Limitations of airway dimension measurement on images obtained using multi-detector row computed tomography.

OBJECTIVES: (a) To assess the effects of computed tomography (CT) scanners, scanning conditions, airway size, and phantom composition on airway dimension measurement and (b) to investigate the limitations of accurate quantitative assessment of small airways using CT images. METHODS: An airway phantom, which was constructed using various types of material and with various tube sizes, was scanned using four CT scanner types under different conditions to calculate airway dimensions, luminal area (Ai), and the wall area percentage (WA%). To investigate the limitations of accurate airway dimension measurement, we then developed a second airway phantom with a thinner tube wall, and compared the clinical CT images of healthy subjects with the phantom images scanned using the same CT scanner. The study using clinical CT images was approved by the local ethics committee, and written informed consent was obtained from all subjects. Data were statistically analyzed using one-way ANOVA. RESULTS: Errors noted in airway dimension measurement were greater in the tube of small inner radius made of material with a high CT density and on images reconstructed by body algorithm (p<0.001), and there was some variation in error among CT scanners under different fields of view. Airway wall thickness had the maximum effect on the accuracy of measurements with all CT scanners under all scanning conditions, and the magnitude of errors for WA% and Ai varied depending on wall thickness when airways of <1.0-mm wall thickness were measured. CONCLUSIONS: The parameters of airway dimensions measured were affected by airway size, reconstruction algorithm, composition of the airway phantom, and CT scanner types. In dimension measurement of small airways with wall thickness of <1.0 mm, the accuracy of measurement according to quantitative CT parameters can decrease as the walls become thinner.

[Waldenström macroglobulinemia complicated with chylothorax].

An 81-year-old male had been diagnosed with Waldenström macroglobulinemia (WM) eight years previously and had thus been administered appropriate treatment. Left chylothorax later developed at 3 years and 8 months after the initial diagnosis. He was hospitalized with severe anemia, general fatigue, and appetite loss one year prior to this presentation and died due to a severe fungal infection. Autopsy revealed the presence of 1,300 ml chylothorax and infiltration of lymphoplasmacytic lymphoma (LPL) cells throughout his entire body. LPL cells were found to have invaded the excitation conducting system in the heart. In an evaluation of a resected lung tissue specimen of pneumothorax, subpleural infiltrated lymphoid cells were observed to show immunohistochemical positivity for IgM and bcl-2. Although these lymphoid cells were initially considered to be non-neoplastic lymphocytes, they were later determined to be LPL cells, which thus induced dilatation and proliferation of the lymph vessels. Chylothorax complications in patients with WM are rare events and only six such cases have so far been reported. The present case is considered to be an instructive one in which autopsy suggested the invasion of LPL cells to be involved in the development of arrhythmia, pneumothorax, and chylothorax before death.

Significance of pulmonary arterial pressure and diffusion capacity of the lung as prognosticator in patients with idiopathic pulmonary fibrosis.

STUDY OBJECTIVES: To evaluate the long-term clinical course of patients with idiopathic pulmonary fibrosis (IPF) complicated with pulmonary arterial hypertension. DESIGN: Prospective analysis of consecutive IPF patients undergoing initial workup with right-heart catheterization (RHC) and pulmonary function testing (PFT). Pulmonary arterial pressure (PAP) and diffusion capacity of the lung for carbon monoxide (Dlco) were focused on. SETTING: University hospital. PATIENTS: Seventy-eight patients with IPF (67 men, 11 women; diagnosis by pathology, n = 59; clinical diagnosis, n = 19) had been followed up after initial workup for a maximum of 14 years. MEASUREMENTS AND RESULTS: RHC data on 61 patients and PFT data on 52 patients were available. Five-year survival rates were 62.2% in the normal-PAP group (mean PAP < 17 mm Hg, n = 37) and 16.7% in the high-PAP group (mean PAP > 17 mm Hg, n = 24) [p < 0.001]; 70.4% in the preserved-Dlco group (percentage of predicted > 40%, n = 27) and 20.0% in the low-Dlco group (percentage of predicted < 40%, n = 25) [p < 0.001]; and 82.6% in group 1 (normal PAP and preserved Dlco, n = 23) and 15.6% in group 2 (high PAP, low Dlco, or both, n = 32) [p < 0.0001]. The relative risks of mortality within 5 years after RHC were 2.20 (95% confidence interval [CI], 1.40 to 3.45) in the high-PAP group, 2.70 (95% CI, 1.46 to 4.99) in the low-Dlco group, and 4.85 (95% CI, 1.97 to 11.97) in group 2. CONCLUSION: Dlco was a critical factor for evaluating disease status and prognosis, and PAP status provided feasible information in the initial workup of IPF patients.

