Monocyte-driven atypical cytokine storm and aberrant neutrophil activation as key mediators of COVID-19 disease severity.

Epidemiological and clinical reports indicate that SARS-CoV-2 virulence hinges upon the triggering of an aberrant host immune response, more so than on direct virus-induced cellular damage. To elucidate the immunopathology underlying COVID-19 severity, we perform cytokine and multiplex immune profiling in COVID-19 patients. We show that hypercytokinemia in COVID-19 differs from the interferon-gamma-driven cytokine storm in macrophage activation syndrome, and is more pronounced in critical versus mild-moderate COVID-19. Systems modelling of cytokine levels paired with deep-immune profiling shows that classical monocytes drive this hyper-inflammatory phenotype and that a reduction in T-lymphocytes correlates with disease severity, with CD8+ cells being disproportionately affected. Antigen presenting machinery expression is also reduced in critical disease. Furthermore, we report that neutrophils contribute to disease severity and local tissue damage by amplification of hypercytokinemia and the formation of neutrophil extracellular traps. Together our findings suggest a myeloid-driven immunopathology, in which hyperactivated neutrophils and an ineffective adaptive immune system act as mediators of COVID-19 disease severity.

Comparison of measured and estimated maximum skin doses during CT fluoroscopy lung biopsies.

PURPOSE: To measure patient-specific maximum skin dose (MSD) associated with CT fluoroscopy (CTF) lung biopsies and to compare measured MSD with the MSD estimated from phantom measurements, as well as with the CTDIvol of patient examinations. METHODS: Data from 50 patients with lung lesions who underwent a CT fluoroscopy-guided biopsy were collected. The CT protocol consisted of a low-kilovoltage (80 kV) protocol used in combination with an algorithm for dose reduction to the radiology staff during the interventional procedure, HandCare (HC). MSD was assessed during each intervention using EBT2 gafchromic films positioned on patient skin. Lesion size, position, total fluoroscopy time, and patient-effective diameter were registered for each patient. Dose rates were also estimated at the surface of a normal-size anthropomorphic thorax phantom using a 10 cm pencil ionization chamber placed at every 30°, for a full rotation, with and without HC. Measured MSD was compared with MSD values estimated from the phantom measurements and with the cumulative CTDIvol of the procedure. RESULTS: The median measured MSD was 141 mGy (range 38-410 mGy) while the median cumulative CTDIvol was 72 mGy (range 24-262 mGy). The ratio between the MSD estimated from phantom measurements and the measured MSD was 0.87 (range 0.12-4.1) on average. In 72% of cases the estimated MSD underestimated the measured MSD, while in 28% of the cases it overestimated it. The same trend was observed for the ratio of cumulative CTDIvol and measured MSD. No trend was observed as a function of patient size. CONCLUSIONS: On average, estimated MSD from dose rate measurements on phantom as well as from CTDIvol of patient examinations underestimates the measured value of MSD. This can be attributed to deviations of the patient's body habitus from the standard phantom size and to patient positioning in the gantry during the procedure.

Invasive staging of the mediastinum.

Staging of patients with lung cancer provides accurate information on the extent of disease and guides the choice of treatment. Non-invasive imaging techniques are safe, however these imaging techniques have limited accuracy in detection of mediastinal lymph node metastases. The American College of Chest Physicians guidelines for lung cancer staging recommend that patients with abnormal lymph nodes on CT or PET, or centrally located tumors without mediastinal LNs, should undergo invasive staging. Mediastinal nodal sampling has traditionally been performed by cervical mediastinoscopy. However, with the development of endoscopic needle aspiration techniques such as endobronchial ultrasound (EBUS) to guide transbronchial needle aspiration (TBNA) and endoscopic ultrasound (EUS), the diagnostic algorithm for lung cancer is changing.

Effect of macrolide on lung function and computed tomography (CT) score in non-cystic fibrosis bronchiectasis.

