Analysis of the MILES cohort reveals determinants of disease progression and treatment response in lymphangioleiomyomatosis.

INTRODUCTION: The Multicenter International Lymphangioleiomyomatosis (LAM) Efficacy of Sirolimus (MILES) trial revealed that sirolimus stabilised lung function in patients with moderately severe LAM. The purpose of this study was to further examine the MILES cohort for the effects of racial, demographic, clinical and physiological patient characteristics on disease progression and treatment response in LAM. METHODS: MILES subjects were stratified on the basis of menopausal status (pre-menopausal/post-menopausal), race (Asian/Caucasian), bronchodilator responsiveness (present/absent), initial forced expiratory volume in 1 s (FEV1; 51-70% versus ≤50% predicted) and tuberous sclerosis complex (TSC) association (yes/no). A linear mixed effects model was used to compare slope differences, and nonparametric tests were used to compare medians and proportions between treatment groups in each stratum. RESULTS: In the MILES placebo group, pre-menopausal patients declined 5-fold faster than post-menopausal patients (mean±se FEV1 slope -17±3 versus -3±3 mL·month-1; p=0.003). Upon treatment with sirolimus, both the pre-menopausal (-17±3 versus -1±2 mL·month-1; p<0.0001) and post-menopausal patients (-3±3 versus 6±3 mL·month-1; p=0.04) exhibited a beneficial response in mean±se FEV1 slope compared with the placebo group. Race, LAM subtype, bronchodilator responsiveness or baseline FEV1 did not impact the rate of disease progression in the placebo group or treatment response in the sirolimus group. Menopausal status and race had differential effects on the adverse event profile of sirolimus. Baseline serum vascular endothelial growth factor (VEGF)-D >600 pg·mL-1 identified subgroups of patients who were more likely to decline on placebo and respond to treatment with sirolimus. CONCLUSIONS: In LAM patients, treatment with sirolimus is beneficial regardless of menopausal status, race, bronchodilator responsiveness, baseline FEV1 or TSC association. Serum VEGF-D and menopausal status can help inform therapeutic decisions.

Official American Thoracic Society/Japanese Respiratory Society Clinical Practice Guidelines: Lymphangioleiomyomatosis Diagnosis and Management.

BACKGROUND: Lymphangioleiomyomatosis (LAM) is a rare cystic lung disease that primarily affects women. The purpose of these guidelines is to provide recommendations for the diagnosis and treatment of LAM. METHODS: Systematic reviews were performed to summarize evidence pertinent to our questions. The evidence was summarized and discussed by a multidisciplinary panel. Evidence-based recommendations were then formulated, written, and graded using the Grading of Recommendations, Assessment, Development, and Evaluation approach. RESULTS: After considering the panel's confidence in the estimated effects, the balance of desirable (i.e., benefits) and undesirable (i.e., harms and burdens) consequences of treatment, patient values and preferences, cost, and feasibility, recommendations were formulated for or against specific interventions. These included recommendations for sirolimus treatment and vascular endothelial growth factor D testing and recommendations against doxycycline and hormonal therapy. CONCLUSIONS: Evidence-based recommendations for the diagnosis and treatment of patients with LAM are provided. Frequent reassessment and updating will be needed.

Efficacy and safety of sirolimus in lymphangioleiomyomatosis.

BACKGROUND: Lymphangioleiomyomatosis (LAM) is a progressive, cystic lung disease in women; it is associated with inappropriate activation of mammalian target of rapamycin (mTOR) signaling, which regulates cellular growth and lymphangiogenesis. Sirolimus (also called rapamycin) inhibits mTOR and has shown promise in phase 1-2 trials involving patients with LAM. METHODS: We conducted a two-stage trial of sirolimus involving 89 patients with LAM who had moderate lung impairment--a 12-month randomized, double-blind comparison of sirolimus with placebo, followed by a 12-month observation period. The primary end point was the difference between the groups in the rate of change (slope) in forced expiratory volume in 1 second (FEV(1)). RESULTS: During the treatment period, the FEV(1) slope was -12±2 ml per month in the placebo group (43 patients) and 1±2 ml per month in the sirolimus group (46 patients) (P<0.001). The absolute between-group difference in the mean change in FEV(1) during the treatment period was 153 ml, or approximately 11% of the mean FEV(1) at enrollment. As compared with the placebo group, the sirolimus group had improvement from baseline to 12 months in measures of forced vital capacity, functional residual capacity, serum vascular endothelial growth factor D (VEGF-D), and quality of life and functional performance. There was no significant between-group difference in this interval in the change in 6-minute walk distance or diffusing capacity of the lung for carbon monoxide. After discontinuation of sirolimus, the decline in lung function resumed in the sirolimus group and paralleled that in the placebo group. Adverse events were more common with sirolimus, but the frequency of serious adverse events did not differ significantly between the groups. CONCLUSIONS: In patients with LAM, sirolimus stabilized lung function, reduced serum VEGF-D levels, and was associated with a reduction in symptoms and improvement in quality of life. Therapy with sirolimus may be useful in selected patients with LAM. (Funded by the National Institutes of Health and others; MILES ClinicalTrials.gov number, NCT00414648.).

