The St. George's Respiratory Questionnaire in Pulmonary Sarcoidosis.

RATIONALE: The Saint George's Respiratory Questionnaire (SGRQ) is a frequently used tool to assess health status in pulmonary disease patients. However, its performance characteristics in sarcoidosis patients are not well characterized. METHODS: Data from a clinical trial of 138 symptomatic adults with sarcoidosis were used to examine the performance characteristics of SGRQ. Data were available at both baseline and week 24. Other assessments included FVC, FEV1, ATS dyspnea score, Borg's CR 10 dyspnea score, 6-min walk distance (6MWD), and Short Form-36 Physical Component Summary (SF-36 PCS) score. RESULTS: Baseline SGRQ was 46.8, indicating impaired health status. At baseline, SGRQ total score correlated significantly with % predicted FVC, FEV1, ATS dyspnea score, Borg's CR 10 dyspnea score, 6MWD, and SF-36 PCS (r = - 0.37, - 0.32, 0.57, 0.40, - 0.55, and - 0.80, respectively, p < 0.001). Change from baseline in SGRQ score also statistically significantly correlated with change from baseline in these parameters at week 24: r = - 0.25, - 0.20, 0.30, 0.22, - 0.20, - 0.45, respectively (p < 0.05). CONCLUSIONS: The SGRQ correlated with other outcome measures in sarcoidosis initially and with treatment. Improvement in FVC % predicted correlated with improvement in SGRQ. These data suggest the SGRQ may function as a reliable endpoint in clinical sarcoidosis trials.

Sarcoidosis extent relates to molecular variability.

The molecular basis of sarcoidosis phenotype heterogeneity and its relationship to effective treatment of sarcoidosis have not been elucidated. Peripheral samples from sarcoidosis subjects who participated in a Phase II study of golimumab [anti-tumour necrosis factor (TNF)-α] and ustekinumab [anti-interleukin (IL)-12p40] were used to measure the whole blood transcriptome and levels of serum proteins. Differential gene and protein expression analyses were used to explore the molecular differences between sarcoidosis phenotypes as defined by extent of organ involvement. The same data were also used in conjunction with an enrichment algorithm to identify gene expression changes associated with treatment with study drugs compared to placebo. Our analyses revealed marked heterogeneity among the three sarcoidosis phenotypes included in the study cohort, including striking differences in enrichment of the interferon pathway. Conversely, enrichments of multiple pathways, including T cell receptor signalling, were similar among phenotypes. We also identify differences between treatment with golimumab and ustekinumab that may explain the differences in trends for clinical efficacy observed in the trial. We find that molecular heterogeneity is associated with sarcoidosis in a manner that may be related to the extent of organ involvement. These findings may help to explain the difficulty in identifying clinically efficacious sarcoidosis treatments and suggest hypotheses for improved therapeutic strategies.

The internal consistency of PRO fatigue instruments in sarcoidosis: superiority of the PFI over the FAS.

INTRODUCTION: The Fatigue Assessment Scale (FAS) is a 10-item patient reported outcome (PRO) questionnaire that is used to measure fatigue in sarcoidosis. After several months of use, we began to question the reliability of the FAS in our clinic population. Therefore, we administered an additional fatigue PRO, the Patient Reported Outcomes Measurement Information Systems (PROMIS) Fatigue Instrument (PFI). Our hypothesis was that the internal consistency/reliability (Cronbach's alpha) of the PFI would be superior to the FAS in sarcoidosis patients because two of the ten FAS items (items #4 and #10) required reverse scoring (these items were scaled in the opposite direction to the other 8 items). METHODS: The FAS and PFI were administered during the same clinic visit to consecutive patients in our sarcoidosis clinic. We calculated a) the Cronbach's alpha for a) the FAS; b) the FAS without items #4 and #10; and c) the PFI. RESULTS: 107 consecutive sarcoidosis patients underwent FAS and PFI testing. The Cronbach's alpha was 0.740, 0.911, and 0.963 for the FAS, FAS with items #4 and #10 removed, and the PFI respectively. In female patients, the Cronbach's alpha of the FAS was 0.663, which is considered as "questionable" in terms of internal consistency. CONCLUSION: We found that the PFI had "excellent" consistency in our sarcoidosis clinic. The FAS did not demonstrate the same degree of internal consistency. The Cronbach's estimate of the FAS with items #4 and #10 removed was vastly superior to the FAS. These data support our contention that FAS items #4 and #10 detract from the internal consistency of this PRO. They also suggest that the PFI is superior to the FAS in terms of reliability.

