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.

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.

Utility of positron emission tomography for the staging of patients with potentially operable esophageal carcinoma.

PURPOSE: A prospective study of preoperative tumor-node-metastasis staging of patients with esophageal cancer (EC) was designed to compare the accuracy of 18-F-fluoro-deoxy-D-glucose (FDG) positron emission tomography (PET) with conventional noninvasive modalities. PATIENTS AND METHODS: Seventy-four patients with carcinomas of the esophagus (n = 43) or gastroesophageal junction (n = 31) were studied. All patients underwent attenuation-corrected FDG-PET imaging, a spiral computed tomography (CT) scan, and an endoscopic ultrasound (EUS). RESULTS: FDG-PET demonstrated increased activity in the primary tumor in 70 of 74 patients (sensitivity: 95%). False-negative PET images were found in four patients with T1 lesions. Thirty-four patients (46%) had stage IV disease. FDG-PET had a higher accuracy for diagnosing stage IV disease compared with the combination of CT and EUS (82% v 64%, respectively; P: =.004). FDG-PET had additional diagnostic value in 16 (22%) of 74 patients by upstaging 11 (15%) and downstaging five (7%) patients. Thirty-nine (53%) of the 74 patients underwent a 2- or 3-field lymphadenectomy in conjunction with primary curative esophagectomy. In these patients, tumoral involvement was found in 21 local and 35 regional or distant lymph nodes (LN). For local LN, the sensitivity of FDG-PET was lower than EUS (33% v 81%, respectively; P: =.027), but the specificity may have been higher (89% v 67%, respectively; P: = not significant [NS]). For the assessment of regional and distant LN involvement, compared with the combined use of CT and EUS, FDG-PET had a higher specificity (90% v 98%, respectively; P: =. 025) and a similar sensitivity (46% v 43%, respectively; P: = NS). CONCLUSION: PET significantly improves the detection of stage IV disease in EC compared with the conventional staging modalities. PET improves diagnostic specificity for LN staging.

Virtual bronchoscopy: accuracy and usefulness--an overview.

Multidetector CT generated virtual bronchoscopy (VB) represents one of the most recent developments in three-dimensional (3D) visualization techniques which allows a 3D evaluation of the airways down to the sixth- to seventh-generation. In comparison with real bronchoscopy, VB has some advantages: it is a non-invasive procedure that can visualize areas inaccessible to the flexible bronchoscope. Virtual bronchoscopy is able to evaluate bronchial stenosis and obstruction caused by both endoluminal pathology (tumor, mucus, foreign bodies) and external compression (anatomical structures, tumor, lymph nodes), can be helpful in the preoperative planning of stent placement and can be used to evaluate surgical sutures after lung transplantations, lobectomy or pneumectomy. In children, in some indications, VB can replace fiber optical bronchoscopy (FB) when this technique is considered too invasive. Finally, VB can also be used to evaluate anatomical malformations and bronchial variants. Virtual bronchoscopy is accurate but its accuracy is not 100% because false-positives and false-negatives occur. Virtual bronchoscopy contributes to a better understanding of tracheo-bronchial pathology. Fiber optical bronchoscopy will, without doubt, remain the golden standard but it can be expected that in the near future, the technique of VB will find a place in the daily routine.

The impact of (18)F-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) lymph node staging on the radiation treatment volumes in patients with non-small cell lung cancer.

PURPOSE: (18)F-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) combined with computer tomography (PET-CT) is superior to CT alone in mediastinal lymph node (LN) staging in non-small cell lung cancer (NSCLC). We studied the potential impact of this non-invasive LN staging procedure on the radiation treatment plan of patients with NSCLC. PATIENTS AND METHODS: The imaging and surgical pathology data from 105 patients included in two previously published prospective LN staging protocols form the basis for the present analysis. For 73 of these patients, with positive LN's on CT and/or on PET, a theoretical study was performed in which for each patient the gross tumour volume (GTV) was defined based on CT and on PET-CT data. For each GTV, the completeness of tumour coverage was assessed, using the available surgical pathology data as gold standard. A more detailed analysis was done for the first ten consecutive patients in whom the PET-CT-GTV was smaller than the CT-GTV. Theoretical radiation treatment plans were constructed based on both CT-GTV and PET-CT-GTV. Dose-volume histograms for the planning target volume (PTV), for the total lung volume and the lung volume receiving more than 20 Gy (V(lung(20))), were calculated. RESULTS: Data from 988 assessed LN stations were available. In the subgroup of 73 patients with CT or PET positive LN's, tumour coverage improved from 75% when the CT-GTV was used to 89% with the PET-CT-GTV (P=0.005). In 45 patients (62%) the information obtained from PET would have led to a change of the treatment volumes. For the ten patients in the dosimetry study, the use of PET-CT to define the GTV, resulted in an average reduction of the PTV by 29+/-18% (+/-1 SD) (P=0.002) and of the V(lung(20)) of 27+/-18% (+/-1 SD) (P=0.001). CONCLUSION: In patients with NSCLC considered for curative radiation treatment, assessment of locoregional LN tumour extension by PET will improve tumour coverage, and in selected patients, will reduce the volume of normal tissues irradiated, and thus toxicity. This subgroup of patients could then become candidates for treatment intensification.

The utility of positron emission tomography for the diagnosis and staging of recurrent esophageal cancer.

