO2 of <300 mm Hg is generally considered evidence of inadequate pulmonary function that contraindicates the use of the lungs for transplantation. METHODS: Between December 1, 2001 and January 24, 2004, the intensive care unit oxygen challenge was compared with the PO2 in samples drawn from each pulmonary vein confluence in the operating room in 91 donors (182 donor lungs) after the lungs were fully inflated (FIO2 1.0). There were 62 males and 29 females, with a median age of 27.5 years (13.6 to 55.4 years). RESULTS: In 40 lungs, the pulmonary vein PO2 was >300 mm Hg, whereas the PO2 was <300 mm Hg on the last intensive care unit O2 challenge. The difference between the intensive care unit PO2 and the operating room pulmonary vein PO2 was greatest for donors with the lowest intensive care unit PO2. Of these 40 lungs, 8 were transplanted, all of whom had excellent graft function with a median intubation of 14.2 hours (6.1 to 23.8 hours). No patient sustained primary graft failure or an airway complication. CONCLUSIONS: The intensive care unit PO2 is an unreliable screening test for donor lung function, particularly when one lung is clear and the other is unclear radiographically. In this setting, intraoperative surgical assessment and pulmonary venous PO2 should be the basis for determining donor lung suitability. This strategy may provide an opportunity to increase donor lung availability.

Sternal approximation for bilateral anterolateral transsternal thoracotomy for lung transplantation.

The traditional incision for bilateral sequential lung transplantation is the bilateral anterolateral transsternal thoracotomy with approximation of the sternal fragments with interrupted stainless steel wire loops; this technique may be associated with an unacceptable incidence of postoperative sternal disruption causing chronic pain and deformity. Approximation of the sternal ends was achieved with peristernal cables that passed behind the sternum two intercostal spaces above and below the sternal division, which were then passed through metal sleeves in front of the sternum, the cables tensioned, and the sleeves then crimped. Forty-seven patients underwent sternal closure with this method, and satisfactory bone union occurred in all patients. Six patients underwent removal of the peristernal cables: 1 for infection (with satisfactory bone union after the removal of the cables), 3 for cosmetic reasons, 1 during the performance of a median sternotomy for an aortic valve replacement, and 1 in a patient who requested removal before commencing participation in football. This technique of peristernal cable approximation of sternal ends has successfully eliminated the problem of sternal disruption associated with this incision and is a useful alternative for preventing this complication after bilateral lung transplantation.

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, Fisher's 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, Fisher's 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).

Pulmonary transplantation for advanced bronchioloalveolar carcinoma.

BACKGROUND: No effective therapy is currently available for the diffuse stage of bronchioloalveolar carcinoma. OBJECTIVE: We tested the hypothesis that total lung replacement with standard lung transplantation techniques would provide curative therapy. METHODS: Nine patients aged 31 to 58 years with bronchioloalveolar carcinoma were entered in the study. Five patients initially had bilateral diffuse tumor. Four patients had recurrence in the contralateral lung after pulmonary resection. RESULTS: Between 1993 and 1998, all 9 patients underwent transplantation (2 single-lung and 7 bilateral transplants, 1 reoperative single-lung transplant, and 1 reoperative bilateral transplant). Two patients had mediastinal node metastasis (level 7) at the time of transplantation, and 1 of these had a frankly invasive adenocarcinoma. Of the 8 patients with pure bronchioloalveolar carcinoma, 6 had recurrent pulmonary tumor after transplantation. In 2 of these patients the tumor was localized and could be resected with left lower lobectomy in one case and left pneumonectomy in the other. One is alive 89 months after transplantation; the other died 82 months after transplantation. Four other patients had a diffuse pattern of pulmonary recurrence. Two died of progressive pulmonary failure; 1 of these had retransplantation with recurrence. A third patient died of cerebral edema shortly after bilateral retransplantation. The other patient is alive with recurrence 39 months after transplantation and has bronchiolitis obliterans. Two patients without recurrence are well with unrestricted performance levels 87 and 76 months after transplantation. CONCLUSIONS: Transplantation produces a powerful palliative outcome in patients with advanced bronchioloalveolar carcinoma, but the recurrence rate is high. Transplantation for this indication remains controversial.

Clinician performance and prominence of diagnoses displayed by a clinical diagnostic decision support system.

Clinical decision support systems (CDSS) can impact both diagnostic and therapeutic decision-making, but physicians sometimes fail to heed the appropriate CDSS advice, or become influenced in a negative way by the CDSS. This study examined the relationships among clinicians' prior diagnostic accuracy, the performance of a diagnostic CDSS, and how the CDSS influenced the accuracy of the clinician's subsequent diagnoses. Results showed that (1) clinicians who already were considering the correct diagnosis prior to using the CDSS were more likely to get the CDSS to produce the correct diagnosis in a prominent position than those not considering it initially; (2) physicians are strongly anchored by their initial diagnoses prior to using the CDSS; and (3) changes in the clinicians' diagnoses after using the CDSS are related to presence or absence of the correct diagnosis in the top 10 diagnoses displayed by the CDSS.

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.

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.

Killing of Klebsiella pneumoniae by human alveolar macrophages.

We investigated putative mechanisms by which human surfactant protein A (SP-A) effects killing of Klebsiella pneumoniae by human alveolar macrophages (AMs) isolated from bronchoalveolar lavagates of patients with transplanted lungs. Coincubation of AMs with human SP-A (25 microg/ml) and Klebsiella resulted in a 68% decrease in total colony forming units by 120 min compared with AMs infected with Klebsiella in the absence of SP-A, and this SP-A-mediated effect was abolished by preincubation with N(G)-monomethyl-L-arginine. Incubation of transplant AMs with SP-A increased intracellular Ca(2+) concentration ([Ca(2+)](i)) by 70% and nitrite and nitrate (NO(x)) production by 45% (from 0.24 +/- 0.02 to 1.3 +/- 0.21 nmol small middle dot 10(6) AMs(-1).h(-1)). Preincubation with 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester inhibited the increase in [Ca(2+)](i) and abrogated the SP-A-mediated Klebsiella phagocytosis and killing. In contrast, incubation of AMs from normal volunteers with SP-A decreased both [Ca(2+)](i) and NO(x) production and did not result in killing of Klebsiella. Significant killing of Klebsiella was also seen in a cell-free system by sustained production of peroxynitrite (>1 microM/min) at pH 5 but not at pH 7.4. These findings indicate that SP-A mediates pathogen killing by AMs from transplant lungs by stimulating phagocytosis and production of reactive oxygen-nitrogen intermediates.