The clinical course of sarcoidosis: presentation, diagnosis, and treatment in a large white and black cohort in the United States.

BACKGROUND: Although numerous reports have described the clinical features of sarcoidosis in various ethnic and racial groups, many have been limited by small size, homogenous populations, and relatively short follow-up periods. We report the clinical characteristics of a large, race-sex-age diverse cohort of sarcoidosis clinic patients followed in a large university medical center for an extended period of time. METHODS: This study included clinical data for sarcoidosis patients followed over a 12-year period at a sarcoidosis clinic at the Medical University of South Carolina. RESULTS: 1774 sarcoidosis patients were identified. Black females were more common (44%) than other race/gender combinations (p = 0.01). The diagnosis of sarcoidosis occurred > 3 months after the onset of symptoms in 48% of the cohort and > 1 year after the onset of symptoms in 25%. Anti-sarcoidosis treatment was required in 61% of the patients. Pulmonary function improved over time and the median corticosteroid requirement lessened. Compared to whites, blacks had more advanced radiographic stages of sarcoidosis (p < 0.0001), more organ involvement (p < 0.0001), and more frequently required anti-sarcoidosis medication (p < 0.0001). Compared to women, men had more advanced radiographic stages of sarcoidosis (p < 0.0001). CONCLUSIONS: The analysis indicates that sarcoidosis tends to improve over time in terms of pulmonary function and medication requirements. The disease was found to be more severe in blacks than whites. Treatment was not necessarily required. These results provide a comprehensive model of the course and treatment of sarcoidosis in the clinical setting.

Endpoints for clinical trials of sarcoidosis.

Over the past few years an increasing number of prospective controlled sarcoidosis treatment trials have been completed. Unfortunately, these studies utilize different endpoints making comparisons between studies difficult. At the recent World Association of Sarcoidosis and other Granulomatous disease (WASOG) meeting, a session was dedicated to the evaluation of clinical endpoints for various disease manifestations. These included pulmonary, pulmonary hypertension, fatigue, cutaneous, and a classification of clinical disease phenotypes. Based on the available literature and our current understanding of the disease, recommendations for clinical evaluation were proposed for each disease category. For example, it was recommended that pulmonary studies should include changes in the forced vital capacity. Additionally, it was recommended that all trials should incorporate measurement of quality of life.

Ambrisentan for sarcoidosis associated pulmonary hypertension.

BACKGROUND: Sarcoidosis associated pulmonary hypertension (SAPH) is associated with significant morbidity and mortality. There is a paucity of information concerning therapy for this condition. METHODS: We performed a prospective, open-label, proof of concept trial of ambrisentan for SAPH. 21 subjects with SAPH received 5 mg/day of ambrisentan for 4 weeks and then 10/mg day for 20 subsequent weeks. RESULTS: No significant change was noted in the 6-minute walk distance over the course of the study (mean change between week 0 and 24: 9.8 +/- 54.6 meters, p: NS). There were also no significant differences between weeks 0 and 24 in terms of dyspnea as measured by the modified Borg scale, serum brain naturetic peptide, diffusing capacity, and quality of life as measured by the Short Form-36. There was a high dropout rate: overall: 11/21, 52%; social reasons: 3/21, 14%; medical reasons: 8/21, 38% because of dyspnea: 6/21, 29% and/or edema: 4/21, 19%. Of those who completed the 24 week study (10/21, 48%), there was an improvement in their WHO functional class and a marked improvement in their health related quality of life as measured by the St. George Respiratory questionnaire (-15.3 +/- 25.0). However both these improvments did not reach statistical significance possibly because of the small sample size. CONCLUSION: Although ambrisentan was not well tolerated by many of these subjects with SAPH, in those who remained in this 24-week trial, improvements in WHO functional class and in health related quality of life suggested a possible benefit of this drug in selected patients.

Defining the clinical outcome status (COS) in sarcoidosis: results of WASOG Task Force.

