Chronic Pulmonary Sarcoidosis Research Articles

Infliximab Therapy in Pulmonary Sarcoidosis

In their article, Baughman and colleagues (1) reported that infliximab therapy in patients with chronic sarcoidosis was associated with a significant improvement in percent predicted FVC after 24 weeks of therapy in a cohort of 138 patients. However, no benefit was demonstrated on the endpoints of the six-minutewalk test (6MWT), St. George’s Respiratory Questionnaire (SGRQ), or Borg’s CR10 dyspnea score. Post hoc analyses further suggested a greater benefit in patients with more severe disease. The authors conclude that the clinical relevance of the observedFVC improvement remains unclear. Nevertheless, they suggest that their data support further evaluation of anti–TNFtherapy in severe chronic sarcoidosis. In our opinion, the conclusions are too optimistic. This may lead to an uncontrolled use of infliximab in patients with chronic pulmonary sarcoidosis outside new study protocols. First, there is a clear limitation of the study in using FVC percent predicted as primary endpoint. Pulmonary function tests characteristically reveal a restrictive pattern with a reduction in DlCO, although it is not unusual for lung function to be normal (2). Endobronchial sarcoidosis may lead to impairment of airflow and obstructive respiratory physiology. There might be several reasons for a decrease in FVC—for example, bad performance or obesity. Measurement of TLC, RV, and DlCO might be more powerful in reflecting improvement of lung function. In our opinion, measurement of dynamic lung volumes is insufficient to reflect the changes occurring in sarcoidosis with pulmonary involvement. An improvement of 2.8% FVC percent predicted corresponds to an absolute increase of only about 0.080 L. Furthermore, endobronchial disease exists in approximately 70% of patients with stage II or III disease. Thus, changes in FEV1 would also be of interest (not mentioned in the article). Even the improvement in radiological findings remains questionable. There is no indication of the severity of sarcoidosis in the study population investigated.A radiological classification of patients into stages II to IVmight be helpful. Furthermore, a computed tomography scan would be more helpful to observe changes in radiological findings concerning both pulmonary involvement and the status of hilar and mediastinal lymphadenopathy. The study protocol has shown that the use of infliximab in these patients seems to be safe. On the other hand, O’Shea and colleagues reported the development of pulmonary sarcoidosis occurring in the context of infliximab treatment for ankylosing spondylitis (3). Since the study design shows several limitations, the investigators cannot suggest a potential beneficial effect of this expensive drug or propose further evaluation.

Expression and role of CCR6/CCL20 chemokine axis in pulmonary sarcoidosis

We have shown previously that the chemokine receptors CXCR3 and CXCR6 are coexpressed by Th1 cells infiltrating the lung and the granuloma of patients with sarcoidosis. In this study, we evaluated the role of CCL20/CCR6 interaction in the pathogenesis of acute and chronic pulmonary sarcoidosis. By flow cytometry and molecular analyses, we have demonstrated that Th1 cells isolated from the bronchoalveolar lavage (BAL) of patients with sarcoidosis and T cell alveolitis are equipped with CCR6. Furthermore, CCR6(+) T cells coexpressed the chemokine receptors CXCR3 and CXCR6. Immunohistochemical analysis of lung specimens has shown that CCR6(+) T cells infiltrate lung interstitium and surround the central core of the granuloma. It is interesting that CCR6 was never detected on the alveolar macrophage (AM) surface, and it is observed in the cytoplasm of AMs from patients with sarcoidosis and alveolitis. The CCR6 ligand CCL20 was expressed by macrophages, multinucleated giant cells, and epithelioid cells infiltrating the granuloma. Furthermore, detectable levels of CCL20 protein are seen in the BAL fluid components of patients with active sarcoidosis, and sarcoid AMs release the CCR6 ligand in vitro. From a functional point of view, sarcoid Th1 cells were able to respond to CXCL10, CXCL16, and CCL20 in migratory assays. In vitro kinetic studies demonstrated that CCR6 is induced rapidly by IL-2, IL-18, and IFN-gamma. In conclusion, T cells expressing CCR6, CXCR3, and CXCR6 act coordinately with respective ligands and Th1 inflammatory cytokines in the alveolitic/granuloma phases of the disease.