Comprehensive description of the prevalence, serological and clinical characteristics, and visceral involvement of systemic sclerosis (scleroderma) in a large cohort from the United Arab Emirates Systemic Sclerosis Registry.

Systemic sclerosis is an autoimmune condition characterized by a wide range of clinical presentations. Registries may serve to expand understanding about systemic sclerosis and aid in patient care and follow-up. The objective of this study was to analyze the prevalence of systemic sclerosis in a large cohort from the United Arab Emirates Systemic Sclerosis Registry and find the significant similarities and differences between the different subsets. All scleroderma patients in the United Arab Emirates were included in this multicenter national retrospective analysis. Data on demographics, comorbidities, serological characteristics, clinical aspects, and treatment were collected and analyzed, highlighting the most common traits identified. A total of 167 systemic scleroderma patients from diverse ethnic backgrounds were enrolled. Overall, 54.5% (91/167) of the patients were diagnosed with diffuse cutaneous systemic sclerosis, and 45.5% (76/167) with limited cutaneous systemic sclerosis. The prevalence of systemic sclerosis was 1.66 per 100,000 for the total registry and 7.78 per 100,000 for United Arab Emirates patients. Almost all patients in the diffuse cutaneous systemic sclerosis and limited cutaneous systemic sclerosis groups tested positive for the immunofluorescence antinuclear antibody. Antibodies against Scl-70 were significantly more associated with diffuse cutaneous systemic sclerosis, whereas anticentromere antibodies were significantly more associated with the limited cutaneous systemic sclerosis group (p < 0.001). Sclerodactyly, shortness of breath, and digital ulcers were more common in diffuse cutaneous systemic sclerosis patients compared with the limited cutaneous systemic sclerosis subtype in terms of clinical symptoms and organ involvement. Telangiectasia was much more common in the limited cutaneous systemic sclerosis group. Furthermore, diffuse cutaneous systemic sclerosis patients had more lung fibrosis (interstitial lung disease) than limited cutaneous systemic sclerosis patients (70.5% vs 45.7%), and pulmonary arterial hypertension was twice as common in limited cutaneous systemic sclerosis patients as it was in diffuse cutaneous systemic sclerosis patients. Local registries are paramount to understanding the clinical/serological characteristics of scleroderma. This study emphasizes the importance of raising disease awareness and distinguishing between the various systemic sclerosis subsets to implement patient-tailored strategies for early detection, better management, and higher quality of care.

Extended valganciclovir prophylaxis to prevent cytomegalovirus after lung transplantation: a randomized, controlled trial.