Cell profiles of bronchoalveolar lavage fluid as prognosticators of idiopathic pulmonary fibrosis/usual interstitial pneumonia among Japanese Patients.

BACKGROUND: The role of bronchoalveolar lavage fluid (BALF) cell profiles in predicting the clinical outcome of idiopathic pulmonary fibrosis (IPF)/usual interstitial pneumonia (UIP) is still under discussion. OBJECTIVE: To determine whether BALF cell profiles affect the survival of patients with UIP diagnosed by surgical lung biopsy/autopsy at the early stage of IPF. METHODS: This hospital-based retrospective cohort study used 81 Japanese patients with histologically proven IPF/UIP who underwent BAL examination. The BALF samples were obtained from non-current smokers: NCS (n = 41) and current smokers: CS (n = 40). The Kaplan-Meier and Cox's proportional hazard methods were used to estimate the survival and evaluate the risk ratio for death in the two groups. To detect the multicollinearity, a stepwise regression was employed. RESULTS: A slight increase in the absolute numbers of BALF neutrophils tended to relate to a decrease in the relative risk for death in NCS patients and CS patients in the univariate analysis. In stepwise regression, the increase in percent vital capacity and the increase in the BALF CD4/CD8 ratio in NCS was detected as a favorable predictor, while increased BALF cells affected the results due to chronic smoking in CS. CONCLUSIONS: Based on the study bias of the biopsy-proven IPF/UIP patients at stable stages, an independent variable indicating a favorable outcome was an increased BALF CD4/CD8 ratio in NCS patients, while it was difficult to identify definite prognosticators in CS patients.

Patient characteristics and clinical features of Japanese sarcoidosis patients with low bronchoalveolar lavage CD4/CD8 ratios.

BACKGROUND: Previous studies have shown that there is an association between low BALF (bronchoalveolar lavage fluid) CD4/CD8 ratio and lower remission rates in sarcoidosis patients. AIM: To investigate the patient characteristics and clinical features of Japanese sarcoidosis patients with low BALF CD4/CD8 ratios. METHODS: 322 Japanese sarcoidosis patients were retrospectively analyzed, and 3 groups were selected according to BALF CD4/CD8 ratios as follows: patients with the BALF CD4/CD8 ratio in the lowest 5 percentile (Group 1: 0.43-1.41), median 5 percentile (Group II: 4.68-5.47), and top 5 percentile (Group III: 12.6-60.1). Each group consisted of 16 patients (5% of 322 patients). The patient characteristics, clinical features, and the short-term prognosis for at least 2 years (average 116 months) were compared among the groups. Multivariate analysis was performed for 322 patients to investigate the determinants of BALF CD4/CD8 ratios. RESULTS: The number of BALF CD8+ cells were greater in Group I than in the other two groups. In Group I, there were higher incidences of younger age, male gender, and lower number of extrathoracic lesions compared with Group III. Multivariate analysis showed that younger age and male gender were independently associated with low BALF CD4/CD8 ratios. The frequency of treatment with corticosteroid and progression to pulmonary fibrosis tended to be higher in Group I. CONCLUSIONS: Low BALF CD4/CD8 ratios were due to increased number of BALF CD8+ cells. Younger age and male gender were independently associated with low BALF CD4/CD8 ratios in sarcoidosis patients.

Polymorphisms of B7 (CD80 and CD86) genes do not affect disease susceptibility to sarcoidosis.