Pulmonary Sarcoidosis

Sarcoidosis, a granulomatous disorder of unknown etiology, characteristically involves multiple organs. However, pulmonary manifestations typically dominate. Chest radiographs are abnormal in 85 to 95% of patients. Abnormalities in pulmonary function tests are common and may be associated with cough, dyspnea, and exercise limitation. However, one third or more of patients are asymptomatic, with incidental abnormalities on chest radiographs. The clinical course and expression of pulmonary sarcoidosis are variable. Spontaneous remissions occur in nearly two thirds of patients. The course is chronic in up to 30% of patients. Chronic pulmonary sarcoidosis may result in progressive (sometimes life-threatening) loss of lung function. Fatalities ascribed to sarcoidosis occur in 1 to 4% of patients. Although the impact of treatment is controversial, corticosteroids may be highly effective in some patients. Immunosuppressive, cytotoxic, or immunomodulatory agents are reserved for patients failing or experiencing adverse effects from corticosteroids. Lung transplantation is a viable option for patients with life-threatening disease failing medical therapy.

Infliximab Therapy in Patients with Chronic Sarcoidosis and Pulmonary Involvement

Evidence suggests that tumor necrosis factor (TNF)-alpha plays an important role in the pathophysiology of sarcoidosis. To assess the efficacy of infliximab in sarcoidosis. A phase 2, multicenter, randomized, double-blind, placebo-controlled study was conducted in 138 patients with chronic pulmonary sarcoidosis. Patients were randomized to receive intravenous infusions of infliximab (3 or 5 mg/kg) or placebo at Weeks 0, 2, 6, 12, 18, and 24 and were followed through Week 52. The primary endpoint was the change from baseline to Week 24 in percent of predicted FVC. Major secondary efficacy parameters included Saint George's Respiratory Questionnaire, 6-min walk distance, Borg's CR10 dyspnea score, and the proportion of Lupus Pernio Physician's Global Assessment responders for patients with facial skin involvement. Patients in the combined infliximab groups (3 and 5 mg/kg) had a mean increase of 2.5% from baseline to Week 24 in the percent of predicted FVC, compared with no change in placebo-treated patients (p = 0.038). No significant differences between the treatment groups were observed for any of the major secondary endpoints at Week 24. Results of post hoc exploratory analyses suggested that patients with more severe disease tended to benefit more from infliximab treatment. Infliximab therapy resulted in a statistically significant improvement in % predicted FVC at Week 24. The clinical importance of this finding is not clear. The results of this Phase 2 clinical study support further evaluation of anti-TNF-alpha therapy in severe, chronic, symptomatic sarcoidosis.

Melatonin is a safe and effective treatment for chronic pulmonary and extrapulmonary sarcoidosis

Chronic sarcoidosis (CS) is often unresponsive to usual treatments. Melatonin, an immunoregulatory drug, was employed in CS patients in whom usual treatments were ineffective or induced severe side effects. Melatonin was given for 2 yr (20 mg/day in the first year, 10 mg/day in the second year) to 18 CS patients. Pulmonary function tests, chest X rays, pulmonary computed tomography, Ga(67) scintigraphy and angiotensin-converting enzyme (ACE) were assayed at baseline and in the follow-up. Normalization of ACE, improvement of pulmonary parameters and resolution of skin involvement were found in the patients given melatonin. After 24 months of melatonin therapy, hylar adenopathy completely resolved in eight patients and parenchymal lesions were markedly improved in all patients; in the five patients with reduced diffusion capacity of the lung for carbon monoxide, the values normalized after 6 months of therapy and remained stable until month 24. After 24 months, Ga(67) pulmonary and extra-pulmonary uptake was totally normalized in seven patients and, at month 12 months, ACE was normalized in six patients in which the values were high at the baseline. Skin lesions, present in three patients, completely disappeared at month 24 months. No side effects were experienced and no disease relapse was observed during melatonin treatment. Melatonin may be an effective and safe therapy for CS when other treatments fail or cause side effects.