BACKGROUND: Cytomegalovirus (CMV) is the most prevalent opportunistic infection after lung transplantation. Current strategies do not prevent CMV in most at-risk patients. OBJECTIVE: To determine whether extending prophylaxis with oral valganciclovir from the standard 3 months to 12 months after lung transplantation is efficacious. DESIGN: Randomized, clinical trial. Patients were randomly assigned by a central automated system to treatment or placebo. Patients and investigators were blinded to treatment status. (ClinicalTrials.gov registration number: NCT00227370) SETTING: Multicenter trial involving 11 U.S. lung transplant centers. PATIENTS: 136 lung transplant recipients who completed 3 months of valganciclovir prophylaxis. INTERVENTION: 9 additional months of oral valganciclovir (n = 70) or placebo (n = 66). MEASUREMENTS: The primary end point was freedom from CMV disease (syndrome or tissue-invasive) on an intention-to-treat basis 300 days after randomization. Secondary end points were CMV disease severity, CMV infection, acute rejection, opportunistic infections, ganciclovir resistance, and safety. RESULTS: CMV disease occurred in 32% of the short-course group versus 4% of the extended-course group (P < 0.001). Significant reductions were observed with CMV infection (64% vs. 10%; P < 0.001) and disease severity (110 000 vs. 3200 copies/mL, P = 0.009) with extended treatment. Rates of acute rejection, opportunistic infections, adverse events, CMV UL97 ganciclovir-resistance mutations, and laboratory abnormalities were similar between groups. During the 6 months after study completion, a low incidence of CMV disease was observed in both groups. LIMITATION: Longer-term effects of extended prophylaxis were not assessed. CONCLUSION: In adult lung transplant recipients who have received 3 months of valganciclovir, extending prophylaxis by an additional 9 months significantly reduces CMV infection, disease, and disease severity without increased ganciclovir resistance or toxicity. A beneficial effect with regard to prevention of CMV disease seems to extend at least through 18 months after transplantation.

Demographic and clinical patterns of severe asthma in the Middle East.

BACKGROUND: Severe asthma is a major burden on health-economic resources; hence, knowing the epidemiology of these patients is important in planning and provision of asthma care. In addition, identifying and managing the comorbidities helps improve symptoms and reduce associated morbidity and mortality. OBJECTIVES: Epidemiology of difficult asthma has not been well studied in the Middle East, so in this study, we present the demographic and clinical characteristics of severe asthma in the United Arab Emirates (UAE). METHODS: We retrospectively reviewed the notes of severe asthma patients attending three tertiary care hospitals between May 2015 and December 2019. Data on baseline demographics, asthma characteristics, treatment, and comorbidities were collected. RESULTS: We reviewed the notes of 458 patients (271 females and 187 males) that fulfilled the 2019 Global Initiative for Asthma guidelines for the diagnosis of severe asthma. The mean age was 47.7 (standard deviation 17.2) years. Males had significantly higher asthma control test scores (17.9 vs. 16, P = 0.01) and mean blood eosinophils (0.401 vs. 0.294, P <0.01) than females. The most common comorbidity observed was allergic rhinitis (52.2%) followed by gastroesophageal reflux disease (27.1%). In total, 109 (23.8%) patients were on biological therapies with most patients being on omalizumab and dupilumab (29 and 18 patients, respectively). Most patients were nonsmokers (97.2%), and majority were of TH2-high phenotype (75.7%). CONCLUSIONS: In this first report of severe asthma characteristics in the UAE, we found a pattern of female preponderance and most patients having a Th2-high phenotype. The findings are likely to help optimize asthma care in the region in the era of biologic therapies.

Low pretransplant IgA level is associated with early post-lung transplant seromucous infection.

OBJECTIVES: Infection is an important cause of morbidity and mortality after lung transplantation. Immunoglobulins are part of both seromucous (IgA) and serum (IgG) infection defense mechanisms. We therefore hypothesized that lower pretransplant IgA levels would be associated with more early post-lung transplant seromucous infections and greater mortality independent of IgG. METHODS: From January 2000 to July 2010, 538 patients undergoing primary lung transplantation had pretransplant IgA (n = 429) and IgG (n = 488) measured as a clinical routine. Median IgA was 200 mg·dL-1 (2% < 70 mg·dL-1, lower limit of normal); median IgG was 970 mg·dL-1 (5% < 600 mg·dL-1). Intensive microbiology review was used to categorize infections and their causative organisms within the first posttransplant year. RESULTS: In total, 397 seromucous infections were observed in 247 patients, most bacterial. Although IgA and IgG were moderately correlated (r = 0.5, P < .0001), low pretransplant IgA was a strong risk factor (P = .01) for seromucous infections, but pretransplant IgG was not (P ≥ .6). As pretransplant IgA levels fell below 200 mg·dL-1, the risk of these posttransplant infections rose nearly linearly. Lower pretransplant levels of IgA were associated with greater posttransplant mortality to end of follow-up (P = .004), but pretransplant IgG was not (P ≥ .3). CONCLUSIONS: Low levels of preoperative IgA, an important immunoglobulin involved in mucosal immunologic defense, but not IgG, are associated with seromucous infections in the year after lung transplantation and increased follow-up mortality. It would appear prudent to identify patients with relative IgA deficiency at listing and to increase vigilance of monitoring for, and prophylaxis against, seromucous infection in this high-risk population.

