Anne Marie McLaughlin

Multidrug-resistant tuberculosis in Europe, 2010-2011.

Ongoing transmission, high levels of drug resistance, and poor diagnostic

Treatment Outcomes in Multidrug-Resistant Tuberculosis

Multidrug-resistant tuberculosis is a major global challenge. This report examines the definition of treatment success and its effect on determining cure.

Macrophage Migration Inhibitory Factor Enzymatic Activity, Lung Inflammation, and Cystic Fibrosis

RATIONALE Macrophage migration inhibitory factor (MIF) is a proinflammatory mediator with unique tautomerase enzymatic activity; the precise function has not been clearly defined. We previously demonstrated that individual patients with cystic fibrosis (CF) who are genetically predisposed to be high MIF producers develop accelerated end-organ injury. OBJECTIVES To characterize the effects of the MIF-CATT polymorphism in patients with CF ex vivo. To investigate the role of MIFs tautomerase activity in a murine model of Pseudomonas aeruginosa infection. METHODS MIF and tumor necrosis factor (TNF)-α protein levels were assessed in plasma or peripheral blood mononuclear cell (PBMC) supernatants by ELISA. A murine pulmonary model of chronic Pseudomonas infection was used in MIF wild-type mice (mif(+/+)) and in tautomerase-null, MIF gene knockin mice (mif (P1G/P1G)). MEASUREMENTS AND MAIN RESULTS MIF protein was measured in plasma and PBMCs from 5- and 6-CATT patients with CF; LPS-induced TNF-α production from PBMCs was also assessed. The effect of a specific inhibitor of MIF-tautomerase activity, ISO-1, was investigated in PBMCs. In the murine infection model, total weight loss, differential cell counts, bacterial load, and intraacinar airspace/tissue volume were measured. MIF and TNF-α levels were increased in 6-CATT compared with 5-CATT patients with CF. LPS-induced TNF-α production from PBMCs was attenuated in the presence of ISO-1. In a murine model of Pseudomonas infection, significantly less pulmonary inflammation and bacterial load was observed in mif(P1G/P1G) compared with mif(+/+) mice. CONCLUSIONS MIF-tautomerase activity may provide a novel therapeutic target in patients with chronic inflammatory diseases such as CF, particularly those patients who are genetically predisposed to produce increased levels of this cytokine.

Networked T Cell Death following Macrophage Infection by Mycobacterium tuberculosis

Background Depletion of T cells following infection by Mycobacterium tuberculosis (Mtb) impairs disease resolution, and interferes with clinical test performance that relies on cell-mediated immunity. A number of mechanisms contribute to this T cell suppression, such as activation-induced death and trafficking of T cells out of the peripheral circulation and into the diseased lungs. The extent to which Mtb infection of human macrophages affects T cell viability however, is not well characterised. Methodology/Principal Findings We found that lymphopenia (<1.5×109 cells/l) was prevalent among culture-positive tuberculosis patients, and lymphocyte counts significantly improved post-therapy. We previously reported that Mtb-infected human macrophages resulted in death of infected and uninfected bystander macrophages. In the current study, we sought to examine the influence of infected human alveolar macrophages on T cells. We infected primary human alveolar macrophages (the primary host cell for Mtb) or PMA-differentiated THP-1 cells with Mtb H37Ra, then prepared cell-free supernatants. The supernatants of Mtb-infected macrophages caused dose-dependent, caspase-dependent, T cell apoptosis. This toxic effect of infected macrophage secreted factors did not require TNF-α or Fas. The supernatant cytotoxic signal(s) were heat-labile and greater than 50 kDa in molecular size. Although ESAT-6 was toxic to T cells, other Mtb-secreted factors tested did not influence T cell viability; nor did macrophage-free Mtb bacilli or broth from Mtb cultures. Furthermore, supernatants from Mycobacterium bovis Bacille de Calmette et Guerin (BCG)- infected macrophages also elicited T cell death suggesting that ESAT-6 itself, although cytotoxic, was not the principal mediator of T cell death in our system. Conclusions Mtb-Infected macrophages secrete heat-labile factors that are toxic to T cells, and may contribute to the immunosuppression seen in tuberculosis as well as interfere with microbial eradication in the granuloma.

