Human antibodies targeting a Mycobacterium transporter protein mediate protection against tuberculosis.

Mycobacterium tuberculosis (Mtb) exposure drives antibody responses, but whether patients with active tuberculosis elicit protective antibodies, and against which antigens, is still unclear. Here we generate monoclonal antibodies from memory B cells of one patient to investigate the B cell responses during active infection. The antibodies, members of four distinct B cell clones, are directed against the Mtb phosphate transporter subunit PstS1. Antibodies p4-36 and p4-163 reduce Mycobacterium bovis-BCG and Mtb levels in an ex vivo human whole blood growth inhibition assay in an FcR-dependent manner; meanwhile, germline versions of p4-36 and p4-163 do not bind Mtb. Crystal structures of p4-36 and p4-170, complexed to PstS1, are determined at 2.1 Å and 2.4 Å resolution, respectively, to reveal two distinctive PstS1 epitopes. Lastly, a prophylactic p4-36 and p4-163 treatment in Mtb-infected Balb/c mice reduces bacterial lung burden by 50%. Our study shows that inhibitory anti-PstS1 B cell responses arise during active tuberculosis.

The effect of anti-tuberculosis treatment on levels of anti-phospholipid and anti-neutrophil cytoplasmatic antibodies in patients with active tuberculosis.

The aim of this study is to determine the prevalence and effect of anti-tuberculosis treatment on anti-phospholipid antibodies and anti-neutrophil cytoplasmatic antibodies (ANCA) in patients with active mycobacterial infections. Thirty-three consecutive patients (age 56 years, 26 males) with recently diagnosed active tuberculosis (TB) were enrolled. Data included clinical disease features, symptom duration, multidrug resistance and presence of HIV. Serum samples taken before and after TB treatment were frozen at -20 °C and tested for anti-cardiolipin IgG (aCL), anti-ß2 glycoprotein IgG (anti-ß2GPI), anti-prothrombin, anti-proteinase 3 (PR3), myeloperoxidase (MPO), bactericidal/permeability (BPI) and lactoferrin. Thirty percent of patients had higher than cut-off value for anti-ß2GPI, and 9 % had increased aCL. The levels of antibodies against ß2GPI and aCL normalized post-treatment. A substantial proportion of patients had high baseline anti-PR3, MPO, BPI and lactoferrin levels. Most anti-lactoferrin and anti-MPO levels decreased post-treatment, while anti-PR3 increased in most of the baseline-positive patients. Some patients had de novo anti-PR3 and MPO formation after 6-month treatment. Patients with active TB have significantly increased anti-ß2GPI and ANCA titers. While anti-ß2GPI titers normalize post-treatment, ANCA behave in a complex way. Anti-TB treatment may induce normalization of anti-lactoferrin and anti-MPO, and de novo anti-PR3 and MPO formation.

The role of interferon-gamma release assays in the diagnosis of active tuberculosis.

BACKGROUND: Interferon-gamma release tests are appealing alternatives to the tuberculin skin test (TST) for latent tuberculosis infection. OBJECTIVES: To determine the yield of the Quantiferon TB Gold test (QFT-G) in the diagnosis of active tuberculosis disease, with a focus on elderly patients, human immunodeficiency virus (HIV) co-infection, and extra-pulmonary tuberculosis (EPTB). METHODS: The QFT-G test was performed in 98 patients suspected of having active tuberculosis. The results were evaluated for each subgroup of patients and compared to the results of the TST. RESULTS: Active tuberculosis was diagnosed in 92 of the 98 patients. Sixteen (17.3%) were elderly patients (over age 70), 15 (16%) were co-infected with HIV, and 14 (15%) had EPTB. QFT-G was positive in 49 patients (53%) and indeterminate in 4. The results were not significantly affected by HIV coinfection (P = 0.17), old age (P = 0.4), orthe presence of EPTB (P = 0.4). There was a good correlation between the TST and the QFT-G test (P < 0.001). In EPTB and in the elderly, the QFT-G test appears to be better than the TST. CONCLUSIONS: The QFT-G test is suboptimal in its ability to detect active tuberculosis and should not be used to exclude it.

Pulmonary resection for multidrug-resistant tuberculosis: the Israeli experience (1998-2011).