RESPONDER ANALYSES IN PATIENTS RECEIVING INFLIXIMAB FOR CHRONIC SARCOIDOSIS WITH PULMONARY INVOLVEMENT

PURPOSE: Response to drug therapy may not be uniform across a heterogeneous population. Responder analyses, which dichotomize the response at a specific level of interest, can be helpful in gauging the utility of an intervention. The objective of this study was to evaluate the response to infliximab therapy in a randomized trial of 138 patients with chronic pulmonary sarcoidosis using clinically meaningful dichotomous endpoints for pulmonary function, symptoms, and physical function.

ASSESSMENT OF INFLIXIMAB EFFICACY IN EXTRAPULMONARY SARCOIDOSIS USING A NOVEL ASSESSMENT TOOL: RESULTS FROM A RANDOMIZED TRIAL

PURPOSE: Anecdotal evidence has suggested improvement in extrapulmonary sarcoidosis with infliximab therapy, but this has not been prospectively studied. The purpose of this study was to evaluate the efficacy of infliximab on extrapulmonary sarcoidosis in patients with chronic pulmonary sarcoidosis who are symptomatic despite treatment.

Identification and possible functions of ADAM33 as an asthma susceptibility gene

SummaryAsthma is a disorder of the conducting airways in which Th‐2 mediated inflammation interacts with structural changes to cause variable airflow obstruction. Fundamental to disordered function is the concept of bronchial hyperresponsiveness (BHR), in which the airways construct too much and too easily. It has been stated that BHR represents the ‘Holy Grail’ of asthma, yet our understanding of its underlying causes(s) is poorly developed [1]. Measurement of BHR has found clinical utility as a diagnostic test to help differentiate asthma from other lung disorders, but unfortunately its specificity is low. However, it is the severity of BHR and its relative independence from measures of baseline airway calibre that differentiates BHR encountered in asthma from that of other diseases such as chronic obstructive pulmonary disease (COPD), sarcoidosis and heart failure.

Indigenous Pulmonary Propionibacterium acnes Primes the Host in the Development of Sarcoid-Like Pulmonary Granulomatosis in Mice

Although many cases of sarcoidosis are self-limiting with spontaneous remission, uncontrolled pulmonary granulomatosis with fibrosis produces intolerable long-term respiratory symptoms in a minority of patients. Individuals with chronic pulmonary sarcoidosis require an alternative therapy to corticosteroidal treatment because of its insufficient effectiveness. Although many researchers have considered infection as the triggering factor for this disease, the mechanisms by which the candidate causative organisms induce this disorder remain unclear. We report here that extrapulmonary sensitization to Propionibacterium acnes, which is one of the candidates to date, induced pulmonary Th-1 granulomas mainly in the subpleural and peribronchovascular regions often observed in sarcoidosis. These granulomas appear to be caused by indigenous P. acnes pre-existing in the lower respiratory tract of the normal lung, which is believed to be germ-free, and by an influx of P. acnes-sensitized CD4(+) T cells from the circulation. Importantly, the eradication of indigenous P. acnes with antibiotics alleviated the granulomatous lung disease. This is the first report to present clear evidence of the contribution of an indigenous pulmonary bacterium to the formation of granulomatous lesions in the lung. We propose that treatment targeting indigenous P. acnes in the lung may be a possible remedy for pulmonary sarcoidosis.

The C-C chemokine receptors CCR4 and CCR8 identify airway T cells of allergen-challenged atopic asthmatics.

In vitro polarized human Th2 cells preferentially express the chemokine receptors CCR3, CCR4, and CCR8 and migrate to their ligands: eotaxin, monocyte-derived chemokine (MDC), thymus- and activation-regulated chemokine (TARC), and I-309. We have studied the expression of chemokines and chemokine receptors in the airway mucosa of atopic asthmatics. Immunofluorescent analysis of endobronchial biopsies from six asthmatics, taken 24 hours after allergen challenge, demonstrates that virtually all T cells express IL-4 and CCR4. CCR8 is coexpressed with CCR4 on 28% of the T cells, while CCR3 is expressed on eosinophils but not on T cells. Expression of the CCR4-specific ligands MDC and TARC is strongly upregulated on airway epithelial cells upon allergen challenge, suggesting an involvement of this receptor/ligand axis in the regulation of lymphocyte recruitment into the asthmatic bronchi. In contrast to asthma, T cells infiltrating the airways of patients with chronic obstructive pulmonary disease and pulmonary sarcoidosis produce IFN-gamma and express high levels of CXCR3, while lacking CCR4 and CCR8 expression. These data support the role of CCR4, of its ligands MDC and TARC, and of CCR8 in the pathogenesis of allergen-induced late asthmatic responses and suggest that these molecules could be considered as targets for therapeutic intervention.