Treatment of lobar atelectasis with bronchoscopically administered recombinant human deoxyribonuclease in cystic fibrosis

Introduction:  Recombinant human deoxyribonuclease (rhDNase) reduces sputum viscosity and improves pulmonary function in cystic fibrosis (CF).

Diffuse panbronchiolitis: East meets West

To the Editors: In the paper by Poletti et al. 1 on diffuse panbronchiolitis, the authors describe the diagnostic criteria for this condition and emphasise its predominance in East Asia, having associations with human leukocyte antigen (HLA)-Bw54 and HLA-A11. We would like to highlight the difficulties and pitfalls in reaching this rare diagnosis in a European cohort of patients by describing the unusual presentation of this condition in a Caucasian female, the first case described in Ireland. A 48-yr-old female attended outpatient clinic for her fifth annual asthma review. She …

Clinical Management of Multidrug-Resistant Tuberculosis in 16 European Countries

&NA; Rationale: Multidrug‐resistant tuberculosis (MDR‐TB) is a major burden to public health in Europe. Reported treatment success rates are around 50% or less, and cure rates are even lower. Objectives: To document the management and treatment outcome in patients with MDR‐TB in Europe. Methods: We performed a prospective cohort study, analyzing management and treatment outcomes stratified by incidence of patients with MDR‐TB in Europe. Treatment outcomes were compared by World Health Organization and alternative simplified definitions by the Tuberculosis Network European Trialsgroup (TBNET). Measurements and Main Results: A total of 380 patients with MDR‐TB were recruited and followed up between 2010 and 2014 in 16 European countries. Patients in high‐incidence countries compared with low‐incidence countries were treated more frequently with standardized regimen (83.2% vs. 9.9%), had delayed treatment initiation (median, 111 vs. 28 d), developed more additional drug resistance (23% vs. 5.8%), and had increased mortality (9.4% vs. 1.9%). Only 20.1% of patients using pyrazinamide had proven susceptibility to the drug. Applying World Health Organization outcome definitions, frequency of cure (38.7% vs. 9.7%) was higher in high‐incidence countries. Simplified outcome definitions that include 1 year of follow‐up after the end of treatment showed similar frequency of relapse‐free cure in low‐ (58.3%), intermediate‐ (55.8%), and high‐incidence (57.1%) countries, but highest frequency of failure in high‐incidence countries (24.1% vs. 14.6%). Conclusions: Conventional standard MDR‐TB treatment regimens resulted in a higher frequency of failure compared with individualized treatments. Overall, cure from MDR‐TB is substantially more frequent than previously anticipated, and poorly reflected by World Health Organization outcome definitions.

Treatment outcomes of MDR-TB and HIV co-infection in Europe

The ongoing HIV epidemic and the increasing number of patients with drug-resistant tuberculosis (TB) are seriously hampering global TB-control activities, including those in the World Health Organization (WHO) Region Europe. Overall, the prevalence of HIV co-infection in TB patients increased from 3.4% in 2008 to 8% in 2014 in the region [1]. The prevalence of multidrug-resistant (MDR)-TB (drug resistance against at least isoniazid and rifampicin) reported for Europe – 15% in newly diagnosed TB patients and 48% in previously treated TB patients – is the highest in the world [1]. HIV-positive patients with MDR-TB demonstrate a very low proportion of relapse-free cure http://ow.ly/r9sk30bqLBP

Paradoxical reaction causing tuberculous arthritis and soft-tissue abscess in a non-HIV infected, lymphopenic, vitamin D deficient patient with disseminated tuberculosis. A coincidence or an immunological conundrum?

Joint Bone Spine - In Press.Proof corrected by the author Available online since mercredi 22 decembre 2010

Educational case: dysphagia caused by lymphadenopathy – what is the differential diagnosis?

A 46-year-old female lifelong non-smoker presented with a 3-month history of sub-sternal chest pain, dysphagia for solids, one stone weight loss and fatigue. Past medical history was remarkable only for endometriosis. The patient, an Indian national, had immigrated to Ireland approximately 40 years previously. Physical examination was unremarkable. Full blood count and blood biochemistry were normal; the erythrocyte sedimentation rate (ESR) was elevated at 83; pulmonary function testing and sputum were normal. Chest radiograph demonstrated a subtle area of increased sub-carinal density (arrow), but no pulmonary consolidation, cavitation or pleural effusion (Fig. 1). A barium swallow (Fig. 2) and computed tomography (CT) thorax (Fig. 3) were arranged.