Sarcoidosis and lymphoma: case series and literature review.

This is a case series and literature review of patients with various types of hematologic disorders and sarcoidosis. The patients were treated in the hematologic day care unit at Shaare Zedek medical center and at the hematology department of Chaim Sheba Medical Center hospital from 1990 until 2008. We report eight cases from two centers where both diseases were diagnosed at different time points. We have shown that there might be coincidence of two rare conditions and emphasize the importance of tissues sampling of lesions suspected to be a relapse of a former biopsy-proven disease, even in the presence of positive PET results.

Normal D-dimer levels in patients with latent tuberculosis infection.

Studies have demonstrated a link between acute pulmonary tuberculosis and a hypercoagulable state, but there are no data on the coagulation state of patients with latent tuberculosis infection (LTI). The present prospective observational study was designed to help fill this gap. The sample included 84 patients (high school students and adults) with suspected LTI referred for the purified protein derivative (PPD) test. Results were read according to the criteria of the American Thoracic Society. Blood samples were collected at admission and assayed for D-dimer, the marker of the coagulation state, with the quantitative Miniquant test. D-dimer values were correlated with the PPD status and clinical parameters. Fifty-seven patients tested positive for LTI and 27 tested negative. There was no significant difference in D-dimer level between these groups (341 +/- 106 and 360 +/- 60 microg/ml, respectively). No significant correlation was found between D-dimer level and PPD status, patient age or occupation (health care worker or not), or clinical indication for the tuberculin test. The normal D-dimer levels in this series suggest that low-level inflammations such as LTI do not lead to a hypercoagulable state.

Time course of bleomycin-induced lung fibrosis.

Intratracheal instillation (IT) of bleomycin is a widely used experimental model for lung fibrosis. In this study we describe the time-course of bleomycin-induced lung fibrosis in mice using computer-assisted morphometry. C57Bl/6J mice were treated with a single IT dose of bleomycin or control saline. Animals were killed 3, 6, 14 and 21 days post-IT. Lung injury was evaluated by analysis of bronchoalveolar lavage (BAL) fluid, hydroxyproline concentration in the lung, routine light microscopic examination resulting in a semiquantitative morphological index (SMI) of lung injury, and quantitative morphological measurements (fibrosis fraction and alveolar wall area fraction) aided by optimas image analysis software. Changes in BAL fluid attributed to bleomycin treatment include increased total cell count (days 14 and 21), and increased percentage of neutrophils (days 3 and 6) followed by a sustained increase in lymphocytes (days 6, 14 and 21). Hydroxyproline levels increased in bleomycin-treated mice on days 14 and 21. Median SMI grades were significantly elevated on days 3, 14 and 21. Computer-assisted morphometry demonstrated a 3-fold increase in fibrosis fraction and a 1.3-fold increase in wall area fraction in bleomycin-treated mice on day 14, with no further increase on day 21. These data also demonstrate that the most suitable time point for assessing lung fibrosis in this model is 14 days after IT instillation of bleomycin, based on the observation that at 14 days the animals developed extensive fibrosis, but had less variability in the fibrotic response and lower mortality than later at 21 days. Computer-assisted morphometry provides objective and quantitative measurements that are a useful tool for the evaluation of bleomycin-induced lung injury.

Elevation of ELISA d-dimer levels in patients with primary pulmonary hypertension.

BACKGROUND: Vasoconstriction, vascular wall remodeling and thrombosis are considered as possible etiologies of primary pulmonary hypertension (PPH). D-dimer, a degradation product of fibrin, has been increasingly used as a marker and prognostic factor in various diseases. OBJECTIVE: To assess elevated ELISA D-dimer levels as a marker of endogenous fibrinolysis in patients with PPH. PATIENTS AND METHODS: Comparison of ELISA D-dimer levels of 12 PPH patients (11 female, 1 male) aged 27-73 years (median 51 years) with those of sex- and age-matched healthy controls. RESULTS: Eleven patients had New York Heart Association (NYHA) class III or IV symptoms, and one patient had NYHA class II symptoms. All patients with PPH were treated with anticoagulants and vasodilators: 5 patients were treated with continuous intravenous prostacyclin, 4 patients with continuous UT-15 and 2 patients with intermittent intravenous iloprost. Mean ELISA D-dimer levels +/- SD were significantly higher in the PPH group than in the matched control group (473 +/- 109 vs. 182 +/- 103 ng/ml; mean difference: 291 +/- 79, 95% CI: 240-341, p < 0.0001). CONCLUSION: These results suggest the possible involvement of endogenous fibrinolysis in the pathophysiology of PPH.