BACKGROUND: B7 proteins (CD80, CD86) are costimulatory molecules expressed on antigen-presenting cells and are essential factors for T cell activation. OBJECTIVES: The aim of this study is to investigate the relationship of B7 gene polymorphisms either to disease susceptibility or to cell profile of bronchoalveolar lavage (BAL) fluid in Japanese sarcoidosis patients. METHODS: Gene polymorphisms located in CD80 promoter, CD80 exon 3 and exon 8 of CD86 were examined in 146 Japanese sarcoidosis patients and 157 healthy controls using single-strand conformation polymorphism and direct sequencing. The distribution of genotypes was compared between the two groups. BAL fluid cell profiles were compared for the various genotypes of the different polymorphisms for the 62 patients who underwent BAL. RESULTS: There were no significant differences in the distribution of genotypes or allele frequencies for all polymorphisms between sarcoidosis and controls. There were no significant differences in BAL fluid cell profiles among the different genotype groups of the various polymorphisms studied. CONCLUSIONS: There was no relationship between the B7 gene polymorphisms studied and disease susceptibility or BAL fluid cell profiles in Japanese sarcoidosis patients.

Multiple bone fractures found in a young sarcoidosis patient with long stable disease.

A 22-year-old Japanese man was found to have bilateral hilar lymphadenopathy (BHL), and was diagnosed with sarcoidosis in 1995. He was followed without treatment until 2002, when a bone fracture due to osseous sarcoidosis was found in his left thumb. Despite systemic treatment with corticosteroid and methotrexate, a new bone lesion developed in his right foot and his right middle finger was fractured. The patient also suffered multiple organ involvements including brain and muscle lesions. This is the first report of a sarcoidosis patient who presented with BHL, and developed bone fractures after a long stable period of more than 5 years.

Diabetes insipidus from neurosarcoidosis: long-term follow-up for more than eight years.

Four patients with sarcoidosis presented as hypothalamic-hypophyseal syndrome including diabetes insipidus (DI) were followed up for more than 8 years from the onset of clinical manifestation. The mean age was 26 years, male : female ratio was 3 : 1 and the mean disease duration of 10 years. All patients had hypogonadism, hyperprolactinemia. Pituitary enlargement with thickening of the pituitary stalk were detected by magnetic resonance imaging (MRI) with gadolinium enhancement and attenuation in the intensity of the posterior lobe of the pituitary was detected without enhancement. Corticosteroid therapy resulted in the initial improvement of symptoms and gradual decrease in the tumor size but failed to cure polyuria due to DI. The use of desmopressin was necessary for a long period. None of these patients died from DI or central neurosarcoidosis.

Cytotoxic T-lymphocyte antigen-4 (CTLA-4) exon 1 polymorphism affects lymphocyte profiles in bronchoalveolar lavage of patients with sarcoidosis.

BACKGROUND: Sarcoidosis is a systemic disease characterized by T-cell activation and subsequent granuloma formation at the site of involvement. Genetic susceptibility is a key factor in the pathogenesis of this disease, and genes involved in T-cell regulation are potential candidates. Cytotoxic T-lymphocyte antigen-4 (CTLA-4) is a negative regulator of T-cell activation expressed on activated T-cells. The G allele of the CTLA-4 exon 1 polymorphism has previously been described to be associated with disease susceptibility in several autoimmune diseases. We investigated the relationship of CTLA-4 to disease susceptibility and cell profiles in bronchoalveolar lavage (BAL) in Japanese sarcoidosis patients. METHODS: Japanese sarcoidosis patients (n = 135) and controls (n = 97) were typed for an A/G bi-allelic polymorphism in exon 1 of CTLA-4 using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), and the distribution of genotypes was compared between both groups. Sixty-seven patients underwent BAL, and cell profiles in BAL fluid were compared between patients with G/G genotype and those with A/A genotype. RESULTS: No significant differences in the distribution of genotype and allele frequencies were found between sarcoidosis (GG: 46%, AG: 39%, AA: 15%) and controls (GG: 42%, AG: 49%, AA: 8%). Patients with G/G genotype had significantly increased lymphocyte ratios, lymphocyte counts, and CD4(+) cell counts in BAL fluid compared with patients with A/A genotype (p < 0.05). CONCLUSIONS: CTLA-4 exonl polymorphism might affect BAL fluid lymphocyte profiles in Japanese sarcoidosis patients.