A Phase II Clinical Trial of an Aromatase Inhibitor for Postmenopausal Women with Lymphangioleiomyomatosis.

RATIONALE: Lymphangioleiomyomatosis (LAM) is a progressive cystic lung disease that predominantly affects women and can worsen with pregnancy, estrogen treatment, and the menstrual cycle, suggesting an important role for estrogen in disease pathogenesis. OBJECTIVES: To assess the efficacy and safety of the aromatase inhibitor letrozole in the treatment of LAM. METHODS: Seventeen postmenopausal women with LAM were enrolled in this phase II trial and randomized to receive letrozole 2.5 mg daily (n = 9) or placebo (n = 8) for a period of 12 months. Five patients in each group were also taking sirolimus at baseline and remained on the drug throughout the treatment period. Lung function, exercise capacity, quality of life, and serum vascular endothelial growth factor D (VEGF-D) were measured at baseline and at 3-month intervals. RESULTS: Fifteen patients completed the study. Two patients withdrew. There were no differences in adverse events in the letrozole and placebo groups. The target enrollment of 25 patients per arm was not met, so the efficacy of letrozole could not be assessed as planned. After adjusting for sirolimus use, we found that the rate of change in FEV1 for all subjects was -3 ± 3 ml/mo (P = 0.4), and for serum VEGF-D, the rate of change was -0.024 ± 0.009 pg/ml/mo (P = 0.015), showing a steeper decline in the letrozole group (-0.029 ± 0.013; P = 0.025). All patients who were taking sirolimus had a reduction in VEGF-D levels from baseline to the last visit, compared with only half of the patients who were not taking sirolimus. In a post hoc analysis, eight matched letrozole-treated-placebo-treated pairs were constructed, six of which demonstrated better FEV1 improvement for the letrozole-treated patients. CONCLUSIONS: Letrozole treatment appears to be safe and well tolerated in postmenopausal patients with LAM, including those taking sirolimus. Enrollment in this trial was compromised by the publication of an effective treatment (sirolimus) in the same month as the study opened, resulting in limited power to detect treatment effects. Post hoc matched pairs exploration studies provide tentative support for additional studies of letrozole in LAM. Considering the reduced rate of lung function decline in postmenopausal patients, future studies will likely require enhanced study designs, such as selective enrollment of those with prognostic biomarkers predictive of decline. Clinical trial registered with www.clinicaltrials.gov (NCT01353209).

Discordant utility of ideal body weight and body mass index as predictors of mortality in lung transplant recipients.

BACKGROUND: An upper limit of 130% predicted ideal body weight (PIBW) has been promulgated for assessing lung transplant (LTx) candidacy, but no data in the lung transplant population support this value. A prior study used body mass index (BMI) to suggest greater mortality risk in obese allograft recipients, but the number of studied patients was small. METHODS: Pre-operative PIBW percentage and BMI were obtained for all first-time, adult LTx recipients at our institution (n = 283). We compared survival data at 90 days and as of July 31, 2002, using multivariable regression and Cox modeling. RESULTS: There were 46 obese (BMI > or = 30) patients and 72 patients >130% PIBW, including 43 patients previously thought to fall within a normal PIBW range who were reclassified as overweight for this analysis. Cox modeling revealed no significant impact of PIBW (>130% or continuous) or BMI (>30 kg/m(2) or continuous) on overall survival. Predicted ideal body weight also had no influence on 90-day mortality. When we tested PIBW in the group previously deemed of acceptable weight, we likewise found no association with mortality at 90 days or overall. For BMI only, 90-day odds ratios for death were significantly greater for obese (BMI > or = 30; odds ratio, 3.16; 95% confidence interval, 1.05-9.48) patients than for normal-weight patients. CONCLUSION: Indices of pre-operative obesity did not predict long-term outcome in this large cohort of LTx recipients. The data suggest that BMI stratification may identify a group of patients at risk for increased short-term mortality, whereas PIBW is not a significant outcome predictor.