All-trans-retinoic acid (ATRA) is of no benefit in bleomycin-induced lung injury.

All-trans-retinoic acid (ATRA) has anti-fibrotic and antiinflammatory properties, and may be useful as a therapeutic agent in lung fibrosis. To test this hypothesis we investigated the effect of ATRA on bleomycin-induced lung fibrosis in Sprague-Dawley rats. Treatment groups included: (1) a single intratracheal (i.t.) instillation of bleomycin and daily intraperitoneal (i.p.) injection of 0.5 mg/kg per day ATRA; (2) i.t. bleomycin and i.p. ATRA, 2 mg/kg per day, (3) i.t. bleomycin and i.p. diluent (cottonseed oil); (4) i.t. saline and i.p. ATRA, 0.5 mg/kg per day, (5) i.t. saline and i.p. ATRA, 2 mg/kg per day; and (6) i.t. saline and i.p. diluent. Animals were studied 14 days after i.t. instillation. Lung injury was evaluated by total and differential cell count in bronchoalveolar lavage fluid, by a semi-quantitative morphological index of lung injury, and by biochemical analysis of lung hydroxyproline content. Overt signs of lung injury were apparent in bleomycin-treated rats by all measures. These changes were not affected by treatment with ATRA at either dose. This study does not support the use of ATRA to prevent or ameliorate lung fibrosis.

Methacholine inhalation challenge: a shorter, cheaper and safe approach.

Increased nonspecific bronchial hyperresponsiveness to pharmacological agents such as histamine or methacholine (MCh) is a hallmark of asthma. The measurement of airway reactivity is quite sensitive but testing is tedious, and time and money consuming. The present aim was, therefore, to design the shortest possible, yet safe inhalation challenge protocol applicable for a lung function referral centre. All records of studies performed in our institution during 1996 were analyzed retrospectively with a baseline ratio (bl) of forced expiratory volume in one second/forced vital capacity (FEV1/FVC) > or = 0.7 (n=449). It was questioned what the initial dose should be, and whether some inhalation steps could have been skipped without losing pertinent information and/or causing an adverse response (a fall in FEV1 >40%). When unavailable, provocative dose causing a 20% fall in FEV1 (PD20) values were obtained by linear inter- or extrapolation of the existing data. The present study showed that three-fold concentration steps could have been employed with minimal change in outcome. Only 151449 patients (3.3%) would have experienced a severe response. Five subjects (of 169, 3.0%) with FEV1/FVCbl 0.7-0.8 reacted to inhalation up to 0.073 micromol. Four subjects (of 280, 1.4%) with FEV1/ FVCbl> or =0.8 reacted to inhalation up to 0.219 micromol. The authors suggest that: 1) an initial dose of 0.219 micromol (initial concentration= 0.21 mg.mL(-1)) may be used when the baseline ratio of forced expiratory volume in one second to forced vital capacity > or =0.8 and 0.073 micromol (initial concentration=0.07 mg.mL(-1)) when the baseline ratio is <0.8; 2) a tripling dose protocol is easier to perform, cheaper and 30.2%, faster, yet just as safe; and 3) other abbreviated protocols used in epidemiologic settings may not be applicable in a referral centre setting.

The effect of suramin on bleomycin-induced lung injury.

Since transforming growth factor beta (TGF-beta) is presumed to play a role in lung fibrosis, we evaluated the effect of suramin (Sur), a substance with an anti-TGF-beta effect, in vivo on bleomycin (Bleo)-induced pulmonary injury in mice and in vitro on human lung fibroblasts. Four groups of C57BL/6 mice each received one of four treatments: (1) intratracheal (i.t.) instillation of Bleo and intraperitoneal (i.p.) injections of Sur, every other day, starting one day before i.t. instillation of Bleo (Bleo-Sur); (2) i.t. Bleo and i.p. injections of saline (Bleo-Sal); (3) i.t. saline and i.p. Sur (Sal-Sur); and (4) i.t. and i.p. saline (Sal-Sal). Animals were sacrificed 14 days after i.t. treatment. Lung injury was evaluated by analysis of bronchoalveolar lavage (BAL) fluid, histologically by the semiquantitative morphological index, and biochemically by analysis of lung hydroxyproline content. In vitro, Sur did not affect TGF-beta induced increase of alpha1 (I) collagen mRNA in human lung fibroblasts. In vivo treatment of mice with Sur did not affect Bleo-induced lung injury. These results indicate that despite its potential anti TGF-beta and lymphocytotoxic effects, Sur is not a therapeutic candidate drug for rescue of lung fibrosis.