Increased Airflow Limitation and Bronchoalveolar Lavage Neutrophils and Eosinophils Define Chronic Pulmonary Sarcoidosis

Increased Airflow Limitation and Bronchoalveolar Lavage Neutrophils and Eosinophils Define Chronic Pulmonary Sarcoidosis

Randomized trial of inhaled fluticasone propionate in chronic stable pulmonary sarcoidosis: a pilot study

Continuous intravenous epoprostenol improves exercise capacity, haemodynamics, and survival in severe primary pulmonary hypertension. Pulmonary hypertension can also be life-threatening in patients with connective tissue diseases. In a prospective open monocentre uncontrolled study, the effects of epoprostenol were evaluated in patients with severe pulmonary hypertension secondary to connective tissue diseases who were unresponsive to oral vasodilators (including calcium channel blockers) and continued to be in the New York Heart Association (NYHA) functional class III or IV despite conventional medical therapy. Seventeen patients received epoprostenol administered by a portable infusion pump associated with conventional therapy (oral anticoagulants, diuretics, supplemental oxygen). During the first six weeks of therapy, two (12%) patients died, of pulmonary oedema (n = 1) and severe sepsis (n = 1). In the fifteen remaining subjects, clinical and haemodynamic parameters improved significantly at six weeks. These patients were subsequently monitored for 80+/-48 (range 14-154) weeks after initiation of epoprostenol. Five (33%) patients died, of right heart failure (n = 2), severe sepsis (n = 2) or syncope (n = 1) and two patients were successfully transplanted 24 and 52 weeks after initiation of epoprostenol. Seven of the remaining eight patients had a persistent clinical improvement. Short-term epoprostenol therapy is effective in some patients with connective tissue diseases as demonstrated by better clinical status and haemodynamics at six weeks. However, this study reports several cases of early and late major complications including severe sepsis and pulmonary oedema. Additional information is needed to evaluate the benefit: risk ratio of long-term epoprostenol therapy in pulmonary hypertension secondary to connective tissue diseases.

Use of Transfer Impedance Measurements for Clinical Assessment of Lung Mechanics

Respiratory transfer impedance (Ztr) measured using the forced oscillation technique requires virtually no patient cooperation and provides a noninvasive approach for acquiring data reflective of lung mechanics. Also, model analysis of Ztr provides reliable estimates of separate airway and tissue properties (1), but only if data out to 64 Hz are acquired. The current study evaluated the clinical utility of Ztr from 1-80 Hz for assessing the degree and type of impaired lung function. Spirometry and Ztr measurements were made on 37 individuals: 11 healthy subjects and 26 patients with lung disease including chronic obstructive pulmonary disease (COPD), asthma, lung cancer, and sarcoidosis. Over the entire patient group, 12 were also smokers. We first established normal ranges for several Ztr features and model estimated mechanical properties. The COPD and smokers groups showed significant differences in portions of their Ztr spectra from that of the healthy group. Key Ztr spectral features included R0, the frequency at which the real part of impedance is zero; and Re4, the real part of impedance at 4 Hz. The key model parameter was airway resistance, Raw. We found Raw, Re4, and R0 to be significantly elevated during disease (p < 0.0005) and to significantly decrease with bronchodilator therapy (p < 0.025). Moreover, we found moderate to strong correlations between R0, Raw, and Re4 versus FVC and R0 versus FEV1. After bronchodilator, changes in R0, Re4, and Raw were correlated with changes in several spirometric indices. The R0 feature has not been previously evaluated since it is typically above 32 Hz (well above 32 Hz in diseased individuals) and not encompassed in previous clinical studies.

