Fluticasone, azithromycin and montelukast therapy in reducing corticosteroid exposure in bronchiolitis obliterans syndrome after allogeneic hematopoietic SCT: a case series of eight patients.

Bronchiolitis obliterans syndrome (BOS) is a devastating pulmonary complication affecting long-term survivors of allogeneic hematopoietic cell transplantation. Treatment of BOS with prolonged courses of high dose corticosteroids is often associated with significant morbidity. Reducing the exposure to corticosteroids may reduce treatment-related morbidity. Our institution has recently begun to treat patients with emerging therapies in an effort to diminish corticosteroid exposure. We retrospectively reviewed the 6-month corticosteroid exposure, lung function and failure rates in eight patients with newly diagnosed BOS who were treated with a combination of fluticasone, azithromycin and montelukast (FAM) and a rapid corticosteroid taper. These patients were compared with 14 matched historical patients who received high-dose corticosteroids, followed by a standard taper. The median 6-month prednisone exposure in FAM-treated patients was 1819 mg (0-4036 mg) compared with 7163 mg (6551-7829 mg) in the control group (P=0.002). The median forced expiratory volume in 1 s (FEV(1)) change in FAM-treated patients was 2% (-3 to 4%] compared with 1% (-4 to 5%) in the control group (P=1.0). Prednisone exposure in FAM patients was one quarter that of a retrospective-matched group of patients, with minimal change in median FEV(1), suggesting that BOS may be spared of the morbidities associated with long-term corticosteroid use by using alternative agents with less side effects.

Influence of oral beclomethasone dipropionate on early non-infectious pulmonary outcomes after allogeneic hematopoietic cell transplantation: results from two randomized trials.

Early non-infectious pulmonary complications represent a significant cause of mortality after hematopoietic cell transplantation (HCT). We tested the hypothesis that oral beclomethasone dipropionate (BDP) is effective for preventing early non-infectious pulmonary complications after allogeneic HCT. We retrospectively reviewed the medical records of 120 patients, 60 in each treatment arm, to identify non-infectious and infectious pulmonary events and pulmonary function test results from all patients who participated in two randomized trials of oral BDP for treatment of acute gastrointestinal GVHD. 17-Beclomethasone monopropionate (17-BMP), the active metabolite of BDP, was evaluated in blood from the right atrium in four patients. Thirty-three of 42 (79%) placebo-treated patients experienced a decrease of the DL(CO) from pretransplant to day 80 after transplant, compared with 27 of 49 (55%) BDP-treated patients (P=0.02). In the first 200 days after randomization, there were no cases of non-infectious pulmonary complications in BDP-treated patients, vs four cases among placebo-treated patients (P=0.04). Levels of 17-BMP were detected in atrial blood at steady state. Delivery of a potent glucocorticoid such as 17-BMP to the pulmonary artery after oral dosing of BDP may be useful in modulating pulmonary inflammation and preventing the development of non-infectious pulmonary complications after allogeneic HCT.

Impact of comorbidity indexes on non-relapse mortality.

Comorbidity indexes (CI) have been reported to predict non-relapse mortality (NRM) and overall survival after allogeneic hematopoietic stem cell transplantation (HSCT) (Charlson's comorbidity index (CCI), hematopoietic cell transplantation CI (HCT-CI) and the pre-transplantation assessment of mortality (PAM) score). Which of these indexes best predict survival is unknown yet. We retrospectively studied 286 patients who underwent allogeneic HSCT. HCT-CI and PAM scores required grading according to pre-transplant pulmonary function tests (PFTs), which were lacking for some patients. We thus designed a reduced HCT-CI and an adjusted PAM, without results of PFTs. Using CCI, 25% of patients had indexes of 1 or more; median reduced HCT-CI score was 1; median adjusted PAM score was 24. The discriminative properties of the three CIs were rather low in our population. Comparison of patients and transplant characteristics between our and Seattle group's cohorts, however, revealed significant differences in more children, in more cord blood HSCT and in HSCT for Fanconi anemia in St Louis. Finally, multivariate analysis of scoring items revealed that age, matched unrelated or mismatched donor and hepatic disease were associated with NRM in our cohort. Translating use for patient's counseling or decision to proceed to transplant of these CIs will need prospective studies in a large independent cohort.

Pulmonary function testing prior to hematopoietic stem cell transplantation.

The pretransplant pulmonary function test plays an important role in the management of noninfectious pulmonary complications after hematopoietic stem cell transplantation (HCT). Although these tests are widely used as standard preoperative assessments in the nontransplant population, common conditions associated with the HCT patient requires that particular attention be given to interpretation of pulmonary function testing (PFT) results, such as comparison of serial pulmonary function tests and evaluation of the diffusion capacity. Although their utility in helping to predict the likelihood of developing post transplant pulmonary complications and mortality is not well established, current data indicate that pretransplant PFTs are important as a reference for the interpretation of post transplant PFTs and for identifying patients at high risk for developing pulmonary complications and/or mortality after HCT. Future studies of pretransplant pulmonary function should consider the advances in HCT, so that pretransplant PFTs will become a useful tool in pretransplant risk assessment and help the transplant oncologist to determine the most appropriate conditioning regimen for a patient with compromised lung function.

Implications of early airflow decline after myeloablative allogeneic stem cell transplantation.