BACKGROUND: Multidrug-resistant tuberculosis (MDR-1B) presents a difficult therapeutic problem due to the failure of medical treatment. Pulmonary resection is an important adjunctive therapy for selected patients with MDR-TB. OBJECTIVES: To assess the efficacy of pulmonary resection in the management of MDR-TB patients. METHODS: We retrospectively reviewed the charts of MDR-TB patients referred for major pulmonary resections as part of a treatment strategy. The operations were performed in the departments of thoracic surgery at Assaf Harofeh and Wolfson Medical Centers. For the period under study, 13 years (1998-2011), we analyzed patients' medical history, bacteriological, medical and surgical data, morbidity, mortality, and short-term and long-term outcome. RESULTS: We identified 19 pulmonary resections (8 pneumonectomies, 4 lobectomies, 1 segmentectomy, 6 wedge resections) from among 17 patients, mostly men, with a mean age of 32.9 years (range 18-61 years). Postoperative complications developed in six patients (35.3%) (broncho-pleural fistula in one, empyema in two, prolonged air leakin two, and acute renal failure in one). Only one patient (5.84%) died during the early postoperative period, three (17.6%) inthe late postoperative period, and one within 2 years after the resection. Of 12 survivors, 9 were cured, 2 are still under medical treatment, and 1 is lost from follow-up because of poor compliance. CONCLUSIONS: Pulmonary resection for MDR-TB patients is an effective adjunctive treatment with acceptable morbidity and mortality.

Active tuberculosis and human immunodeficiency virus co-infection in Israel: a retrospective study.

BACKGROUND: Tuberculosis is the most common opportunistic infection among people infected with human immunodeficiency virus and its first cause of morbidity and mortality. OBJECTIVES: To analyze the characteristics of a population in Israel with both tuberculosis disease and HIV infection in order to identify factors that contribute to outcome. METHODS: The study group comprised patients hospitalized in the Pulmonary and Tuberculosis Department of Shmuel Harofeh Hospital during the period January 2000 to December 2006. They were located by a computer search of the hospital registry and the pertinent data were collected. RESULTS: During the study period 1059 cases of active tuberculosis disease were hospitalized; 93 of them were co-infected with HIV. Most of them came from endemic countries (61.2% from Ethiopia and 20.4% from the former Soviet Union; none of them was born in Israel). Ten percent of the cases were multiple-drug resistant and 32% showed extrapulmonary involvement. The response rate to the treatment was good, and the median hospitalization time was 70 days. The mortality rate was 3.2%. CONCLUSIONS: Despite the high prevalence of pulmonary disease in our group, the short-term outcome was good and the Mycobacterium was highly sensitive to first-line drugs. These encouraging results can be attributed to the fact that tuberculosis patients in Israel are identified early and treated continuously and strictly, with early initiation of antiretroviral therapy, which together ensure that the development of drug resistance is low.

The anti-cyclic citrullinated peptide response in tuberculosis patients is not citrulline-dependent and sensitive to treatment.

INTRODUCTION: Patients with tuberculosis (TB) frequently produce anti-citrullinated protein antibodies (ACPA). The objective of this study is to characterize the citrulline-dependence of the ACPA reactivity in sera of patients with mycobacterium infections. METHODS: Serum samples of 134 patients with untreated mycobacterium infections (122 TB, 12 nontuberculous mycobacterium) were tested for antibodies against both the citrullinated (Cit) and the non-citrullinated (Arg) form of 2 cyclic synthetic peptides. In 33 patients, a follow-up sample was tested six months after starting anti-mycobacterial drugs. RESULTS: A substantial proportion of patients with mycobacterial infections demonstrated antibodies against 0401Cit, 0401Arg, 0722Cit and 0722Arg. Fourteen patients demonstrated anti-0401Cit, 83 anti-0401Arg, 22 anti-0722Cit and 61 anti-0722Arg, while none of these antibodies were detected in the 20 healthy controls. All the patients but one, who were anti-0401Cit and anti-0722Cit positive, demonstrated reactivity against the respective Arg peptide. In the subset of 33 patients with a follow-up test six months after starting treatment, the mean levels of antibodies to 0401Cit, 0401Arg, 0722Cit and 0722Arg significantly decreased after treatment. All the patients who were anti-0401Cit and anti-0722Cit positive turned negative after treatment. The presence of anti-0401Cit/Arg and anti-0722Cit/Arg was found to be significantly correlated with the presence of HIV. CONCLUSIONS: ACPA may be found in patients with TB. In most of the cases, the reactivity is citrulline independent. A positive cyclic citrullinated peptide (CCP) test in these patients should therefore be interpreted with care, and preferably followed by a control ELISA with a non-citrullinated antigen.