空洞化をきたした慢性進行性肺サルコイドーシス (サ症) の一例

空洞化をきたした慢性進行性肺サルコイドーシス (サ症) の一例

Increased Levels of Serum Interferon-gamma in Pulmonary Sarcoidosis and Relationship with Response to Corticosteroid Therapy

The aim of this study was to evaluate serum levels of the lymphokine interferon-gamma (IFNg) in patients with chronic pulmonary sarcoidosis, and to investigate its value as a predictive marker of clinical response to corticosteroid therapy. Twenty-five patients and 28 age-matched control subjects were studied. All the patients had parenchymal shadows (Stage II or Stage III) and none had clinical evidence of extrathoracic disease. Before therapy, serum IFNg levels were significantly higher in the patient group (p less than 0.001), and 20 (80%) had values above the normal range. After oral treatment with corticosteroids for a median 13 months (range, 3 to 49 months) the levels decreased significantly (p less than 0.01). However, the falls were less pronounced in patients who had a better outcome in terms of achieving complete radiographic resolution and in those who improved in forced vital capacity by greater than or equal to 10%. The prognostic value of the pretreatment serum IFNg was explored, and a significant relationship was found between higher pretreatment levels and lower grades or radiographic abnormality assessed 3 yr after commencement of treatment (p less than 0.01). In addition, the patients who had cleared completely while receiving steroids and remained in remission had significantly higher pretreatment serum IFNg levels than did those with incomplete resolution of parenchymal shadows or radiographic relapses (p less than 0.05). We conclude that elevated levels of circulating IFNg are detectable in most untreated patients with Stage II/III pulmonary sarcoidosis and that patients with the highest levels appear to have a better chance of achieving complete resolution with corticosteroid therapy.

Chronic pulmonary sarcoidosis: relationship between lung lavage cell counts, chest radiograph, and results of standard lung function tests.

Thirty three consecutive untreated patients with pulmonary sarcoidosis, confirmed histologically or by Kveim test, were investigated to correlate cell counts in bronchoalveolar lavage fluid with clinical features, the chest radiograph, and results of lung function tests. A persistently abnormal radiograph had been observed for one year or more in 26 (79%) and for two years or more in 20 (61%), but only 24% had dyspnoea. Twenty (61%) of 33 patients showed an increased percentage of lymphocytes in bronchoalveolar lavage fluid, although only eight (24%) exceeded 28%. A moderate increase of neutrophils, up to 12%, was found in 14 (42%). Lymphocyte percentage counts were higher in the group of patients without evidence of radiographic contraction suggesting fibrosis, and this contrasted with higher percentage neutrophil counts in those with contraction. There was also a correlation between the percentages of neutrophils and increasing radiographic profusion scores (p less than 0.001), suggesting that neutrophils may reflect the severity of the parenchymal legions as well as fibrotic distortion, and an inverse correlation with vital capacity (p less than 0.001) and transfer factor (TLCO) (p less than 0.1 greater than 0.05). No significant correlation was found between the lymphocyte counts and radiographic profusion scores, vital capacity or TLCO; but it was noted that all eight patients with high lymphocyte counts (greater than 28%) had radiographic profusion scores less than 12. This study shows that, especially in sarcoidosis with more extensive radiographic shadows of long duration, bronchoalveolar lavage neutrophils may be important as well as lymphocytes in clinical assessment of "activity" of disease. These observations are important because they throw doubt on whether the lavage lymphocyte count alone can be used as an indicator of the need to start corticosteroid treatment.

Treatment of Cutaneous Sarcoidosis With Isotretinoin

A patient with chronic cutaneous and pulmonary sarcoidosis, unresponsive to oral corticosteroid therapy, was treated with isotretinoin. The patient's cutaneous manifestations of sarcoidosis showed consistent improvement during the course of retinoid therapy. The lesions that responded earliest either resolved or showed the greatest reduction in size. The patient's WBC count increased and her angiotensin-converting enzyme level decreased during the first two months of isotretinoin therapy; both returned to pretreatment levels during the third month of therapy. Pulmonary function tests were unchanged after four months of treatment. Isotretinoin may be a useful therapeutic agent for cutaneous sarcoidosis. However, the possibility of spontaneous remission of the disease during the course of therapy cannot be excluded.