A retrospective review of clinical features and treatment outcomes in steroid-resistant interstitial lung disease from polymyositis/dermatomyositis.

INTRODUCTION: We reviewed our experience with immunosuppressive agents in patients with steroid-resistant Interstitial Lung Disease in the setting of Polymyositis/Dermatomyositis (PM/DM-ILD) to determine whether there were major differences in outcomes. METHODS: We identified all patients treated for PM/DM-ILD and assessed cyclophosphamide (CYC), azathioprine (AZA) and mycophenolate (MMF) when used as first-line steroid sparing therapy for effects on pulmonary function variables, dyspnea and tolerance at six and twelve months. RESULTS: Among 46 patients meeting the inclusion criteria, 24 were treated with CYC, 13 with AZA and 9 with MMF. There were no baseline differences between the three treatment groups for any of the demographic or physiologic variables, dyspnea score, the presence of >30% fibrosis on CT, or the baseline steroid dose. At the six months assessment, the overall median change in FVC was 5.0% (25th, 75th percentile -3, 11.5%), corresponding to +.20 L (.09, 0.42 L) and the DLCO increased by 2.93% (-4, 9%), corresponding to 1 mm/ml/Hg (-.58, 2.3). The severity of dyspnea decreased substantially, prednisone dose could be reduced and no important difference in side effects was found in the whole group of patients. This effect was sustained after twelve months of therapy. CONCLUSIONS: In patients with PM/DM-ILD related, treatment with CYC, AZA or MMF was associated with stabilization of pulmonary physiology, improved dyspnea, and a reduction of steroid dose.

Serum VEGF-D a concentration as a biomarker of lymphangioleiomyomatosis severity and treatment response: a prospective analysis of the Multicenter International Lymphangioleiomyomatosis Efficacy of Sirolimus (MILES) trial.

BACKGROUND: VEGF-D is a lymphangiogenic growth factor that has a key role in tumour metastasis. Serum VEGF-D concentrations are increased in most patients with lymphangioleiomyomatosis, a rare neoplasm associated with mTOR-activating tuberous sclerosis gene mutations, lymphadenopathy, metastatic spread, and pulmonary cyst formation. We used data from the Multicenter International Lymphangioleiomyomatosis Efficacy of Sirolimus (MILES) trial to assess the usefulness of serum VEGF-D concentration as a marker of severity and therapeutic response to sirolimus in patients with lymphangioleiomyomatosis. METHODS: In the MILES trial, patients with lymphangioleiomyomatosis who had forced expiratory volume in 1 second (FEV1) of 70% or less of predicted were randomly assigned (1:1) to 12 months masked treatment with sirolimus or placebo. Serum VEGF-D concentrations were measured at baseline, 6 months, and 12 months. We used a linear regression model to assess associations of baseline VEGF-D concentrations with markers of disease severity, and a linear mixed effects model to assess the associations of VEGF-D concentrations with between-group differences in clinical, physiological, and patient-reported outcomes. FINDINGS: We included 42 patients from the placebo group and 45 from the sirolimus group in our analysis. Baseline VEGF-D concentrations in individual patients varied from 0·34 ng/mL to 16·7 ng/mL. Baseline VEGF-D concentrations were higher in patients who needed supplemental oxygen than in those who did not need supplemental oxygen (1·7 ng/mL [IQR 0·99­3·36] vs 0·84 ng/mL [0·52­1·39]; p<0·0001) and in those who had a bronchodilator response than in those who did not (2·01 ng/mL [0·99­2·86] vs 1·00 ng/mL [0·61­2·15]; 0·0273). Median serum VEGF-D concentrations were similar at baseline in the sirolimus and placebo groups, and fell from baseline at 6 and 12 months in the sirolimus group but remained roughly stable in the placebo group. Each one-unit increase in baseline log(VEGF-D) was associated with a between-group difference in baseline-to-12-month FEV1 change of 134 mL (p=0·0007). In the sirolimus group, improvement in baseline-to-12-month FEV1 occurred in 15 of 23 (65%) VEGF-D responders (ie, those in whom baseline-to-12-month VEGF-D concentrations decreased by more than they did in any patients in the placebo group) and four of 15 (27%) VEGF-D non-responders (p=0·0448). INTERPRETATION: Serum VEGF-D is a biologically plausible and useful biomarker in lymphangioleiomyomatosis that correlates with disease severity and treatment response. Measurement of serum VEGF-D concentrations could inform the risk­benefit analysis of sirolimus therapy in patients with lymphangioleiomyomatosis and reduce the numbers of patients needed for clinical trials. FUNDING: National Institutes of Health, US Department of Defense.