Lymphokines in bleomycin-induced lung injury in bleomycin-sensitive C57BL/6 and -resistant BALB/c mice.

To study the pattern of lymphokines in bleomycin-induced lung injury, T cells were isolated from lung interstitial tissue (LIL), peribronchial lymphatic tissue (PBLT), and bronchoalveolar lavage (BAL) fluid of bleomycin-"sensitive" C57Bl/6 and bleomycin-"resistant" BALB/c mice at 3, 6, and 14 days following intratracheal instillation of bleomycin or saline. After 48 hours in culture, conditioned media were collected and assayed with specific enzyme-linked immunosorbent assay (ELISA) for interferon (IFN)-gamma, interleukin (IL)-2, IL-4 and IL-5. In bleomycin-treated C57B1/6 mice, IFN-gamma production was increased up to 20-fold at 3 and 6 days in LIL, and at 3 days in PBLT lymphocytes. IL-4 production was slightly decreased in LIL and PBLT lymphocytes at 14 days. IL-2 and IL-5 were not changed by bleomycin. In BALB/c mice, IFN-gamma production was increased 5-fold at 14 days, and IL-2 production at 6 days, in LIL but not PBLT. IL-4 and IL-5 were not significantly changed. The increase in IFN-gamma may play a role in the pathogenesis of bleomycin-induced lung injury. Differences in the cytokine pattern between the strains of mice may contribute to the variable strain susceptibility in bleomycin-induced lung injury.

[Early detection of exacerbation of lung infections in patients with cystic fibrosis by means of daily spirometry]. / Früherkennung pulmonaler Infektexazerbationen bei Patienten mit zystischer Fibrose mittels täglicher Spirometrie.

UNLABELLED: The clinical course of cystic fibrosis is characterised by pulmonary involvement with mucus retention, chronic pulmonary infection and parenchymal inflammation. Recurrent infectious exacerbations are usually accompanied by a fall in lung volumes. This pilot study investigated whether exacerbations can be detected early by daily spirometry. Ten patients with cystic fibrosis (5 female; 5 male; mean age 24.9 years) performed daily spirometry using a portable transtelephonic spirometer (Spirophone). Infectious exacerbations were diagnosed on clinical grounds and treated without knowledge of the spirometry results. Data of 9 patients recorded over a period of 5-11 months were analysed. One patient was excluded due to non-compliance. A total of 20 infectious exacerbations occurred during the observation period. A fall of at least 20% in one or more of the following parameters was observed in 90% (18/20) of exacerbations: FVC, FEV1, PEF, and FEF25/75. A daily drop in lung volumes of 0.7% to 1.2% was recorded beginning at a median of 33 (20 to 120) days before infectious exacerbations were diagnosed. There was a 2-3% daily improvement in spirometric data under treatment with antibiotics. CONCLUSION: Daily spirometry allows early recognition of pulmonary infectious exacerbations in patients with cystic fibrosis. Daily spirometry may be used as an indicator for early antibiotic treatment.

A comparison of a new transtelephonic portable spirometer with a laboratory spirometer.

The Spirophone is a new, portable transtelephonic spirometer which records the slow and the forced expiratory vital capacity tests. Data can be transmitted via the telephone to a remote receiving centre, where a volume-time curve and the flow-volume curve are displayed on screen in real time. The aim of this study was to compare the newly developed transtelephonic spirometer, with a laboratory spirometer according to the American Thoracic Society (ATS) testing guidelines. Spirometry indices (slow vital capacity (SVC), forced vital capacity (FVC), forced expiratory volume in one second (FEV1), peak expiratory flow (PEF), forced expiratory flow at 25, 50 and 75% of FVC (FEF25, FEF50, and FEF75, respectively)) were measured from the SVC and the FVC tests in 45 subjects (30 patients, 15 healthy volunteers) according to the ATS standards. The data obtained with the laboratory system were compared to those from the Spirophone. The Spirophone measurements of SVC, FVC, FEV1, PEF, FEF25, FEF50 and FEF75 correlated closely (r=0.91-0.98) to those from the laboratory system, whereas FEF25, FEF50, and FEF75 were significantly higher with the Spirophone. It is concluded that the Spirophone is comparable to the standard spirometry for home monitoring of slow vital capacity, forced vital capacity, forced expiratory volume in one second and peak expiratory flow. The validity of the manoeuvre can be assessed on screen in real time.

