Voriconazole and squamous cell carcinoma after lung transplantation: A multicenter study.

This study evaluated the independent contribution of voriconazole to the development of squamous cell carcinoma (SCC) in lung transplant recipients, by attempting to account for important confounding factors, particularly immunosuppression. This international, multicenter, retrospective, cohort study included adult patients who underwent lung transplantation during 2005-2008. Cox regression analysis was used to assess the effects of voriconazole and other azoles, analyzed as time-dependent variables, on the risk of developing biopsy-confirmed SCC. Nine hundred lung transplant recipients were included. Median follow-up time from transplantation to end of follow-up was 3.51 years. In a Cox regression model, exposure to voriconazole alone (adjusted hazard ratio 2.39, 95% confidence interval 1.31-4.37) and exposure to voriconazole and other azole(s) (adjusted hazard ratio 3.45, 95% confidence interval 1.07-11.06) were associated with SCC compared with those unexposed after controlling for important confounders including immunosuppressants. Exposure to voriconazole was associated with increased risk of SCC of the skin in lung transplant recipients. Residual confounding could not be ruled out because of the use of proxy variables to control for some confounders. Benefits of voriconazole use when prescribed to lung transplant recipients should be carefully weighed versus the potential risk of SCC. EU PAS registration number: EUPAS5269.

Risk-adjusted relationship between voriconazole utilization and non-melanoma skin cancer among lung and heart/lung transplant patients.

BACKGROUND: We examined the relationship between voriconazole utilization and non-melanoma skin cancer (NMSC) development among adult lung and heart/lung transplant patients who were continuously enrolled in a large U.S. commercial health plan. METHODS: Cox proportional hazards regression models were constructed to assess both the crude and adjusted effect of voriconazole usage on NMSC development. Overall, 467 adult lung (98%) and heart/lung (2%) transplant patients (60% male) with median age of 58 years were analyzed. RESULTS: Fifty-seven (12%) patients developed NMSC over a median follow-up time of 610 days. At the crude level, patients with any (vs. none) claim for voriconazole were more likely to develop NMSC (19% vs. 12%, hazard ratio [HR]: 1.74, 95% confidence interval [CI]: 1.02, 2.96, P = 0.04). However, after statistical adjustment for demographic and clinical factors, the effect was largely diminished and no longer statistically significant (HR: 1.23, 95% CI: 0.71, 2.14, P = 0.45). Results were similar when modeling average and total dose of voriconazole. Risk factors significantly related to NMSC development were being male, older age, sun exposure, history of chronic obstructive pulmonary disorder, and history of immune disorder. CONCLUSION: Results suggest that the relationship between voriconazole utilization and NMSC among lung transplant patients may be a result of confounding by indication, and that controlling for underlying patient characteristics is paramount.

Lung transplantation for cystic fibrosis: an update and practical considerations for referring candidates.

In this article, the authors provide an update to Maurer and Chaparro's 1995 review in this journal of lung transplantation for cystic fibrosis. Bilateral (sequential) cadaver donor transplantation is the usual procedure of choice. The four-year survival rate for adult, all-disease, double-bilateral lung transplantation has improved to 53%. Because of lower [corrected] survival rate among adults, living-donor lobar transplantation should be performed only when cadaver lungs are unlikely to become available. The International Society for Heart and Lung Transplantation and the Cystic Fibrosis Foundation have promulgated uniform guidelines for transplantation candidate selection. Issues of diabetes mellitus, mechanical ventilation, osteoporosis, malnutrition, fungi and drug-resistant bacteria, pleural fibrosis, and sinusitis in relation to transplantation candidacy are discussed. Some practical points regarding transplantation center referral are presented, and a list of cystic fibrosis transplantation centers in the United States is supplied.

Management of the severe asthmatic.

Asthma morbidity and mortality continue to increase. The clinical characteristics of the high risk asthmatic patient continue to be elucidated. These include historical features, current disease characteristics and psychosocial factors. Beta-Adrenergic agonists continue to be the mainstay of acute therapy. The following review details these topics.