BACKGROUND: The few studies addressing the effect of macrolides in non-cystic fibrosis bronchiectasis (NCFB) range from no decline to significant improvement. There are no data evaluating macrolides on CT score. OBJECTIVES: To retrospectively evaluate the effect of initiation of macrolides on spirometry and HRCT in a NCFB population. METHODS: We performed a word search in the electronic patient file data of the University Hospital of Leuven, Belgium, identifying all NCFB patients observed during a 41 month period and treated with macrolides. Records of all NCFB patients were manually reviewed, evaluating spirometry and CT scans, before and after/during macrolide treatment, treatment scheme, Pseudomonas status and other relevant data. CT scoring was done by using a modified version of the Brody score. RESULTS: Evaluation of 131 patients showed a mean FEV1 improvement of 185 ml (p<0.0001) or 7.7% (p<0.0001) and a mean FVC improvement by 234 ml (p<0.001) or 7.4% (p<0.001). Smoking history, gender, Pseudomonas colonization and baseline lung function did not affect improvement in lung function. Patients with NCFB due to an immunodeficiency showed a significant larger macrolide-associated improvement in FEV1% (p=0.0075) and FVC% (p=0.0063) than patients with NCFB due to other causes. An improvement was noted in CT subscores for bronchiectasis (p=0.0053), mucus plugging (p=0.0256), peribronchial thickening (p=0.0037), parenchyma (p=0.026) and total modified Brody score (p=0.001) after versus before macrolide therapy. CONCLUSION: Macrolides, as part of a multimodal and individualized therapy may significantly improve FVC, FEV1 and the modified Brody score in patients with NCFB, especially those with NCFB due to immunodeficiency.

Late recurrent ovarian carcinoma metastatic to the thoracic wall.

Ovarian cancer is the second most common gynaecologic malignancy. Ovarian carcinomas typically metastasize to multiple sites via exfoliation, lymphatic spread or direct invasion. We present a rare case of a very late recurrence of ovarian carcinoma into the thoracic wall, heralded by thoracic pain in a patient otherwise disease-free for 23 years. This unusual and late presentation of an ovarian cancer metastasis underscores the need for continued awareness and attention to new symptoms in patients with ovarian cancer who show prolonged disease-free intervals.

Staging of lung cancer. Do we need a diagnostic CT of the brain after an integrated PET/CT for the detection of brain metastases?

Brain CT has been recommended in staging of patients with lung cancer because of its usefulness in the detection of metastases. Purpose of this study is to examine if a diagnostic brain CT (CT,) can be obviated when an integrated PET/CT (PET/CT) is available. 87 consecutive patients underwent a diagnostic brain CT and a whole-body PET/CT within a period of 3 weeks to stage a known primary tumour. CT examinations were evaluated by two experienced neuroradiologists on the detection of brain lesions (benign and malignant). The results of PET/CT and CT reading were compared and both readings were compared with the clinical results. Statistical analysis was done by measuring sensitivity, specificity, PPV, NPV and accuracy. The relative accuracies were compared by a McNemar (exact) test for correlated proportions. Considering the CT, as standard of reference, sensitivity, specificity, PPV, NPV and accuracy for the brain CT of PET/CT (CT2) and PET/CT were respectively 83%, 96%, 77%, 97%, 94% and 69%, 98%, 90%, 95%, 94%. Considering the clinical diagnosis as standard of reference these figures were for CT1, CT2 and PET/CT respectively 80%, 100%, 100%, 96%, 96% and 66%, 95%, 77%, 93%, 90% and 66%, 97%, 83%, 93%, 91%. There was no statistical difference between CT1 and CT2. The comparison of the additional CT in PET/CT with a diagnostic CT of the brain did not yield a statistical difference in the detection of brain lesions despite the inferior quality of the CT component of PET/CT. A diagnostic brain CT can be obviated when a PET/CT is available.

Integrated PET/CT and cancer imaging.

