Hasib Ahmadzai

Exhaled breath condensate: a comprehensive update

Abstract Since the late 1990s, a surge in interest in the analysis of exhaled breath condensate (EBC) resulted in the American Thoracic Society and European Respiratory Society (ATS/ERS) organising a Task Force in 2001 to develop guidelines on EBC collection and measurement of biomarkers. This Task Force published their guidelines in 2005 based on literature and expert opinions at that time, and multiple shortcomings and knowledge deficits were also identified. The clinical application of EBC collection and its biomarkers are currently still limited by several of these knowledge gaps, hence further guidelines for standardisation are required to ensure external validity. Using related articles produced since the publication of the ATS/ERS Task Force report, this paper attempts to provide a comprehensive update to the original guideline and review the methodological shortcomings identified. This review can hopefully serve as a yardstick for future studies involving this emerging clinical tool.

Peripheral blood responses to specific antigens and CD28 in sarcoidosis.

BACKGROUND Potential antigens inducing sarcoid inflammation include mycobacterial and auto-antigens. Paradoxically, peripheral anergy to common recall antigens also occurs, possibly due to impaired dendritic cell or regulatory T-cell responses, or impaired T-cell co-stimulation. The purpose of this study was to compare peripheral blood responses of patients with sarcoidosis to candidate antigens, and examine CD28 T-cell co-stimulation. METHODS Peripheral blood mononuclear cell (PBMC) responses were examined from patients with sarcoidosis (n=16) and healthy control subjects (n=22) following PBMC stimulation with: anti-CD3/CD28 coated beads; Mycobacterium tuberculosis ESAT-6 and KatG peptides; vimentin and lysyl tRNA peptides; and common recall antigens, including cytomegalovirus (CMV) cell lysate as well as CMV, Epstein-Barr virus, influenza virus (CEF) peptides. RESULTS ESAT-6/KatG peptide stimulation induced greater numbers of IFN-γ producing T-cells, and elevated IL-2, IL-6 and TNF-α production in sarcoidosis compared to purified protein derivative (PPD)-negative healthy control subjects. PBMCs from patients with sarcoidosis showed reduced IFN-γ producing T-cells following stimulation with CMV lysate, CEF peptides and CD3/CD28 beads; and reduced IL-4 and TNF-α production following CD3/CD28 activation. CONCLUSIONS Patients with sarcoidosis exhibit greater PBMC responses to M. tuberculosis antigens compared to PPD-negative controls, but reduced T-cell responses to common recall antigens. One contributing mechanism may be impairment of T-cell CD28 co-stimulation.

The potential of the immunological markers of sarcoidosis in exhaled breath and peripheral blood as future diagnostic and monitoring techniques

Sarcoidosis is characterised by non-caseating granulomatous inflammation, with exaggerated immune responses at sites of disease and derangements of normal tissue architecture. The lungs are most commonly involved and progressive inflammation may result in pulmonary fibrosis. The immunopathogenesis and aetiology remain uncertain, which has made it difficult to identify a single sufficiently sensitive or specific diagnostic marker. Further investigation is needed to identify sensitive and specific markers of disease, such as in peripheral blood and exhaled breath condensate (EBC). Identification of disease markers may also be useful for investigating disease activity and predicting progression to fibrosis. This review explores the literature on the cytokine profiles of blood and bronchoalveolar lavage lymphocytes following ex vivo stimulation, as well as disease markers measured using the medium of EBC.

Fat embolism syndrome following percutaneous vertebroplasty: a case report

BACKGROUND CONTEXT Vertebroplasty is commonly performed for management of pain associated with vertebral compression fractures. There have been two previous reports of fatal fat embolism following vertebroplasty. Here we describe a case of fat embolism syndrome following this procedure, and also provide fluoroscopic video evidence consistent with this occurrence. PURPOSE The purpose of this study was to review the literature and report a case of fat embolism syndrome in a patient who underwent percutaneous vertebroplasty for compression fracture. STUDY DESIGN/SETTING The study design for this manuscript was of a clinical case report. METHODS A 68-year-old woman who developed sudden back pain with minimal trauma was found to have a T6 vertebral compression fracture on radiographs and bone scans. Percutaneous vertebroplasty of T5 and T6 was performed. RESULTS Fluoroscopic imaging during the procedure demonstrated compression and rarefaction of the fractured vertebra associated with changes in intrathoracic pressure. Immediately after the procedure, the patients back pain resolved and she was discharged home. Two days later, she developed increasing respiratory distress, confusion, and chest pain. A petechial rash on her upper arms also appeared. No evidence of bone cement leakage or pulmonary filling defects were seen on computed tomography-pulmonary angiography. Brain magnetic resonance imaging demonstrated hyperintensities in the periventricular and subcortical white matter on T2/fluid-attenuated inversion recovery sequences. A diagnosis of fat embolism syndrome was made, and the patient recovered with conservative management. CONCLUSIONS Percutaneous vertebroplasty is a relatively safe and simple procedure, reducing pain and improving functional limitations in patients with vertebral fractures. This case demonstrates an uncommon yet serious complication of fat embolism syndrome. Clinicians must be aware of this complication when explaining the procedure to patients and provide prompt supportive care when it does occur.