Peripheral arterial stiffness and endothelial dysfunction in idiopathic and scleroderma associated pulmonary arterial hypertension.

OBJECTIVE: Pulmonary endothelial dysfunction and increased reflection of pulmonary pressure waves have been reported in pulmonary arterial hypertension (PAH). However, the systemic vascular involvement is not fully understood. Our study focused on the systemic arterial stiffness and endothelial involvement in idiopathic and scleroderma associated PAH. METHODS: Peripheral arterial stiffness and endothelial function were evaluated in 38 patients with idiopathic (n = 28) and scleroderma associated (n = 10) PAH, and 21 control subjects (13 healthy; 8 with scleroderma and normal pulmonary pressure). All participants underwent clinical and cardiopulmonary evaluation. Arterial stiffness was measured through the fingertip tonometry derived augmentation index (AI), which is the boost increase in the late systolic pressure wave after the initial systolic shoulder. Endothelial function was measured by forearm blood flow dilatation response to brachial artery occlusion by a noninvasive plethysmograph (EndoPAT 2000), which is associated with nitric oxide-dependent vasodilatation and yields a peripheral arterial tone (PAT) ratio. RESULTS: Mean systolic pulmonary pressure was 70.5 +/- 21.6 mm Hg (idiopathic-PAH) and 69.3 +/- 20 mm Hg (scleroderma-PAH). AI was higher in scleroderma patients (10.5% +/- 19.6% in healthy controls, 9.0% +/- 21.5% in idiopathic-PAH, 20.1% +/- 19.1% in scleroderma-PAH, and 24.4% +/- 18.9% in scleroderma-controls; nonsignificant). PAT ratio was significantly lower (p < 0.05) than control values in idiopathic-PAH and scleroderma-PAH (PAT ratio: control 2.20 +/- 0.25; idiopathic 1.84 +/- 0.51; scleroderma 1.66 +/- 0.66). AI was not correlated to endothelial dysfunction. There were no differences between the 2 PAH patient groups in age, body mass index, New York Heart Association classification, or 6-min walk test. CONCLUSION: Our study shows a trend towards increased arterial stiffness in scleroderma (nonsignificant), and also peripheral endothelial dysfunction in idiopathic-PAH and in scleroderma-PAH. These findings suggest involvement of different vessels in scleroderma-PAH compared to idiopathic-PAH.

Combination therapy with prostacyclin and tadalafil for severe pulmonary arterial hypertension: a pilot study.

Despite the introduction of new drugs that have changed the course of pulmonary arterial hypertension (PAH), some patients are still refractory to treatment and deteriorate rapidly. Long-acting phosphodiesterase-5 inhibitors are a new class of drugs that are effective in PAH. This prospective study assessed the potential of combination therapy with prostacyclin and tadalafil for treatment of severe PAH. We report four cases of severe PAH that deteriorated despite prostacyclin therapy. Two patients had Eisenmenger syndrome, one had pulmonary hypertension associated with scleroderma and one had histiocytosis X. All were treated with tadalafil, 10-20 mg once daily, in addition to prostacyclin. After 3 months of treatment, all patients improved clinically, with an increase in mean 6MWD from 214 to 272 m. In three patients, the New York Heart Association functional class decreased from IV to III. Echocardiograms showed no significant changes in pulmonary arterial pressure. Although this study was limited by the small sample size, it suggests that tadalafil in combination with prostacyclin is an effective treatment for severe PAH. Tadalafil may be beneficial for the treatment of patients with advanced disease.

Peripheral endothelial dysfunction in patients with pulmonary arterial hypertension.