The clinical outcome of sarcoidosis is quite variable. Several scoring systems have been used to assess the level of disease and clinical outcome. The definition of clinical phenotypes has become an important goal as genetic studies have identified distinct genotypes associated with different clinical phenotypes. In addition, treatment strategies have been developed for patients with resolving versus non resolving disease. A task force was established by the World Association of Sarcoidosis and Other Granulomatous diseases (WASOG) to define clinical phenotypes of the disease based on the clinical outcome status (COS). The committee chose to examine patients five years after diagnosis to determine the COS. Several features of the disease were incorporated into the final nine categories of the disease. These included the current or past need for systemic therapy, the resolution of the disease, and current status of the condition. Sarcoidosis patients who were African American or older were likely to have a higher COS, indicating more chronic disease. The COS may be useful in future studies of sarcoidosis.

C-reactive protein predicts response to infliximab in patients with chronic sarcoidosis.

BACKGROUND: This study assessed the value of C-reactive protein as a predictor of disease severity and response to infliximab therapy in patients with chronic pulmonary sarcoidosis. DESIGN: Sera were collected through week 52 from 138 patients with chronic pulmonary sarcoidosis who received placebo or infliximab in a randomized, double-blind, placebo-controlled study. We evaluated the response to therapy by baseline CRP using a dichotomous cutpoint (0.8 mg/dL) for the change from baseline in percent-predicted forced vital capacity (FVC), Saint George's Respiratory Questionnaire (SGRQ), 6-minute walk distance (6MWD), Borg's CR10 dyspnea score, and Physician Organ Assessment (POA). RESULTS: CRP was elevated in 36% of patients at baseline, and was significantly reduced by infliximab by week 2. Among patients with elevated baseline CRP, infliximab-treated patients improved significantly compared with placebo-treated patients in percent-predicted FVC (+2.5 versus -2.6%), 6MWD (+8.0 versus -34.1), Borg's CR10 dyspnea score (pre-6MWD -0.8 versus +0.9, post-6MWD -1.1 versus +0.8), and POA (-3.1 versus -0.3). Patients with lower CRP levels at baseline did not show significant differences between the placebo and infliximab groups in most endpoints evaluated. CONCLUSIONS: In chronic sarcoidosis patients, elevated CRP appears to identify a subset with more severe disease who may respond better to treatment with infliximab.

Inhaled iloprost for sarcoidosis associated pulmonary hypertension.

RATIONALE: Patients with sarcoidosis associated pulmonary hypertension (SAPH) have responded to systemic prostacyclin therapy. OBJECTIVES: To determine the rate of response to inhaled prostacyclin, iloprost, in SAPH. METHODS: Sarcoidosis patients with pulmonary hypertension and no evidence for left ventricular dysfunction were enrolled in an open label, prospective study. Patients underwent right heart catheterization and six minute walk (6MW) test. Quality of life was evaluated using several instruments, including the Saint George Respiratory Questionnaire (SGRQ). Patients received 5 mcg of inhaled iloprost every 2-3 hours while awake. After four months of therapy, patients underwent repeat cardiac catheterization, 6 MW test, and completed quality of life questionnaires. MEASUREMENTS AND MAIN RESULTS: Of the 22 patients enrolled, 15 completed all 16 weeks of therapy. The most common reasons for study discontinuation included drug associated cough (3 patients) and compliance with the prescribed number of treatments per day (2 patients). Six patients experienced a 20% or greater decrease in pulmonary vascular resistance (PVR) from baseline with five of these six patients also showing > or = 5 mm Hg reduction in PA mean. Although three patients improved the 6MW distance by at least 30 meters, only one had a decrease in PVR. At 16 weeks a significant decrease was reported in the SGRQ activity score (p = 0.0273), with seven patients having a 4 point or greater decrease. CONCLUSION: Inhaled iloprost as monotherapy was associated with an improvement in pulmonary hemodynamics and quality of life as assessed by the SGRQ activity score in some sarcoidosis patients with SAPH.

Efficacy of infliximab in extrapulmonary sarcoidosis: results from a randomised trial.