Biomarkers in sarcoidosis: a review

License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. Permissions beyond the scope of the License are administered by Dove Medical Press Limited. Information on how to request permission may be found at: http://www.dovepress.com/permissions.php Current Biomarker Findings 2014:4 93–106 Current Biomarker Findings Dovepress

Laboratory Investigations and Immunological Testing in Sarcoidosis

Sarcoidosis is a systemic granulomatous disease of unknown aetiology, which can affect virtually any organ and is thus characterised by a variable clinical presentation and course. The disease is generally considered to be a T helper-1 (TH1) type of reaction, although TH2 and TH17 features have also been identified. Approximately 90% of patients demonstrate disease involvement of the lungs and thoracic lymph nodes and although sarcoidosis is usually subacute and self-limiting, progressive inflammation can lead to pulmonary fibrosis and death. Despite these features, there is currently no definitive single laboratory investigation used to identify sarcoidosis, indicating the need for improved understanding of the immuno‐ pathogenesis and identification of disease-specific biomarkers. Currently, sarcoidosis is generally a diagnosis of exclusion that is best confirmed by clinical and radiological findings and tissue biopsies revealing non-caseating granulomas in the absence of known granuloma‐ genic agents. Laboratory testing is nonetheless beneficial in further supporting a diagnosis of sarcoidosis and assessing disease severity.

An unusual case of a pituitary fossa aspergilloma in an immunocompetent patient mimicking infiltrative tumour

Sellar aspergillosis is a rare infection commonly mistaken for a pituitary tumour. We present a rare case of pituitary fossa Aspergillus fumigatus mycetoma in an immunocompetent 90-year-old female, who presented with headaches. Magnetic resonance imaging scans demonstrated an enhancing pituitary fossa mass that appeared to infiltrate the sphenoid sinus, suggestive of an invasive tumour. Stereotactic trans-sphenoidal resection confirmed localized A. fumigatus infection. The abscess was debrided and the dura was left intact. Her headaches resolved post-operatively and she was treated with voriconazole. This indicates that aspergilloma should be considered as a differential for an unexplained pituitary lesion even in elderly immunocompetent patients.

Treatment of refractory neurosarcoidosis with TNF-inhibitors: what lies ahead?

We read with interest the case series on the treatment of refractory neurosarcoidosis with infliximab. We were interested to know whether the serum and cerebrospinal fluid angiotensin converting enzyme or other makers of sarcoidosis might have been ascertained (such as increased cerebrospinal fluid CD4/CD8 lymphocyte ratios, lysozyme and b2-microglobulin), as these can have a role in monitoring disease activity, and in supporting a diagnosis if a patient (e.g. Case 1) declines biopsy. Likewise, a gallium or positron-emission tomography scan may indicate accessible disease worthy of biopsy, for example, salivary glands or lymph nodes. Sarcoidosis refractory to glucocorticosteroids is an important and difficult area, and although there have not been any randomised controlled treatment trials for isolated neurosarcoidosis, there is now a large body of evidence from placebo-controlled studies that anti-TNF-a agents have a relatively modest effect in modulating this disease, which is disappointing given the logical choice of TNF antagonists in sarcoidosis. Nonetheless, individual trials of therapy may be worthwhile as in the refractory cases reported, if monitored carefully, and the therapy discontinued quickly if ineffective, particularly with the awareness that tuberculosis might be unmasked as being the true diagnosis, rather than sarcoidosis. We also note that Pereira et al. tested azathioprine in two of their patients although did not assess anti-malarials. Azathioprine, as well as chloroquine and hydroxychloroquine have also been reported as being useful in a few small case series of neurosarcoidosis, but no clinical trial data exist. Hopefully, better agents that target CD4+ type 1 helper T-cell (TH1) immunity and associated sarcoid inflammatory pathways will become available as the immunology of this fascinating disease becomes apparent.

Sarcoidosis: a state of the art review from the Thoracic Society of Australia and New Zealand.

Sarcoidosis is a systemic disease of unknown aetiology, characterised by non-caseating granulomatous inflammation. It most commonly manifests in the lungs and intrathoracic lymph nodes but can affect any organ. This summary of an educational resource provided by the Thoracic Society of Australia and New Zealand outlines the current understanding of sarcoidosis and highlights the need for further research. Our knowledge of the aetiology and immunopathogenesis of sarcoidosis remains incomplete. The enigma of sarcoidosis lies in its immunological paradox of type 1 T helper cell-dominated local inflammation co-existing with T regulatory-induced peripheral anergy. Although specific aetiological agents have not been identified, mounting evidence suggests that environmental and microbial antigens may trigger sarcoidosis. Genome-wide association studies have identified candidate genes conferring susceptibility and gene expression analyses have provided insights into cytokine dysregulation leading to inflammation. Sarcoidosis remains a diagnosis of exclusion based on histological evidence of non-caseating granulomas with compatible clinical and radiological findings. In recent years, endobronchial ultrasound-guided transbronchial needle aspiration of mediastinal lymph nodes has facilitated the diagnosis, and whole body positron emission tomography scanning has improved localisation of disease. No single biomarker is adequately sensitive and specific for detecting and monitoring disease activity. Most patients do not require treatment; when indicated, corticosteroids remain the initial standard of care, despite their adverse side effect profile. Other drugs with fewer side effects may be a better long term choice (eg, methotrexate, hydroxychloroquine, azathioprine, mycophenolate), while tumour necrosis factor-α inhibitors are a treatment option for patients with refractory disease.

Proinflammatory and Regulatory Cytokines in Sarcoidosis

Abstract Sarcoidosis is a multisystem granulomatous disease of undetermined etiology with heterogeneous clinical presentation. While in the majority of patients the disease is acute and self-limiting, other patients experience chronic disease and a minority develop life-threatening complications. Macrophages, Th1, and Th17 cells as well as regulatory T-cells all contribute to the pathogenesis of the disease via the elaboration of a complex network of effector and regulatory cytokines. These cytokines orchestrate all stages of the disease from the initiation and accumulation of granulomas, effector phase, and resolution or development of fibrosis. Currently, predicting the clinical progression of the disease is difficult. Improved understanding of role of proinflammatory and regulatory cytokines in sarcoidosis could result in the identification of novel therapeutic targets, or potential biomarkers which may help to guide clinical decisions.