Significance of lung shrinkage on CXR as a prognostic factor in patients with idiopathic pulmonary fibrosis.

OBJECTIVE: The aim of this study was to determine whether the presence of lung shrinkage on CXR can predict diminished survival in patients with idiopathic pulmonary fibrosis (IPF)/usual interstitial pneumonia (UIP). METHODOLOGY: In a hospital-based cohort study 68 subjects diagnosed with IPF/UIP by surgical lung biopsy or at autopsy were observed for a mean of 7.6 years. The radiographic scores from Cherniack's method, pulmonary function tests, arterial blood gas, and haematological data were obtained at initial presentation. Longitudinal radiographic changes over a mean interval of 2.7 years were measured. Survival analysis was performed using Kaplan-Meier and Cox's proportional hazards regression analysis. RESULTS: At some point during the observation period 36 (53%) of 68 patients did not exhibit lung shrinkage and 32 (47%) of 68 patients showed lung shrinkage. Patients with lung shrinkage were more likely to have a diminished survival than those with lung preservation; median survival was 4.4 vs 7.8 years, respectively. Lung shrinkage during the observation period (hazard ratio, 3.89; 95% CI = 1.68-9.01; P= 0.001) was associated with lower rates of survival. CONCLUSION: In patients with IPF/UIP, lung shrinkage on CXR during the observation period was a poor prognostic factor.

Sarcoidosis complicated with IgA nephropathy.

Though IgA nephropathy (IgAN) and sarcoidosis have been reported simultaneously in patients occasionally, it remains controversial whether there is any association between the two. In this report we describe our experience with one definite and two subclinical cases of IgAN diagnosed during the clinical course of sarcoidosis. Our findings suggest a possible association between these disorders, and a higher incidence of subclinical IgAN among sarcoidosis patients than among the general population. We also discuss the common immunological background shared by these two diseases.

Cyclophosphamide-induced late-onset lung disease.

We report the case of a 58-year-old woman who was considered to have died of cyclophosphamide (CPA)-induced late-onset lung disease. She underwent a right-sided mastectomy due to breast cancer at the age of 50 followed by daily administration of 50 mg CPA and 20 mg tamoxifen for 2 years. A refractory cough and dyspnea began at the age of 56. Chest radiographs revealed diffuse infiltrates and pleural thickening. Her vital capacity was markedly reduced. Corticosteroid therapy was ineffective. The disease rapidly progressed with occasional episodes of pneumothoraces to her death. Postmortem examination revealed pulmonary fibrosis with marked elastosis.

Sarcoidosis with bilateral epididymal and testicular lesions.

We report a case of genital sarcoidosis that presented characteristic features on MRI. A 25-year-old man sarcoidosis patient with ocular and lung lesions presented a painful mass in the left scrotum together with systemic symptoms of fever, appetite loss, headache, and stomach-ache during the tapering of steroids. The patient was hypercalcemic, and this was thought to be the cause of his systemic symptoms. MRI showed multiple nodules of bilateral testes and enlargement of bilateral epididymis; the patient was diagnosed with testicular and epididymal lesions of sarcoidosis. An increased steroid dosage improved his hypercalcemia and genital lesions.

Serial evaluation of high-resolution computed tomography findings in patients with idiopathic pulmonary fibrosis in usual interstitial pneumonia.

