Caralee Forseen

Evidence of microvascular dysfunction in patients with cystic fibrosis.

Cystic fibrosis (CF) is a genetic, multisystemic disorder with broad clinical manifestations apart from the well-characterized pulmonary dysfunction. Recent findings have described impairment in conduit vessel function in patients with CF; however, whether microvascular function is affected in this population has yet to be elucidated. Using laser-Doppler imaging, we evaluated microvascular function through postocclusive reactive hyperemia (PORH), local thermal hyperemia (LTH), and iontophoresis with acetylcholine (ACh). PORH [518 ± 174% (CF) and 801 ± 125% (control), P = 0.039], LTH [1,338 ± 436% (CF) and 1,574 ± 620% (control), P = 0.045], and iontophoresis with ACh [416 ± 140% (CF) and 617 ± 143% (control), P = 0.032] were significantly lower in patients with CF than control subjects. In addition, the ratio of PORH to LTH was significantly (P = 0.043) lower in patients with CF (55.3 ± 5.1%) than control subjects (68.8 ± 3.1%). Significant positive correlations between LTH and forced expiratory volume in 1 s (%predicted) (r = 0.441, P = 0.013) and between the PORH-to-LTH ratio and exercise capacity (r = 0.350, P = 0.049) were observed. These data provide evidence of microvascular dysfunction in patients with CF compared with control subjects. In addition, our data demonstrate a complex relationship between microvascular function and classical markers of disease severity (i.e., pulmonary function and exercise capacity) in CF.

Fatal Aspergillus fumigatus and Candida glabrata infections with posaconazole prophylaxis after stem cell transplantation

Sir, Invasive fungal infections (IFIs) are associated with igh mortality following allogeneic stem cell translantation (ASCT). Diagnosis of IFI can be difficult nd may cause delayed treatment and less successful reatment outcomes. Antifungal prophylaxis is therefore erceived as a reasonable approach in high-risk patients. osaconazole is an effective prophylactic agent in patients eceiving steroids for graft-versus-host disease (GvHD) 1]. A 57-year-old man was diagnosed with acute lymhoblastic lymphoma (ALL) in September 2004. The patient nderwent ASCT in June 2006 for relapsed ALL. Fluonazole (400 mg daily) was started as IFI prophylaxis n Day 1. In August 2006 the patient developed acute vHD. Prednisone 1 mg/kg/day was started. Antifungal rophylaxis was changed to voriconazole (200 mg twice aily) in September and later to posaconazole (200 mg hree times daily) in December. In March, infliximab was dministered for worsening GvHD. Within 24 h the patient equired hospitalisation because of hypotension, tachycaria and altered mental status. A new left upper lobe ulmonary infiltrate was noted on the chest radiograph. iposomal amphotericin B was started for possible IFI. bronchoscopy with bronchoalveolar lavage (BAL) was erformed. Biopsies were obtained from ulcerated lesions n the left upper lobe bronchi. BAL fluid grew Candida labrata and Aspergillus fumigatus. Giemsa and silver ethenamine stains for Pneumocystis as well as a galacomannan antigen assay were negative in the BAL fluid. The iopsy specimen culture yielded C. glabrata. Histopathoogical examination of the biopsy specimen revealed poorly ormed granulomas with fungal hyphae. Serum and BAL uid galactomannan antigen assays were negative. Despite ggressive measures, the patient died 48 h later. In vitro suseptibility test results for the C. glabrata isolate obtained fter the patient’s death showed minimal inhibitory conentrations at 24 h and 48 h, respectively, as follows: mphotericin B, 0.25 g/mL and 0.25 g/mL; caspofunin, <0.03 g/mL and 0.06 g/mL; fluconazole, 2 g/mL nd 4 g/mL; itraconazole, 0.06 g/mL and 0.25 g/mL; oriconazole, 0.06 g/mL and 0.25 g/mL; posaconazole, p o c ntimicrobial Agents 32 (2008) 363–371 365

A single bout of maximal exercise improves lung function in patients with cystic fibrosis

BACKGROUND Responses to a single bout of exercise may provide critical information for maximizing improvements in pulmonary function following exercise training in cystic fibrosis (CF). We sought to determine if acute maximal exercise improves pulmonary function in patients with CF. METHODS Thirty-three patients with CF completed a comprehensive assessment of pulmonary function to determine forced vital capacity (FVC), forced expiratory volume in one second (FEV1), and lung clearance index (LCI) prior to and immediately following maximal aerobic exercise on a cycle ergometer. RESULTS Following exercise, FVC (∆0.08±0.14L) and FEV1 (∆0.06±0.15L) increased, while LCI decreased (∆-0.71±0.93) (all p<0.05). Changes in FEV1 (%predicted) were associated with peak work (r=0.40, p=0.02) and peak pulmonary ventilation (r=0.45, p=0.01). CONCLUSIONS A single bout of maximal exercise acutely improves pulmonary function in patients with CF and improvements may be related to peak work and peak pulmonary ventilation.