Critical care management of the asthmatic patient.

The incidence and severity of asthma continue to increase despite advances in therapy. Two types of severe asthma exacerbations have been described: "sudden onset" and "slow onset." Beta-adrenergic agonists and corticosteroids are still the mainstay of therapy in the intensive care unit. Hypercapnic hypoventilation is advocated as a mode of mechanical ventilation to maintain oxygenation while minimizing barotrauma. Sedating and paralytic agents must be used with caution to prevent complications such as myopathy, which may occur with prolonged use of these agents. Future avenues of study could include the use of leukotriene and platelet-activating factor inhibitors. Asthma management guidelines should be practiced to prevent worsening of bronchospasm to the point of severe exacerbation.

Cystic fibrosis: bilateral living lobar versus cadaveric lung transplantation.

Living donor transplantation is now an acceptable option that should be considered for selected cystic fibrosis patients with end-stage lung disease. Two lungs obtained from live donors can adequately support an adult cystic fibrosis patient. The morbidity from lobectomy to the healthy donor is minimal.

Role of transplantation (lung, liver, and heart) in sarcoidosis.

Organ transplantation is an option for sarcoidosis patients with end-stage lung, liver or heart disease. Survival statistics vary for the organ transplanted but are not too different from survival rates for other systemic disorders. Although infection and rejection are troublesome for all organ recipients including those with sarcoidosis, there is the added problem of recurrence of sarcoidosis in the allograft. Sarcoidosis is not an absolute contraindication for organ transplantation for the majority of transplantation centers.

Newer therapeutic interventions for pulmonary transplant rejection.

Rejection of the lung allograft remains a significant problem and the primary cause of morbidity and mortality for the transplant recipient. Various strategies have been developed to prevent and minimize episodes of rejection. These methods involve either specific inhibitors or using a combination of barriers at precise sites in the immune response to induce graft tolerance. Another technique would be to create a tranquil environment between opposing populations of immunocompetent cells from both the donor and recipient by enhancing chimerism. Finding potent immunosuppressive agents is not the only impediment to prolonged graft survival. The challenge is also to develop techniques and agents that do not have global immunosuppressive properties that would cause the host to become more susceptible to infectious agents, as well as to prevent toxicity to other vital organs. A review of available new pharmaceutical therapies and an overview of potential future methods are presented here.

Bilateral lobar transplantation utilizing living related donors.

As the recipient list for patients requiring lung transplantation continues to increase, cadaveric donor lung availability has remained static. Our experience with utilizing lobes from living related donors for bilateral pulmonary transplantation in 20 patients has yielded a 75% survival at 1 year follow-up. Morbidity and mortality have been predominately due to infection. Rejection episodes have been mild and unilateral and have responded to augmented corticosteroids. Pulmonary function tests in the recipients tend to improve steadily during the first year postoperatively, and the patients have excellent functional capacity. There have been no significant complications in the donors. On the basis of our clinical experience, we have found that bilateral lobar transplantation utilizing living related donors has resulted in organ availability that can be lifesaving in critically ill patients and can provide a good alternative in certain noncritical, deteriorating patients.

Lung transplantation in interstitial lung disease.

A discussion of transplantation as an optional therapeutic modality for patients with end-stage interstitial lung disease follows. Single lung transplantation for pulmonary fibrosis has been shown to be a successful modality with good survival rates. A limited cadaveric donor pool has affected the number of patients who can undergo transplantation. Selection criteria have been established to identify the most appropriate candidates. Transplantation of lung lobes obtained from living-related donors has recently been performed successfully in a patient suffering from pulmonary fibrosis. Living-related donors can potentially increase the donor pool. Successful transplantation of sarcoidosis patients is clearly possible. Recurrence of sarcoidosis in the lung allograft has been recognized but the clinical significance is not yet clear.