The clinical significance of early airflow decline after myeloablative allogeneic hematopoietic SCT is uncertain. We performed a retrospective cohort analysis to determine if airflow decline by day 100 is associated with later development of transplant-related airflow obstruction (AFO) and increased mortality risk. Overall, 750 (40%) patients had airflow decline by day 100. Development of airflow decline by day 100 was associated with an increased risk for AFO at 1 year (relative risk 2.6, 95% confidence interval 2.1-3.1) but not with an increase in mortality risk (hazard ratio (HR) 0.86, P=0.05). However, patients with the fastest rate of decline between day 100 and 1 year (12.5% per year +/-24) had the highest mortality risk (HR 3.2, P<0.001). In conclusion, airflow measurements made on day 100 do not predict the rate of airflow decline between day 100 and 1 year, and therefore are not useful as a single measurement for determining mortality risk associated with development of AFO. Closer monitoring of the rate of airflow decline during the first year may facilitate the timely detection and treatment of early airflow decline and prevent the development of fixed AFO and increased mortality risk after hematopoietic stem cell transplant.

Association of TLR4 mutations and the risk for acute GVHD after HLA-matched-sibling hematopoietic stem cell transplantation.

Lipopolysaccharide (LPS) has been implicated in the pathogenesis of graft-versus-host disease (GVHD). The toll-like receptor (TLR)-4 has been recently identified as a major receptor for LPS. Mutations of TLR4 have been associated with LPS hyporesponsiveness. We hypothesized that TLR4 mutations reduce the risk of acute GVHD in allogeneic marrow transplant recipients. In a preliminary study to determine the frequency of TLR4 mutations and their possible association with GVHD, we tested 237 patients and their HLA-identical sibling donors for 2 TLR4 polymorphisms. All patients received methotrexate and cyclosporine for GVHD prophylaxis. One or more mutants were detected in 10.8% of patients and 10.6% of donors. Multivariable logistic regression models were used to analyze the association between TLR4 mutations and probability (1-sided) of GVHD. The odds ratio (adjusted for advanced disease, total body irradiation dose, and patient age) for development of grades II to IV GVHD when a mutation was present in the recipient was 0.63 (95% confidence interval [CI], 0.25-1.60; P = .16). When a mutation was present in the donor, the adjusted odds ratio was 0.88 (95% CI, 0.36-2.17; P = .40). When a mutation was present in both recipient and donor, the odds ratio was 0.72 (95% CI, 0.22-2.32; P = .29). Among 24 patients with TLR4 mutations in either donor or recipient, 4 (16.7%) developed gram-negative bacteremia. Among 213 patients without mutations, 14 (6.6%) developed gram-negative bacteremia (P = .09). The data indicate that a reduced risk of acute GVHD is associated with TLR4 mutations and that TLR4 mutations may increase the risk for gram-negative bacteremia. However, these associations are not statistically significant in recipients of HLA-matched sibling marrow transplants who are prophylactically treated for infections and GVHD. A much larger study population would be needed to confirm the role of LPS in the pathogenesis of GVHD in humans.

Viral pneumonias. Infection in the immunocompromised host.

Three herpesviruses--herpes simplex, varicella-zoster, and cytomegalovirus--commonly cause respiratory tract infections in immunocompromised patients. Adenoviruses and measles virus are also significant causes of respiratory disease in this population. Diagnosis of herpesvirus infections is difficult because these viruses can establish latency and are often shed intermittently in the absence of invasive disease. A positive respiratory tract culture of herpesviruses alone is not diagnostic of active invasive disease. Preventive measures should focus on limiting the patient's exposure to active infection, broad use of available vaccines in children and susceptible adults, and use of hyperimmune globulin and chemoprophylaxis in high-risk patients. Adenovirus pneumonia is diagnosed by viral culture and rapid antigen detection assays, whereas measles pneumonia is often identifiable by the characteristic rash. Treatment of either adenovirus or measles pneumonia is primarily supportive.

Use of linezolid, an oxazolidinone, in the treatment of multidrug-resistant gram-positive bacterial infections.

We report our experience with linezolid in an investigation of its use against resistant gram-positive bacterial infections. Fifteen patients who had renal failure (n=6), recent liver transplantation (n=5) or surgery (n=6), cancer (n=3), endocarditis (n=2), or human immunodeficiency virus infection (n=1), along with infections due to vancomycin-resistant enterococcus (VRE), and 2 patients with infections due to methicillin-resistant Staphylococcus species who had adverse reactions to vancomycin were treated with linezolid (600 mg every 12 h for 5-42 days (mean+/-SD, 20.5+/-3.5 days). Abscess drainage or prosthetic device removal was undertaken. Microbiological cure occurred in all 10 patients who completed therapy, and all 7 patients alive at follow-up were free of infection. No deaths were attributable to the index infection. Adverse events associated with linezolid use were mild leukopenia in 1 patient and nausea in another. It appears that administration of linezolid, in conjunction with surgical intervention or device removal, is an effective treatment option for serious resistant gram-positive bacterial infections.

Paradoxical reactions in HIV and pulmonary TB.

We present a case of paradoxical clinical deterioration during antituberculosis therapy in an HIV-infected adult with pulmonary TB. The clinical course was characterized by marked cervical and mediastinal adenopathy accompanied by fever and weight loss during simultaneous treatment of TB and HIV disease. After extensive investigation for causes of therapeutic failure, the paradoxical reaction was attributed to partial immune reconstitution related to highly effective antiretroviral therapy. Due to the high prevalence of TB in HIV-infected patients, it is important to recognize this phenomenon and understand that it is usually self-limited.