Integrated Positron Emission Tomography/Computed Tomography (PET/CT) is an imaging technique that was introduced in clinical practice in 1998. PET/CT is the combination of two different examination techniques in one machine: Computed Tomography (CT) giving anatomic information and Positron Emission Tomography (PET) giving metabolic information. PET/CT has two major advantages: CT can be used for attenuation correction and PET/CT improves diagnostic accuracy when compared to CT and PET alone.The quality of PET/CT images depends on different parameters such as CT dose, patient respiration, and the use of intravenous (i.v.) and per oral (PO) contrast. A rapidly expanding amount of literature demonstrates the additional value of PET/CT in the diagnosis, staging, prognosis, treatment planning, assessment of treatment response and diagnosis of recurrence of many tumor types. CT increases the sensitivity of the PET/CT examination, but the most beneficial effect of having the CT data is the increase of the specificity of the PET data. PET data also helps to specify CT information.The utility of PET/CT for tumor staging, which is one of the major imaging study indication, seems to be very high, and therefore PET/CT may become the scanner of the future. Till this moment there are no many published studies about the cost-effectiveness of PET/CT. The integration of PET/CT in clinical practice will result in higher equipment running costs, but these costs are likely not to be prohibitive to the diffusion of this combined technology.

Follicular bronchiolitis: a rare cause of bronchiolitis obliterans syndrome after lung transplantation: a case report.

This case report is the first confirmed case of follicular bronchiolitis (FB), a rare bronchiolar disorder characterized by peribronchiolar lymphoid follicles, in a series of over 400 lung transplantations performed in our center. It is to our knowledge, the first publication describing FB after lung transplantation (LTx), presenting as chronic allograft dysfunction or bronchiolitis obliterans syndrome (BOS).

Integrated PET/CT in the staging of nonsmall cell lung cancer: technical aspects and clinical integration.

Lung cancer is a common disease and is a leading cause of death in many countries. The management of lung cancer is directed by an optimal staging of the tumour. Integrated positron emission tomography (PET)/computed tomography (CT) is an anatomo-metabolic imaging modality that has recently been introduced to clinical practice and combines two different techniques: CT, which provides very detailed anatomic information; and PET, which provides metabolic information. One of the advantages of PET/CT is the improved image interpretation. This improvement can result in the detection of lesions initially not seen on CT or PET, a more precise location of lesions, a better characterisation of the lesion as benign or malignant and a better differentiation between tumour and surrounding structures. Initial studies demonstrate better results for PET/CT in the staging of lung cancer in comparison with PET alone, CT alone or visual correlation of PET and CT. The purpose of the present article is to discuss technical aspects of integrated PET/CT and to attempt to outline how to introduce integrated PET/CT in clinical and daily practice.

A dichotomy in bronchiolitis obliterans syndrome after lung transplantation revealed by azithromycin therapy.

Bronchiolitis obliterans syndrome (BOS) is the most important cause of late mortality following lung transplantation, resulting in major morbidity and a huge burden on healthcare resources. Treatment options are limited, resulting in a mere stabilisation of the lung function decline. Recent introduction of the macrolide antibiotic azithromycin raised new hope after demonstrating lung function improvement in subsets of patients. The present study aimed to provide an overview of the clinical effects on azithromycin in the setting of BOS after lung transplantation, with special emphasis on the anti-inflammatory actions. Moreover, the authors proposed a new frame of thinking centred on a dichotomy in the pathogenesis and clinical phenotype of BOS. Subsets of BOS patients were identified who do or do not respond to azithromycin (regarding forced expiratory volume in one second (FEV(1)), bronchoalveolar lavage (BAL) neutrophilia/interleukin-8). These observations have shed new light on the current belief that BOS represents a homogenous clinical entity in which the neutrophil is the main culprit. Recent clinical observations, supported by research findings, have revealed a dichotomy in the clinical spectrum of BOS with neutrophilic (partially) reversible allograft dysfunction (responding to azithromycin) and fibroproliferative BOS (not responding to azithromycin). This concept is reinforced by unique data obtained in BOS patients, consisting of histology specimens, physical and radiological examination, FEV(1 )and BAL examination. The acceptance of this dichotomy can improve understanding of the heterogeneous pathological condition that constitutes bronchiolitis obliterans syndrome, thus encouraging a more accurate diagnosis and, ultimately, better tailored treatment for each bronchiolitis obliterans syndrome patient.