BACKGROUND: Pulmonary endothelium plays an important role in the mechanism of pulmonary arterial hypertension (PAH). However, there is only a few data regarding the systemic endothelium in this syndrome. This study focused on the systemic endothelial involvement in PAH. METHODS: Endothelial function was evaluated in 54 patients with idiopathic (n=28), scleroderma-associated (n=10), chronic thromboembolic (n=7), or Eisenmenger (n=9) PAH and 21 controls (13 healthy; eight scleroderma and normal pulmonary pressure). All underwent clinical evaluation, pulmonary assessment, echocardiography, and pulmonary cardiac stress test. Endothelial function was evaluated by measuring the forearm blood flow dilatation response to brachial arterial occlusion by a non-invasive plethysmograph, yielding a peripheral arterial tone (PAT) ratio. RESULTS: The PAT ratio was significantly lower (p<0.05) than healthy controls in all patients except the Eisenmenger group (control: 2.20+/-0.25; idiopathic 1.84+/-0.51; scleroderma 1.66+/-0.66; thromboembolic 1.89+/-0.32; Eisenmenger 2.17+/-0.62). The impaired hyperemic response significantly correlated with disease severity, as measured by NYHA classification (r=-0.210, p=0.035), pulmonary pressure (r=-0.228, p=0.035), 6 min walking distance (r=0.215, p=0.047), and oxygen desaturation on effort (r=0.207, p=0.038). Mean systolic pulmonary pressure among patients was 54-99 mmHg. CONCLUSION: A systemic component of endothelial dysfunction might be involved in idiopathic, scleroderma-associated and chronic thromboembolic PAH that is correlated with disease severity.

Successful lung transplantation for talcosis secondary to intravenous abuse of oral drug.

Talcosis due to intravenous injection of oral drugs can cause severe pulmonary disease with progressive dyspnea even when drug use is discontinued. We describe a 54-year-old woman with severe emphysema who underwent left lung transplantation. The patient had a remote history of intravenous injection of crushed methylphenidate (Ritalin) tablets. Chest computed tomography showed severe emphysematous changes, more prominent in the lower lobes. Microscopic examination of the extracted lung demonstrated multinucleated giant cells with birefringent crystals, compatible with talcosis. At follow-up, daily symptoms were completely alleviated and lung function was good. We recommend that lung transplantation be considered as a viable option in the treatment of talcosis.

Protective effect of immunosuppression on granulation tissue formation in metallic airway stents.

OBJECTIVES/HYPOTHESIS: The use of self-expanding metallic airway stents has been extended in recent years in inoperable patients with malignant and benign airway diseases. The risk of granulation tissue formation in the stent is a major concern. The objective of the present study was to determine whether immunosuppression modulates granulation tissue formation in airway stents, as seen in coronary stents. STUDY DESIGN: The study included 19 patients with benign airway obstructions and 11 recipients of lung transplants with anastomotic obstructions who were receiving immunosuppression therapy. METHODS: The degree of in-stent granulation tissue formation was evaluated (score range, 0-3) every 3 months for 2 years. RESULTS: Granulation tissue formation was significantly lower in the transplant recipients than in the nontransplant patients at 3 months (score 0.7 vs. 1.6, P = .031), 15 months (score 0 vs. 1.1, P = .026), and 18 months (score 0 vs. 1.8, P = .020). During the 2 years of follow-up, the transplant recipients underwent significantly fewer laser resections and brachytherapy treatments for in-stent granulation. CONCLUSIONS: The immunosuppression given to lung transplant recipients may have an inhibitory effect on granulation tissue formation in metallic airway stents. Further studies are needed to evaluate the effect of systemic therapy or coated stents with drugs such as sirolimus.

[Azithromycin as a novel treatment for bronchiolitis obliterans syndrome].

Bronchiolitis obliterans syndrome (BOS) is one of the main causes of mortality after lung and bone marrow transplantation. Up to 75% of lung transplantation patients develop BOS within 5 years, whereas after bone marrow transplantation 14% of the patients develop the disease with 65% mortality within 3 years. Patients demonstrate gradual decrease in pulmonary functions with no significant anatomic/imagine findings. Therapeutic trials with high dose systemic corticosteroids, immune suppression and immunomodulation did not show any significant success. However, macrolides and especially azithromycin have recently been reported as highly efficient for BOS. This review summarizes information on the disease focusing on the clinical experience with azithromycin as a treatment for BOS.