The technique of percutaneous transthoracic needle aspiration biopsy.

Consider percutaneous transthoracic needle aspiration biopsy when specimens of pulmonary malignancies or infections are needed and bronchoscopy is contraindicated or the lesion is in a peripheral location. Percutaneous needle aspiration biopsy can be performed rapidly, and its diagnostic yield is good to excellent. The chief limitation of this procedure is the high incidence of pneumothorax, which makes the technique unsuitable for ventilated patients. A needle is inserted through the chest wall under fluoroscopic or CT guidance; a small sample is then aspirated through the needle. Operator skill and the use of thin needles help reduce the incidence of complications.

Lymphocytic subpopulation profiles in bronchoalveolar lavage fluid and peripheral blood from tobacco and marijuana smokers.

The effect of heavy, habitual marijuana use compared with tobacco smoking on the composition of bronchoalveolar and peripheral blood lymphocytic phenotypes was examined. Bronchoalveolar lavage (BAL) and peripheral blood (PB) samples were taken from 14 nonsmokers (NS), 14 tobacco smokers (TS), 19 heavy, habitual marijuana smokers (MS), and 9 marijuana and tobacco smokers (MTS). In BAL fluid, marijuana use was associated with significantly higher alveolar macrophage concentrations, whereas tobacco smoking was associated with significantly higher alveolar macrophage, as well as higher bronchoalveolar lymphocyte and neutrophil concentrations. The bronchoalveolar T-lymphocytic phenotypic profiles of marijuana users differed from those of tobacco smokers. Tobacco, not marijuana, was found to have a significant effect toward lower percentages of bronchoalveolar CD4 cells, toward higher concentrations of bronchoalveolar CD8 cells, and toward lower bronchoalveolar CD4:CD8 ratios. Marijuana use had a significant effect toward lower percentages of bronchoalveolar CD8 cells. In peripheral blood, marijuana, but not tobacco, use was associated with significantly higher percentages of CD4 cells, lower percentages of CD8 cells, and higher CD4:CD8 ratios. These findings suggest that tobacco and marijuana have effects on bronchoalveolar and peripheral blood immunoregulatory T-lymphocytic subpopulations that differ in type or magnitude.

Enhanced alveolar monocytic phagocyte (macrophage) proliferation in tobacco and marijuana smokers.

We tested the hypothesis that enhanced cell division accounted for the augmented numbers of monocytic phagocytes with characteristics attributed to alveolar macrophages (AM) found in the lungs of habitual tobacco (T) and marijuana (M) smokers. The monocytic phagocytes, that is, alveolar macrophages, were obtained by bronchoalveolar lavage (BAL) from 12 nonsmoking subjects; 10 subjects who smoked T only (TS); 13 subjects who smoked M only (MS); and 6 smokers of both T and M (MTS). The replication of these cells was determined by measuring the incorporation of [3H]thymidine into the DNA of dividing cells and visually counting 2,000 cells on autoradiographically prepared cytocentrifuge cell preparations. This study demonstrated that the number of [3H]thymidine-labeled monocytic phagocytes with characteristics of alveolar macrophages from either TS or MS have a higher proliferative index compared to cells (macrophages) from nonsmokers, p less than 0.05 by one-way ANOVA. The total number of BAL macrophages that are in mitosis in TS (17.90 +/- 4.50 labeled AM x 10(3)/ml) or MTS (10.50 +/- 4.20 labeled AM x 10(3)/ml) are 18- and 10-fold greater, respectively, than the number obtained from nonsmokers (1.01 +/- 0.18 labeled AM x 10(3)/ml). Interestingly, the number of [3H]thymidine-labeled macrophages from MS (2.90 +/- 0.66 labeled AM x 10(3)/ml) are also greater than the number obtained from nonsmokers, although this is not statistically significant. The stimulus augmenting alveolar macrophage replication is as yet unknown but may likely be found in the T or M smoke.(ABSTRACT TRUNCATED AT 250 WORDS)