Proinflammatory cytokine levels in patients with lung cancer and carcinomatous pleurisy.

Increased levels of interleukin-6 (IL-6) and interleukin-8 (IL-8) have been reported in various diseases, including lung cancer. The role of the soluble form of the IL-6 receptor (sIL-6R) remains to be explored. We therefore measured IL-6, IL-8 and sIL-6R in effusion fluid and blood serum of 10 lung cancer patients with carcinomatous pleurisy (5 men, 5 women, age 64.3 +/- 4.4 years) by enzyme-linked immunosorbent assays. Serum levels of healthy individuals served as control. Concentrations of sIL-6R were much higher in serum compared to pleural effusion fluids of tumor patients (25,698 +/- 1,993 vs. 9,438 +/- 1,407 pg/ml: p < 0.0001). In contrast, IL-6 and IL-8 were found at high concentrations in carcinomatous pleural effusions in comparison to serum (IL-6: 964 +/- 176 vs. 10.2 +/- 1.3 pg/ml, p < 0.0001; IL-8: 319 +/- 85 vs. 9.6 +/- 9.6 pg/ml, p < 0.0001). The serum concentrations of IL-6 were not significantly increased in lung cancer patients (10.2 +/- 1.3 pg/ml) in comparison to controls (7.3 +/- 1.0 pg/ml). IL-8 was detected in the serum of only 1 patient and in low levels in the serum of controls (8.0 +/- 1.5 pg/ml; all values are mean +/- SEM). We conclude from this study that decreased levels of sIL-6R, but increased levels of IL-6 and IL-8, are found in pleural effusion fluid of patients with lung cancer and carcinomatous pleurisy. The low sIL-6R levels in the presence of high IL-6 levels in pleural effusions and the high sIL-6R levels in the presence of low IL-6 levels in serum may suggest a downregulation of sIL-6R expression of sIL-6R shedding in the presence of excessive amounts of IL-6.

Compartmentalization of pro-inflammatory cytokines in tuberculous pleurisy.

Increased levels of interleukin-6 (IL-6) and IL-8 are found in various immunologically mediated inflammatory disorders. Concentrations of IL-6, IL-8 and the soluble form of the IL-6 receptor (sIL-6R) were determined in serum and effusion fluid of 25 patients with tuberculous pleurisy utilizing enzyme linked immunosorbent assays (EIA). Serum IL-6 levels were only slightly increased in patients with tuberculous pleurisy in comparison to controls (11.1 +/- 2.1 vs 7.3 +/- 1.0 pg ml-1). IL-8 could not be detected in the serum of tuberculosis patients, but it was detected in the serum of healthy controls (8.0 +/- 1.5 pg ml-1). In comparison to serum, IL-6 and IL-8 were found in high concentrations in pleural effusions (IL-6: 932 +/- 70 vs 11.1 +/- 2.1 pg ml-1, P < 0.0001; IL-8: 450 +/- 85 vs 0 +/- 0 pg ml-1). In contrast, sIL-6R concentrations were much higher in serum compared to pleural effusion levels [30,477 +/- 1905 vs 9881 +/- 1177 pg ml-1, P < 0.0001 (mean +/- SEM)]. The authors conclude that elevated levels of IL-6 and IL-8 in pleural effusions are compartmentalized at the site of active disease. The low levels of sIL-6R in the presence of high levels of IL-6 in pleural effusions, and the high levels of sIL-6R in the presence of low levels of IL-6 in serum suggest that the expression or shedding of sIL-6R may be downregulated in the presence of excessive amounts of IL-6.

[Endoscopic contamination with Mycobacterium tuberculosis]. / Endoskopische Kontamination mit Mycobacterium tuberculosis.

A 60-year-old woman who had been investigated and treated unsuccessfully for chronic cough was referred for a bronchoscopy. The cultures of bronchial aspirates were positive for Mycobacterium tuberculosis. The radiological and endobronchial findings were typical of chronic bronchitis, but in the light of the positive cultures endobronchial tuberculosis was diagnosed and the patient was started on a standard 3-drug regimen. She developed a classical hypersensitivity reaction to isoniazid. Later the diagnosis had to be revised when molecular typing demonstrated contamination.