OBJECTIVE: To study the utility of whole-body positron emission tomography with (18)F-fluoro-deoxy-D -glucose (FDG-PET) for the evaluation of recurrence after curative resection of cancer of the esophagus or gastroesophageal junction. METHODS: Forty-one patients with a clinical or radiologic suspicion of recurrent disease underwent conventional diagnostic work-up, including a spiral computed tomographic scan, an endoscopic ultrasound, and a dedicated whole-body FDG-PET. PET lesions were classified as equivocal or suspicious recurrence. The conventional diagnostic work-up and PET findings were correlated with pathology or with radiologic and clinical follow-up. Equivocal lesions were classified as positive. RESULTS: Forty recurrences were found in 33 patients. The lesions were perianastomotic (n = 9), regional (n = 12), and at distant sites (n = 19). For the diagnosis of a perianastomotic recurrence, the sensitivity, specificity, and accuracy of FDG-PET were 100%, 57%, and 74%, versus 100%, 93%, and 96% for conventional diagnostic work-up, respectively (P = not significant). False-positive PET lesions were found in patients with a progressive anastomotic stenosis requiring repetitive endoscopic dilatation. For the diagnosis of regional and distant recurrences, the sensitivity, specificity, and accuracy of PET were 94%, 82%, and 87%, versus 81% (P = not significant), 82% (P = not significant), and 81% (P =.0771) for conventional diagnostic work-up. All false-positive PET lesions (n = 4) had been reported as equivocal. On a patient base, PET provided additional information in 11 of 41 (27%) patients. A major impact on diagnosis was found in 5 patients with equivocal or negative findings on complete diagnostic work-up in whom PET provided a true-positive diagnosis. In 5 other patients the diagnosis was staged upward from localized to extended recurrent disease, and in 1 patient with an equivocal complete diagnostic work-up, PET correctly excluded malignancy. CONCLUSION: FDG-PET allows a highly sensitive diagnosis and accurate whole-body staging of symptomatic recurrent esophageal cancer. Further studies in asymptomatic patients are needed to assess the potential benefit on survival.

Antibiotic prophylaxis in clean and clean-contaminated ear surgery.

BACKGROUND: Ear surgery may be performed in the treatment of chronic otitis media, ossicular chain disorders, tympanic membrane perforations and otitis media with effusion. Postoperative infection in ear surgery may result in: Wound infections Infection of the middle ear or mastoid resulting in discharge from the ear canal Failure of the tympanic membrane to close Labyrinthitis due to infection in, or adjacent to, the inner ear These complications may be associated with discomfort and inconvenience for the patient, an increase in morbidity and an increase in the costs of medical care. OBJECTIVES: The objective of this review was to assess the effects of local and/or systemic antibiotics for preventing complications such as postoperative discharge, graft failure and labyrinthitis in patients undergoing clean or clean-contaminated ear surgery. SEARCH STRATEGY: We searched MEDLINE (searched January 1966 to December 2002), EMBASE (searched January 1980 to December 2002), the Science Citation Index, The Cochrane Central Register of Controlled Trials (CENTRAL) (Cochrane Library, Issue 4 2002); the Cochrane Acute Respiratory Infections Group and Cochrane Ear, Nose and Throat Group Specialised Registers and proceedings of scientific meetings. The date of the last search was December 2002. We also contacted investigators in the field (Govaerts, Antwerp). Bibliographies of identified articles were screened for further relevant trials. No language restriction was applied. SELECTION CRITERIA: Randomised or quasi-randomised trials involving: PARTICIPANTS: patients undergoing clean or clean-contaminated types of ear surgery. Skull base surgery was excluded. INTERVENTION: any regimen of local and/or systemic antibiotic prophylaxis administered at or around the time of surgery compared to placebo, no antibiotic, or an alternative intervention group. OUTCOME MEASURES: infection, discharge, graft failure, labyrinthitis, adverse effects of prophylaxis. DATA COLLECTION AND ANALYSIS: When possible, investigators were contacted for additional information on data and methodological issues. At least two reviewers independently extracted data and assessed trial quality. MAIN RESULTS: Eleven studies were included in the review. The methodological quality of the trials was fair to good. However, most studies presented insufficient detail on methodological data. Although definitions of outcome measures were heterogeneous, pooling of results was possible. There were no significant differences between antibiotic prophylaxis groups and control groups in terms of reduction of postoperative infections, graft failures, draining outer ear canals and adverse drug effects. REVIEWERS' CONCLUSIONS: There is no strong evidence that the large scale use of prophylactic of antibiotics in clean and clean-contaminated ear surgery is helpful in reducing postoperative complications such as wound infection, discharge from the outer ear canal, labyrinthitis and graft failure.

[Selective embolization of an aneurysm in a massive angiomyolipoma of the kidney]. / Selectieve embolisatie van een aneurysma in een massief angiomyolipoom van de nier.

Forty to 80% of patients with tuberous sclerosis exhibit renal angiomyolipomas which are often multiple and bilateral. Renal ultrasonography has a low sensitivity and a low specificity in the diagnosis of renal angiomyolipomas. Some patients have so many angiomyolipomas that ultrasonography indicates a confluence of angiomyolipomatous tissue throughout the kidney, in which case the size of a separate angiomyolipoma is difficult to estimate and the actual size may be underestimated. However it is an important tool in the follow-up of smaller lesions. With CT and magnetic resonance imaging, the diagnosis of these angiomyolipomas can always be confirmed due to the characteristic fat component. In addition, a better visualisation of the extension of the lesions can be obtained. Once the diagnosis of angiomyolipoma has been established a sonographic follow-up every 6 months is mandatory and feasible. Renal angiomyolipomas larger than 3.5 cm in diameter have a substantial risk for severe hemorrhage which should be treated by selective embolization.

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.

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.

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.

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.