Sarcoidosis and Aspergilloma: The Role of Surgery

Fibrocystic pulmonary disease is a common sequel of chronic pulmonary sarcoidosis, and the subsequent development of intracavitary aspergillomas is frequent, especially in black patients. Pulmonary hemorrhage from aspergilloma is second only to cardiorespiratory failure as the cause of death in sarcoidosis. Opinions regarding the role of resectional surgery are conflicting. We report observations on 38 patients with biopsy evidence of antecedent sarcoidosis and cultural or serologic identification of Aspergillus species as cause of the fungus balls. Pulmonary fibrosis was bilateral and extensive in most cases, making surgical treatment perilous. Ten patients had moderate impairment of pulmonary function. Seven had surgical resection with six satisfactory results and one death. Three patients in this category have not required surgery. Twenty-eight patients had severely compromised pulmonary function. Surgery was performed in seven because of intractable bleeding; four survived, but three later died of respiratory failure. Of the 21 in this category not treated by surgery, six survived, four died of hemorrhage and 11 of respiratory failure. Of the 37 patients with aspergilloma whose status is known, 19 are dead, 14 survived with positive precipitins and four, all treated surgically, recovered. It is concluded that surgical treatment of aspergilloma in patients with sarcoidosis should be avoided if possible, but is inescapable in a third of cases.

Sarcoidosis and aspergilloma

Ten instances of aspergilloma occurring in patients with chronic pulmonary sarcoidosis are reported. Cystic cavities in the upper lobe are a frequent development in sarcoidosis, and aspergilli in such circumstances will often proliferate to form fungus balls. Invasion of the lung and systemic dissemination are rare, but erosion of the cavity wall is a common cause of pulmonary hemorrhage, which may be fatal. In other cases spontaneous healing occurs. Medical therapy is unlikely to be effective, and resection is indicated for recurrent hemoptysis when the underlying sarcoidosis and consequent impairment of respiratory function permit surgery.

Pulmonary sarcoidosis

During the last nine years 123 patients with intrathoracic localization of sarcoidosis have been observed. There were six deaths from sarcoidosis. Thirty-nine patients showed varying degrees of pulmonary fibrosis, and eighteen patients among the survivors were left with significant respiratory difficulty. Intrathoracic lesions could be assigned to one of three broad chronologic stages according to the roentgen pattern present on the initial chest film: early, transitional and late. In the early stage, for those patients whose film showed enlarged mediastinal nodes without pulmonary lesions the outlook was best. It was not so favorable for patients whose films showed miliary nodulation of the lung fields and still less favorable when the film first showed a patchy bronchopneumonic pattern. Patients in the transitional and late fibrotic stages often showed disabling symptoms, and five of the six deaths caused by sarcoidosis were in patients with pulmonary lesions in these stages. Scalenus fat pad biopsies and the Nickerson-Kveim intracutaneous reaction are valuable diagnostic aids when involved tissue is not easily accessible for biopsy verification. Cortisone and corticotrophin generally act favorably upon intrathoracic sarcoidosis although the benefits usually prove temporary. In severe pulmonary insufficiency occasionally seen in the early stage and more often in the late fibrotic stage of pulmonary involvement, hormones may be the only means to tide a patient over the crucial period. In early stage lesions consisting of mediastinal lymphadenopathy, treatment is unnecessary because spontaneous regression is the rule. It is still debatable whether patients with asymptomatic miliary nodulation or bronchopneumonic patches in the lung fields should receive hormonal therapy in an attempt to forestall widespread pulmonary fibrosis. In chronic pulmonary sarcoidosis the effects of the hormones are variable. Sometimes symptomatic relief is dramatic and sustained. More often the relief is partial and relapse occurs promptly after the hormones are withdrawn. Pulmonary fibrosis may proceed even while the patient continues to receive the drugs. Indications for the treatment of extrathoracic lesions of sarcoidosis are listed.