An unusual cause of massive pleural effusion

Pleural effusions in ovarian hyperstimulation syndrome, whether transudative or exudative, can occur in up to 30% of cases. This disorder is always reversible but may have various clinical presentations and degrees of severity. Although assessing for risk factors to predict clinical severity is helpful, it is rare for ovarian hyperstimulation syndrome to present as a massive pleural effusion requiring emergent intervention. In this study, such a case is reported.

Exercise testing in patients with cystic fibrosis—importance of ventilatory parameters

BackgroundVentilatory parameters obtained during exercise predict survival in several chronic diseases; however, long-term changes in exercise ventilatory parameters in patients with cystic fibrosis (CF) have yet to be examined and potential differences between sexes in CF are unknown.PurposeWe sought to examine the change in exercise ventilatory parameters over time in patients with CF and determine if the change is different between sexes.MethodsExercise capacity (VO2 peak) and exercise ventilatory parameters (VE/VO2 peak, VE/VCO2 peak, and VE/VCO2 slope) were determined from a maximal cardio-pulmonary test on a cycle ergometer on two visits separated by 39 ± 16 months in 20 patients with CF (10 female, 10 male).ResultsNo differences between sexes were observed at visit 1 (all p > 0.05). Overall, exercise ventilatory parameters significantly (p < 0.05) deteriorated between visits, with no change (p > 0.05) in VO2 peak. Moreover, compared to males, female patients exhibited greater deteriorations in VE/VO2 peak (p = 0.001), VE/VCO2 peak (p = 0.002), and VE/VCO2 slope (p = 0.016) between visits.ConclusionsThese data in patients with CF indicate that exercise ventilatory parameters decline over time despite no change in VO2 peak, and female patients exhibit a more rapid deterioration compared to males.

SILDENAFIL IMPROVES VASCULAR ENDOTHELIAL FUNCTION IN PATIENTS WITH CYSTIC FIBROSIS

Cystic fibrosis (CF), characterized by defective CFTR function, is associated with multiple systemic complications, including vascular dysfunction. Sildenafil, a phosphodiesterase type 5 inhibitor, not only enhances nitric oxide (NO) metabolism but has been shown to improve CFTR functionality as well. Thus, sildenafil has been proposed as a therapy to improve vascular health in CF; however, its potential therapeutic role has yet to be determined. We sought to investigate the effect of sildenafil on endothelial function in patients with CF. Patients with CF completed a randomized, double-blind, placebo-controlled, crossover study with an acute dose of sildenafil (50 mg) or placebo followed by a 4-wk open-label extension with sildenafil (20 mg/day). Flow-mediated dilation (FMD) was used to evaluate endothelial function before and after treatments. In addition, phosphorylated endothelial NO synthase (pNOS3) and total NOS3 protein expression was determined from endothelial cells that were exposed to plasma from the patients before and after 4 wk of sildenafil treatment. No changes ( P ≥ 0.110) in endothelial function were observed after the acute dose of sildenafil. However, FMD significantly ( P = 0.029) increased after 4 wk of treatment (∆FMD: 1.5 ± 2.2%). Moreover, pNOS3 protein expression significantly ( P = 0.013) increased after 4 wk of treatment (∆pNOS3: 0.31 ± 0.39 arbitrary units) and was associated ( r = 0.593, P = 0.033) with the change in FMD. These data suggest that 4 wk of sildenafil treatment can improve vascular endothelial function in patients with CF, likely through an increase in NOS3 phosphorylation. NEW & NOTEWORTHY Findings from the present study demonstrate, for the first time, significant improvement of endothelial function in patients with cystic fibrosis treated with sildenafil that is associated with greater phosphorylation of endothelial nitric oxide synthase. These results support the use of sildenafil as a potential novel therapy for this patient population.

A 67-Year-Old Woman With Cough and Shortness of Breath

67-year-old woman was admitted to the hospital with complaints of cough and shortness of breath. She had immigrated to the United States from Pakistan 4 months earlier and subsequently developed the cough, which had worsened over the past months. Two weeks prior to admission she developed worsening dyspnea on exertion. The patient did not speak English, and her daughter did the translation. Her cough was mostly dry with occasional production of minimal whitish-brown sputum. She had received amoxicillinclavulanate and ciprofl oxacin for her symptoms by her primary care physician without any benefi t. She denied any complaints of persistent fever, night sweats, chest pain, skin rash, joint pains, hemoptysis, or weight loss. Her remaining medical history was signifi cant for hypertension, diabetes mellitus, and asthma. Her medications included amlodipine, metformin, glyburide, and albuterol metered-dose inhaler. She denied any history of tobacco or alcohol abuse; however, she had been exposed to biomass fuels as a child. There was no history of prior pulmonary infection or positive purifi ed protein derivative skin test.