The aim of the present study was to investigate the efficacy of infliximab for the treatment of extrapulmonary sarcoidosis. A prospective, randomised, double-blind, placebo-controlled trial was conducted, with infliximab at 3 and 5 mg x kg(-1) body weight administered over 24 weeks. Extrapulmonary organ severity was determined by a novel severity tool (extrapulmonary physician organ severity tool; ePOST) with an adjustment for the number of organs involved (ePOSTadj). In total, 138 patients enrolled in the trial of infliximab versus placebo for the treatment of chronic corticosteroid-dependent pulmonary sarcoidosis. The baseline severity of extrapulmonary organ involvement, as measured by ePOST, was similar across treatment groups. After 24 weeks of drug-therapy study, the change from baseline to week 24 in ePOST was greater for the combined infliximab group compared with the placebo group. After adjustment for the number of extrapulmonary organs involved, the improvement in ePOSTadj observed in the combined infliximab group was also greater than that observed in placebo-treated patients, after 24 weeks of therapy. The improvements in ePOST and ePOSTadj were not maintained during a subsequent 24-week washout period. Infliximab may be beneficial compared with placebo in the treatment of extrapulmonary sarcoidosis in patients already receiving corticosteroids, as assessed by the severity tool described in the present study.

Presenting characteristics as predictors of duration of treatment in sarcoidosis.

BACKGROUND: Some sarcoidosis patients never need therapy, but many still require therapy more than 2 years after initial diagnosis. AIM: To determine what features at initial presentation are associated with treatment 2 years later. METHODS: Patients with biopsy-confirmed sarcoidosis enrolled in the ACCESS (A Case Control Etiologic Study of Sarcoidosis) study were initially evaluated within 6 months of diagnosis. Pulmonary function, chest X-ray and dyspnoea score were measured, and systemic therapy for the sarcoidosis recorded. Organ involvement was assessed using a standardized instrument. A subset (n = 215) were seen 18-24 months later for follow-up, and these patients constitute our study group. RESULTS: Ten patients had only received therapy before the first visit, with no further therapy, and were excluded from analysis. Of the remaining 205, 95 were not on therapy at the initial visit and 75 (79%) of these were never treated during follow-up. Of the 110 initially on therapy, 52 (47%) remained on therapy at follow-up. Other initial features associated with continued therapy were the level of dyspnoea and predicted vital capacity. On logistic regression, only dyspnoea and therapy at initial visit remained significant. Patients on systemic therapy at initial evaluation were more likely to be on therapy at follow-up (OR 3.6, p = 0.003). Neither ethnicity nor gender independently predicted therapy at follow-up. DISCUSSION: This study group represents a sample of newly diagnosed sarcoidosis patients. However, this is a referral population, and there was no set protocol for treatment. Use of systemic therapy within the first 6 months after diagnosis appears to be strongly associated with continued use of therapy 2 years later.

A current assessment of rurally linked exposures as potential risk factors for sarcoidosis.

PURPOSE: To identify and quantify the risk of developing sarcoidosis associated with specific rural exposures previously recognized as potential risk factors for this disease. METHODS: A matched case-control design was carried out with a 2-to-1 ratio of controls to cases. Case exposure histories were determine from a detailed questionnaire collecting self-reported information covering the period from birth through disease development and comparing that to exposure histories for the corresponding period in age-, race-, and gender-matched controls identified using Random Digit Dial survey methodology. Conditional logistic regression was used to analyze the matched data while controlling for several baseline variables. RESULTS: A number of exposures were found to be univariately associated with the development of sarcoidosis including: the use of wood stoves, the use of fireplaces, the use of nonpublic water supplies, and living or working on a farm. A dose-response gradient was detected from exposure to wood stoves and fireplaces continued to be significantly associated with sarcoidosis in multivariable models. CONCLUSIONS: The results of this study provide further support for the hypothesis that behaviors associated with rural living play some role in the development of sarcoidosis. This study further suggests that exposures involving the handling or burning of wood such as using wood stoves or fireplaces for home heating may, in part, explain this rural association.

The treatment of pulmonary aspergilloma.

Aspergillomas are fungal balls within lung cavities. The natural history of patients affected is variable. Hemoptysis is a dangerous sequela. Factors associated with a poor prognosis have been defined and therapy is difficult because of the lack of a blood supply. Randomized trials are lacking. Surgical treatment is definitive but many patients are ineligible. Percutaneous therapy and bronchial artery embolization is appropriate for some patients and itraconazole has produced favorable results in several studies.

An approach to the treatment of pulmonary sarcoidosis with corticosteroids: the six phases of treatment.