BACKGROUND: The development of well-matured fibrosis in usual interstitial pneumonia (UIP) is strongly associated with an unfavorable outcome of patients with idiopathic pulmonary fibrosis (IPF). However, differences in the rates of development are likely to result in variable clinical courses in IPF patients. OBJECTIVE: We tried to evaluate the progression of honeycombing and ground-glass opacity on CT using a scoring system, and to examine those serial changes in the clinical course of disease. METHODS: A hospital-based, retrospective cohort study. Twenty-three patients with IPF diagnosed as UIP by surgical lung biopsy were analyzed during the initial examination by scoring the presence of honeycombing (HC: range, 0-24) and ground-glass opacity (GG: range, 0-24) on CT scan. We also compared the serial changes observed in the CT scores (interval: 2-42 months, 2-6 examinations). RESULTS: (1) The serial change in the HC score in treated patients (n = 10) was similar to that in untreated patients (n = 16); (2) the HC score at the time of the initial examination and the rate of HC progression were both higher in the non-surviving patients (HC 12.3 +/- 3.7, mean +/- SD; deltaHC 4.2 +/- 1.3 per year) than in the surviving patients (HC 5.8 +/- 2.7; deltaHC 1.2 +/- 0.7 per year) (p < 0.05); (3) the GG score did not correlate with the HC score at any of the examinations; (4) the HC score was higher in the lower lung field than in the upper and middle lung fields. CONCLUSIONS: Scoring of the honeycombing and its serial changes using the high-resolution computed tomography scoring method was useful for predicting the prognosis in patients with IPF/UIP. Corticosteroid treatment did not prevent the progression of HC.

Serum concentrations of ionized calcium reflect renal function in patients with sarcoidosis.

BACKGROUND AND AIM OF THE WORK: Decrease in renal function was investigated in relation to altered metabolism of calcium in patients with sarcoidosis. METHODS: Fifty consecutive patients with pulmonary sarcoidosis (23 men and 27 women, 47 +/- 15 years as mean +/- SD) were studied on a daily diet consisting of 500 mg of calcium and 1000 mg of phosphorus. Renal functions were evaluated with Z scores of creatinine clearance (Ccr). RESULTS: Decreased renal function (Ccr Z score < -1) was detected in 13 out of 50 sarcoidosis patients (26.0%). In seven patients (14.0%) Ccr Z scores were less than -2; relative risk (RR) and 95% confidence interval (95% CI) were 13.9 and 2.97 to 64.7, respectively. Ccr Z score correlated most significantly with serum concentration of ionized calcium (sCa2+) (r = -0.574, 95% CI, -0.735 to -0.352, p < 0.0001). A stepwise regression analysis adjusting for observation time, serum concentration of calcium and 1,25-Dihydroxyvitamin D, urinary excretion of calcium, and urinary calcium crystals showed that sCa2+, together with angiotensin-converting enzyme activity in serum, was the most contributory variable to decrease in renal function in sarcoidosis patients (R2 = 0.391, p < 0.0001). A cutoff value of sCa2, 1.30 mmol/L obtained with a discriminant analysis showed 69.2% of sensitivity and 89.2% of specificity for decreased renal function. CONCLUSIONS: We reported increased prevalence of decreased renal function among sarcoidosis patients. sCa2+ was a significant index that reflected the alteration of renal function.

Open-label compassionate use one year-treatment with pirfenidone to patients with chronic pulmonary fibrosis.

OBJECTIVE: We attempted to evaluate the feasibility (therapeutic efficacy, tolerance, and clinical courses after treatment) of pirfenidone, an anti-fibrotic drug for patients with chronic pulmonary fibroses such as idiopathic pulmonary fibrosis (IPF). METHODS: Open-label one-year treatment for compassionate-use. PATIENTS OR MATERIALS: Oral pirfenidone (40 mg/kg body weight) was administered to 8 patients with advanced IPF and 2 with interstitial pneumonia associated with diffuse systemic sclerosis. The plasma concentration of the drug was serially followed. Radiographic scores, pulmonary functions, and arterial blood oxygen pressure were compared at three time points: at one-year before treatment, at the time of entry, and at one-year after entry. RESULTS: While pirfenidone did not show a definite therapeutic effect on overall survival (2 years after entry). During one-year treatment, there was no significant deterioration in terms of chest radiographic scores and arterial oxygen pressure, and the drug was well tolerated with minimal adverse effects within the ranges observed in this study, plasma pirfenidone concentrations did not seem to relate to the appearance of adverse effects or differences in therapeutic effects. CONCLUSION: The feasibility of Pirfenidone as a therapeutic drug was confirmed for patients with advanced pulmonary fibrosis.