Association of elevated levels of vascular endothelial growth factor in obstructive sleep apnea syndrome with patient age rather than with obstructive sleep apnea syndrome severity.

BACKGROUND: Although certain studies report high levels of vascular endothelial growth factor (VEGF) in obstructive sleep apnea syndrome (OSAS), the effect of systemic hypoxia on circulating VEGF remains controversial. OBJECTIVES: To study the association of serum VEGF and OSAS in a large group of patients. METHODS: One hundred patients with OSAS (mean age 58.1+/-12.4 years, mean body mass index 30.6+/-5.4 kg/m2) were tested for serum VEGF levels, and the findings were correlated with the severity of OSAS, as determined by the apnea-hypopnea index (AHI) on the basis of polysomnography and background data. RESULTS: The mean AHI was 40.0+/-21.2 (range 10-106). Mean minimal oxygen saturation was 80.6+/-11.7% (range 43-98%) and mean time of oxygen saturation under 90% was 50.0+/-75.0 min (range 0-300 min). The mean VEGF level was 445.2+/-289.8 pg/ml in the study group (vs. 280 pg/ml reported in normal controls). The mean platelet count was 233.8+/-64.4 10(3)/ml and the mean VEGF/platelet ratio was 1.95+/-1.40 pg/10(6). There was no association of VEGF or VEGF/platelets with the severity of OSAS. However, both factors showed a significant correlation with patient age (r=0.224, p=0.01 and r=0.425, p=0.01, respectively). Age was the only parameter to significantly predict VEGF and VEGF/platelets on multivariate analysis (R2=0.713, p=0.001 and R2=0.844, p=0.001, respectively). CONCLUSION: The elevation of serum VEGF in OSAS is not associated with the severity of the disease, but it is associated with patient age. VEGF might be involved in the long-term adaptive mechanism in OSAS, and its age-dependent increase might partly explain the reduced mortality in elderly OSAS patients.

Right upper lobe 'window' in right main bronchus stenting.

Stent insertion for bronchial stenosis has become common practice in lung transplantation and advanced lung malignancy, and for external compression of the airways for other reasons. Right main bronchus stenting may require blocking the right upper lobe by the stent, placing the patient at risk of recurrent pneumonia and atelectasis. In this study, three patients after insertion of a metal stent to the right main bronchus are described. In all cases, the right upper lobe was covered by the stent, and a laser (Nd:YAG) procedure was used to open a 'window' in the stent toward the right upper lobe with a follow-up of 1 year. We conclude that stent insertion to the right main bronchus may be followed by a laser therapy to open a 'window' toward the right upper lobe.

Pulmonary arterial hypertension associated with autoimmune disease: a single medical center experience.

BACKGROUND: New drugs have significantly improved the prognosis and quality of life of patients with pulmonary arterial hypertension. However, PAH associated with autoimmune disease, particularly progressive sclerosis, remains a very serious problem. OBJECTIVES: To evaluate whether the course of the disease and survival is significantly different in patients with PAH related to autoimmune disease as compared to other patients with PAH and to determine the prognostic factors in these patients. METHODS: We retrospectively compared 24 patients with PAH associated with autoimmune disease to 42 patients with other causes of PAH. We focused on the clinical and hemodynamic parameters and on the outcome. RESULTS: The early mortality rate was slightly higher in patients with PAH associated with autoimmune disease (13% after the first year, 25% after the fifth year). The prognostic factor was a shorter distance on the 6 minute walking distance test (r = 0.2, P= 0.01). CONCLUSIONS: The early detection of PAH associated with autoimmune disease should encourage earlier and more aggressive treatment than in idiopathic PAH.

Development of malignancy following lung transplantation.