Corticosteroid therapy for pulmonary sarcoidosis is not standardized. There is no consensus on which patients should receive treatment, how patients should be monitored, and the dose of corticosteroids once the decision to treat has been made. These issues are important for several reasons. First, inappropriate use of corticosteroids may result in unnecessary toxic reactions. Second, inadequate use of corticosteroids might result in permanent pulmonary and extrapulmonary organ dysfunction from sarcoidosis. Third, patients who are inappropriately labeled as "corticosteroid failures" may be subjected to other potentially toxic drugs or even lung transplantation. Corticosteroid dosing involves six phases: (1) initial high doses to control inflammation; (2) tapering to a maintenance dose that will continue to suppress the inflammation but lessen the risk of corticosteroid toxic reactions; (3) continuing to receive the maintenance dose until a decision to taper off corticosteroids is made; (4) tapering off corticosteroid therapy; (5) observation for relapse; and (6) treatment if relapse occurs. Although these phases of treatment have been alluded to in the literature, few of them have been studied rigorously. This article describes the use of corticosteroids for pulmonary sarcoidosis in terms of the above six phases. The proposed dosing schedules are based on the natural history of the disease and the results from published treatment studies.

Endobronchial lesions in HIV-infected individuals.

Endobronchial manifestations of HIV infection are rare. The endobronchial appearance and clinical presentation of these lesions may suggest the correct diagnosis. Establishing an appropriate differential diagnosis at the time of visualization of the endobronchial lesion is important because some lesions require specific biopsy techniques or special stains. The bronchoscopist must consider the risks vs benefits of biopsy when confronted with an endobronchial lesion. With the notable exception of pseudomembranous necrotizing tracheobronchial aspergillosis, there are no specific endobronchial lesions associated with HIV infection which increase the risk of complications when they are biopsied. Although EKS is a vascular lesion and an early case report suggested that endobronchial biopsy might result in excessive bleeding, this complication was not observed in two subsequent series. Fortunately, a presumptive diagnosis of EKS can usually be made without biopsy by the characteristic appearance of the lesions. EKS is the most common endobronchial lesion associated with HIV infection; however, its incidence will probably decline as the incidence of KS declines. Many of the other endobronchial lesions described herein have been reported recently. We suspect these and other lesions will be found more frequently, as the epidemic of HIV continues to evolve.

Bullous sarcoidosis: a report of three cases.

Three cases of pulmonary sarcoidosis presented as bullous emphysema with severe airflow obstruction, and the diagnosis of sarcoidosis was unsuspected for at least 2 years. Potential mechanisms of bullous emphysema from sarcoidosis are discussed. The physician should suspect sarcoidosis as the cause of bullous emphysema when young patients who have smoked relatively few pack-years present with emphysema or severe airflow obstruction. Additional clues are the presence of mediastinal adenopathy on a chest radiograph or a CT scan and a history consistent with extrapulmonary sarcoidosis.

A case report of a dactylaria fungal infection in a lung transplant patient.

Dematiaceous fungi such as Dactylaria gallopava are becoming more prevalent in transplant patients, with 50% of outcomes being fatal. In this report, we describe a 32-year-old woman who presented with swelling in the right shoulder area and right lateral neck. On further investigation with a CT scan, a fluid collection in the shoulder was identified, drained, and subsequently grew D gallopava. We report the successful treatment of an invasive Dactylaria infection in a lung transplant patient predominantly by medical chemotherapy, although surgical incision and drainage was performed on one of the fungal lesions.

Treatment of a solitary pulmonary sarcoidosis mass by CT-guided direct intralesional injection of corticosteroid.

A case is reported of 38-year-old woman with chest pain attributed to a left lung sarcoidosis mass. The mass failed to diminish and symptoms failed to resolve with systemic corticosteroid therapy. CT-guided direct intralesional transthoracic injection of dexamethasone resulted in resolution of the patient's symptoms and a dramatic reduction in the size of the mass within 2 months.

Primary pulmonary involvement of Fusarium solani in a lung transplant recipient.

A case of cavitary lung disease caused by Fusarium solani in a lung transplant recipient is presented. A mechanism for development of this infection is proposed. Lipid complex amphotericin B (Abelcet) was effective in eradicating this infection. To our knowledge, invasive lung disease caused by the Fusarium species has not been previously reported in a solid organ transplant recipient.