Radiologist experience and CT examination quality determine metastasis detection in patients with esophageal or gastric cardia cancer.

We aimed to separate the influence of radiologist experience from that of CT quality in the evaluation of CT examinations of patients with esophageal or gastric cardia cancer. Two radiologists from referral centers ('expert radiologists') and six radiologists from regional non-referral centers ('non-expert radiologists') performed 240 evaluations of 72 CT examinations of patients diagnosed with esophageal or gastric cardia cancer between 1994 and 2003. We used conditional logistic regression analysis to calculate odds ratios (OR) for the likelihood of a correct diagnosis. Expert radiologists made a correct diagnosis of the presence or absence of distant metastases according to the gold standard almost three times more frequently (OR 2.9; 95% CI 1.4-6.3) than non-expert radiologists. For the subgroup of CT examinations showing distant metastases, a statistically significant correlation (OR 3.5; 95% CI 1.4-9.1) was found between CT quality as judged by the radiologists and a correct diagnosis. Both radiologist experience and quality of the CT examination play a role in the detection of distant metastases in esophageal or gastric cardia cancer patients. Therefore, we suggest that staging procedures for esophageal and gastric cardia cancer should preferably be performed in centers with technically advanced equipment and experienced radiologists.

Integrated PET/CT in lung cancer imaging: history and technical aspects.

Integrated PET/CT is a new anatomo-metabolic imaging modality combining two different techniques: Computed Tomography (CT) that provides very detailed anatomic information and Positron Emission Tomography (PET) that provides metabolic information. Integrated PET/CT has several advantages. One of the advantages is the use of CT data for attenuation correction that is significantly faster compared to that in conventional PET systems. Due to the use of CT data for attenuation correction, artefacts can be generated on PET images related to the use of intravenous or oral CT contrast agents, CT beam-hardening artefacts due to metallic implants and motion artefacts (respiratory motion, physical bowel motion, cardiac motion). The purpose of this review is to discuss some technical considerations concerning the CT protocol that can be used for PET/CT in lung cancer imaging and to give a short overview of the initial results of staging of non-small cell lung cancer (NSCLC).

Detection of extrapulmonary lesions with integrated PET/CT in the staging of lung cancer.

The aim of the present study was to assess retrospectively the additional value of positron emission tomography (PET)/computed tomography (CT) in the detection of unexpected extrapulmonary lesions in the staging of patients with a malignant pulmonary lesion in comparison with CT and PET used alone. A total of 217 patients with a pathologically proven lung tumour underwent PET/CT. CT, PET and PET/CT were evaluated in the detection of extrapulmonary lesions. These abnormalities were compared with the final diagnosis obtained from the medical records and statistical analysis was carried out. In total, 108 lesions were clinically detected. PET/CT showed a sensitivity, specificity, positive and negative predictive values and accuracy of 100, 81, 71, 100 and 87%, respectively, for the detection of extrapulmonary lesions and 92, 98, 89, 98 and 97%, respectively, for the detection of malignant extrapulmonary lesions. PET/CT was significantly better than CT and PET used alone. Conventional staging work-up has a poor sensitivity in detecting second primary cancers or unexpected metastases. The detection of malignant extrapulmonary lesions is necessary for correct tumour staging. By combining both metabolic and anatomical information, positron emission tomography/computed tomography is able to depict more unexpected extrapulmonary lesions than computed tomography and positron emission tomography used alone, and positron emission tomography/computed tomography provides more additional information of malignancy or benignancy of lesions detected with one of the two imaging modalities alone.