Pretransplant gastroesophageal reflux compromises early outcomes after lung transplantation.

OBJECTIVES: Gastroesophageal reflux disease (GERD) is implicated as a risk factor for bronchiolitis obliterans syndrome after lung transplantation, but its effects on acute rejection, early allograft function, and survival are unclear. Therefore, we sought to systematically understand the time-related impact of pretransplant GERD on graft function (spirometry), mortality, and acute rejection early after lung transplantation. METHODS: From January 2005 to July 2008, 215 patients underwent lung transplantation; 114 had preoperative pH testing, and 32 (28%) had objective evidence of GERD. Lung function was assessed by forced 1-second expiratory volume (FEV(1); percent of predicted) in 97 patients, mortality by follow-up (median, 2.2 years), and acute rejection by transbronchial biopsy. RESULTS: Pretransplant GERD was associated with decreased FEV(1) early after lung transplantation (P = .01) such that by 18 months, FEV(1) was 70% of predicted in double lung transplant patients with GERD versus 83% among non-GERD patients (P = .05). A similar decrease was observed in single lung transplantation (50% vs 60%, respectively; P = .09). GERD patients had lower survival early after transplant ( P = .02)-75% versus 90%. Presence of GERD did not affect acute rejection (P = .6). CONCLUSIONS: For lung transplant recipients, pretransplant GERD is associated with worse early allograft function and survival, but not increased acute rejection. The compromise in lung function is substantial, such that FEV(1) after double lung transplant in GERD patients approaches that of single lung transplant in non-GERD patients. We advocate thorough testing for GERD before lung transplantation; if identified, aggressive therapy early after transplant, including fundoplication, may prove efficacious.

Sleep-related breathing disorders in patients with idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic and usually fatal lung disease of unknown etiology. The aim of this study was to describe clinical and polysomnographic features of sleep-related breathing disorders (SRBD) and to identify predictors of obstructive sleep apnea (OSA) in IPF patients. Eight hundred fifty-seven patients with IPF were admitted to the Cleveland Clinic from 2001 to 2005. An all-night polysomnogram (PSG) was performed in 18 of them to investigate complaints suggestive of sleep-disordered breathing. OSA was confirmed in 11 of the 18 IPF patients with complaints suggestive of sleep apnea, while the remain 7 patients had a diagnosis of primary snoring or upper airway resistance syndrome (UARS). All patients showed a reduction in sleep efficiency, REM sleep, and slow wave sleep. The apnea-hypopnea index (AHI) was positively correlated with body mass index (p < 0.0001, r = 0.80). The REM AHI and overall AHI were negatively correlated with FEV(1) (p = 0.008, r = -0.59 and p = 0.04, r = -0.49, respectively) and FVC percentages (p = 0.03, r = -0.50 and p = 0.08, r = -0.42, respectively). Our study is the first describing SRBD in IPF patients. An increased BMI and a significant impairment in pulmonary function testing may be predictors of OSA in this population. In the absence of effective treatments for IPF, the diagnosis and treatment of comorbid SRBD may lead to improvements in quality of life.

Lung transplantation in the management of patients with lymphangioleiomyomatosis: baseline data from the NHLBI LAM Registry.