BACKGROUND: A substantial excess risk of certain malignancies has been demonstrated after organ transplantation. Immunosuppressive treatment to prevent allograft rejection is probably the main cause. METHODS: We reviewed retrospectively all medical records of the 121 patients that underwent lung and heart-lung transplantation from 1992 until December 2004. We compared our results to the International Society for Heart and Lung Transplantation (ISHLT) registry data and previous reports concerning lung transplantation. RESULTS: 102 of the 121 patients survived for 3 months to 12 years. Malignancies developed in 16 patients, as follows: lymphoproliferative disorder in 3, Kaposi's sarcoma in 3, other nonmelanoma skin cancers in 7, urinary bladder transitional cel carcinoma in 3, and colon cancer in 1. Patients with malignancy were older at transplantation than those without (mean +/- SD, 54.1+/-7.8 vs. 49.5+/-14.2 years; P=0.03). Fourteen had smoked in the past. Four died of bronchiolitis obliterans. In comparison with the ISHLT, we observed more skin cancer and transitional cell carcinoma (12.8% vs. 0.7% and 3.8% vs. 0.03%, respectively) and a similar frequency of posttransplant lymphoproliferative disease. CONCLUSIONS: We conclude that malignancy is a common complication after lung transplantation. In Israel, which is sunny most of the year, skin cancers and transitional cell carcinoma of bladder are more common. Modification of the immunosuppression late posttransplantation may reduce the risk of cancer. Patients should also be counseled to avoid sun exposure and ensure adequate hydration.

Two successful lung transplantations from a dialysis-dependent donor.

The shortage of organs for lung transplantation has led to the growing use of "marginal" donors. Although patients on hemodialysis are still excluded as lung transplant donors because of the possible effects of renal failure on the lungs, recent data suggest that they may be suitable in selected cases. This article describes the successful transplantation of two lungs from a single donor who had been receiving long-term hemodialysis treatment. In the absence of other causes of pulmonary diseases, such as smoking or lung infection, lungs from dialysis-dependent patients may be acceptable for lung transplantation.

Pregnancy outcome in patients with pulmonary arterial hypertension receiving prostacyclin therapy.

BACKGROUND: Pregnancy is contraindicated in cases of pulmonary hypertension, a highly morbid disease affecting young women of childbearing age. CASES: We describe the pregnancies of 3 patients with pulmonary arterial hypertension (idiopathic, Eisenmenger syndrome, and related to systemic lupus erythematosus). They received epoprostenol and low-molecular-weight heparin throughout pregnancy. The patient with Eisenmenger syndrome started epoprostenol in gestational week 16. Cesarean delivery under general anesthesia was performed at 28-33 weeks of gestation; early delivery was necessary in the patient with Eisenmenger syndrome because of fetal growth restriction. All deliveries were uneventful, and birth weights were 1,700, 1,500, and 795 g. There were no postpartum complications. CONCLUSION: Pregnancy in women with pulmonary hypertension should still be considered high risk for both mother and child, but stable patients on epoprostenol may successfully complete pregnancy.

Accuracy of virtual bronchoscopy for grading tracheobronchial stenosis: correlation with pulmonary function test and fiberoptic bronchoscopy.

STUDY OBJECTIVES: To compare the accuracy of virtual bronchoscopy (VB) with fiberoptic bronchoscopy (FOB) and pulmonary function testing (PFT) for the assessment of tracheal stenosis and bronchial anastomotic stenosis. DESIGN: Prospective case series. SETTING: Pulmonary institute of major tertiary university-affiliated center. PATIENTS: The study group included 10 lung transplant recipients and 13 patients with central airway stenosis. INTERVENTIONS: All patients underwent PFT, VB, and FOB. All cases were graded by each modality on a scale of 1 to 3, and the findings were compared between modalities. RESULTS: Mean +/- SD stenosis score was 2.0 +/- 0.79 for PFT, 1.62 +/- 0.73 for FOB, and 1.82 +/- 0.77 for VB. A statistically significant correlation was found between VB and FOB scores (p < 0.0001, r = 0.76) and between VB scores and PFT (p = 0.03, r = 0.45). There was no correlation between PFT and FOB. CONCLUSIONS: VB grading of tracheobronchial stenosis is well correlated with PFT. VB may be used to evaluate patients with known tracheobronchial stenosis after treatment and thereby reduce the frequency of repeated invasive FOB performed for that purpose. The correlation of VB with PFT may improve the reliability of this approach.