BACKGROUND: In 1997, the National Heart, Lung, and Blood Institute of the National Institutes of Health established a Registry to better characterize the demographic, clinical, physiologic and radiographic features of patients with lymphangioleiomyomatosis (LAM). Herein we report data collected at enrollment from patients who had either undergone transplant prior to enrollment, underwent transplant during the 5-year study, or were evaluated/wait-listed for lung transplant during the 5-year study. METHODS: The LAM Registry enrolled patients from six clinical centers between August 1998 and October 2001. On entry, patients filled-out questionnaires covering their medical history, symptoms, treatment and quality of life (SF-36 and St. George's Respiratory Questionnaire). Enrollees underwent blood laboratory work and testing for arterial blood gases and pulmonary function. Follow-up was done at 6-month and/or yearly intervals. Diagnoses were confirmed by biopsy or typical clinical presentation plus computerized tomography (CT) findings confirmed by independent expert radiologists. A total of 243 women were enrolled. Of these, 13 (5.3%) had been transplanted at time of entry (Group A), 21 (8.6%) were transplanted during the study (Group B), and 48 (19.8%) were either wait-listed for transplant or underwent evaluation after enrollment during the study period (Group C). The remaining 161 (66.3%) registrants were neither considered for nor listed for transplant during the Registry period (Group D). RESULTS: One-third of patients in a large sample of LAM patients had either been transplanted or were being considered for transplant. At enrollment, patients who had already been transplanted and those not in need of transplant (Groups A and D) had better pulmonary function and quality-of-life scores compared with patients who subsequently underwent lung transplant during the Registry period (Group B). CONCLUSIONS: In this large Registry of LAM patients, lung transplantation appears to be associated both with significantly improved lung function and quality of life compared with patients with advanced disease.

The NHLBI lymphangioleiomyomatosis registry: characteristics of 230 patients at enrollment.

RATIONALE: Pulmonary lymphangioleiomyomatosis is a progressive cystic lung disease that is associated with infiltration of atypical smooth muscle-like cells. Previous descriptions of clinical characteristics of subjects with lymphangioleiomyomatosis have been based on a limited number of patients. OBJECTIVES: To describe the clinical characteristics of subjects with pulmonary lymphangioleiomyomatosis, both sporadic and tuberous sclerosis-related forms. METHODS: Over a 3-yr period, from 1998 to 2001, 243 subjects with pulmonary lymphangioleiomyomatosis were enrolled into a national registry; 13 subjects who had already undergone lung transplantation were excluded for the purposes of this report. MEASUREMENTS AND MAIN RESULTS: All 230 subjects were women, aged 18 to 76 yr (mean +/- SE, 44.5 +/- 0.65 yr). The average age at onset of symptoms was 38.9 +/- 0.73 yr and at diagnosis was 41.0 +/- 0.65 yr. Tuberous sclerosis complex was present in 14.8% of subjects. Pulmonary manifestations, most commonly spontaneous pneumothorax, were the primary events leading to the diagnosis in 86.5% of cases. Nearly 55% of the subjects were being treated with a progesterone derivative. An obstructive pattern on pulmonary function testing was observed in 57.3% of the subjects, whereas 33.9% had normal spirometric results. Women with tuberous sclerosis-related lymphangioleiomyomatosis were younger and had less impaired lung function compared with those with the sporadic form. CONCLUSIONS: The age range of women afflicted with pulmonary lymphangioleiomyomatosis is broader than previously appreciated and the degree of pulmonary function can be quite variable, with one-third of subjects having normal spirometry at enrollment into this registry.

Site of pegylation and polyethylene glycol molecule size attenuate interferon-alpha antiviral and antiproliferative activities through the JAK/STAT signaling pathway.

Therapeutic pegylated interferon-alphas (IFN-alpha) are mixtures of positional isomers that have been monopegylated at specific sites on the core IFN-alpha molecule. The pegylation results in lower in vitro specific activity associated with the core IFN-alpha molecule that is related to the site of pegylation and size of polyethylene glycol (PEG) attached. We prepared purified, homogeneous, positional pegylation isomers of IFN-alpha2b that were monopegylated using 5-30-kDa linear PEG molecules attached at 7 primary reactive amino acid residues: Cys(1), His(34), Lys(31), Lys(83), Lys(121), Lys(131), and Lys(134). The isomers were evaluated for STAT translocation and antiviral and antiproliferative activity. The site of pegylation strongly influenced activity relative to an IFN-alpha2b control. The highest residual activity was observed with the His(34) positional isomers, and the lowest was observed with the Cys(1) positional isomers. The Lys positional isomers demonstrated intermediate activity, with a general order of Lys(134) > Lys(83) approximately Lys(131) approximately Lys(121) > Lys(31). The progressive relationship between decreased activity and increased PEG size suggests that pegylation may interfere with interaction and binding of IFN-alpha to the IFNAR1-IFNAR2 heterodimeric receptor. The higher specific activity associated with the His(34) positional isomer suggests that this site may be favorable for pegylating IFN-alpha2b molecules.