Diagnosis of cystic lung diseases: a position statement from the UK Cystic Lung Disease Rare Disease Collaborative Network.

BACKGROUND: Rare cystic lung diseases are increasingly recognised due the wider application of CT scanning making cystic lung disease management a growing part of respiratory care. Cystic lung diseases tend to have extrapulmonary features that can both be diagnostic but also require surveillance and treatment in their own right. As some of these diseases now have specific treatments, making a precise diagnosis is crucial. While Langerhans cell histiocytosis, Birt-Hogg-Dubé syndrome, lymphoid interstitial pneumonia and lymphangioleiomyomatosis are becoming relatively well-known diseases to respiratory physicians, a targeted and thorough workup improves diagnostic accuracy and may suggest other ultrarare diseases such as light chain deposition disease, cystic pulmonary amyloidosis, low-grade metastatic neoplasms or infections. In many cases, diagnostic information is overlooked leaving uncertainty over the disease course and treatments. AIMS: This position statement from the Rare Disease Collaborative Network for cystic lung diseases will review how clinical, radiological and physiological features can be used to differentiate between these diseases. NARRATIVE: We highlight that in many cases a multidisciplinary diagnosis can be made without the need for lung biopsy and discuss where tissue sampling is necessary when non-invasive methods leave diagnostic doubt. We suggest an initial workup focusing on points in the history which identify key disease features, underlying systemic and familial diseases and a clinical examination to search for connective tissue disease and features of genetic causes of lung cysts. All patients should have a CT of the thorax and abdomen to characterise the pattern and burden of lung cysts and extrapulmonary features and also spirometry, gas transfer and a 6 min walk test. Discussion with a rare cystic lung disease centre is suggested before a surgical biopsy is undertaken. CONCLUSIONS: We suggest that this focused workup should be performed in all people with multiple lung cysts and would streamline referral pathways, help guide early treatment, management decisions, improve patient experience and reduce overall care costs. It could also potentially catalyse a national research database to describe these less well-understood and unidentified diseases, categorise disease phenotypes and outcomes, potentially leading to better prognostic data and generating a stronger platform to understand specific disease biology.

Idiopathic chronic productive cough and response to open-label macrolide therapy: An observational study.

BACKGROUND AND OBJECTIVE: Adult patients with chronic productive cough of unknown cause are commonly seen in respiratory clinics. We have previously described a subgroup of these patients who have a short-lived response to standard antibiotic treatment but a prolonged response to 3 months of low-dose azithromycin therapy. METHODS: This observational study describes the physiological, radiological and pathological features of this patient cohort along with their response to a 12-week open-label trial of 250 mg azithromycin thrice weekly. RESULTS: A total of 30 subjects with a mean age of 57 were recruited. The majority demonstrated airway dilatation on high-resolution computed tomography (HRCT) scan without evidence of established bronchiectasis (n = 21) and non-specific chronic inflammatory changes on bronchial biopsy (n = 15/17). Twenty-nine subjects completed 3 months of azithromycin with a significant improvement in median Leicester Cough Questionnaire (LCQ) score (-6.3 points, P < 0.00001), reduction in median 24-h sputum volume (-5.8 mL, P = 0.0003) and improvement in sputum colour (P = 0.003). Patients responsive to azithromycin (n = 22) demonstrated neutrophilic or paucigranulocytic airway inflammation, whereas five subjects with eosinophilic airways inflammation did not respond symptomatically to azithromycin. CONCLUSION: We describe a cohort of patients with chronic productive cough not adequately described by existing disease labels whose symptoms responded well to low-dose azithromycin. Many of the features are similar to the paediatric condition protracted bacterial bronchitis.

Presence of a prothrombotic state in people with idiopathic pulmonary fibrosis: a population-based case-control study.

BACKGROUND: Laboratory studies suggest that the clotting cascade is activated in fibrotic lungs. Since humans vary in their tendency to clot due to a variety of inherited or acquired defects, we investigated whether a prothrombotic state increases the chance of developing idiopathic pulmonary fibrosis (IPF) and/or worsens the prognosis of IPF. METHODS: We recruited 211 incident cases of IPF and 256 age- and sex-matched general population controls and collected data on medical history, medication, smoking habit, blood samples as well as lung function and high-resolution CT scans done as part of routine clinical care. A prothrombotic state was defined as the presence of at least one inherited or acquired clotting defect or marker of fibrinolytic dysfunction. We used logistic regression to quantify the association between a prothrombotic state and IPF adjusted for age, sex, smoking habit and highly sensitive C reactive protein. Cox regression was used to determine the influence of a prothrombotic state on survival. RESULTS: Cases were more than four times more likely than controls to have a prothrombotic state (OR 4.78, 95% CI 2.93 to 7.80; p<0.0001). Cases with a prothrombotic state were also likely to have more severe disease (forced vital capacity <70% predicted) at presentation (OR 10.79, 95% CI 2.43 to 47.91) and had a threefold increased risk of death (HR 3.26, 95% CI 1.09 to 9.75). CONCLUSIONS: People with IPF are more likely to have a prothrombotic state than general population controls and the presence of a prothrombotic state has an adverse impact on survival.

Clinical utility of diagnostic guidelines and putative biomarkers in lymphangioleiomyomatosis.

BACKGROUND: Lymphangioleiomyomatosis is a rare disease occurring almost exclusively in women. Diagnosis often requires surgical biopsy and the clinical course varies between patients with no predictors of progression. We evaluated recent diagnostic guidelines, clinical features and serum biomarkers as diagnostic and prognostic tools. METHODS: Serum vascular endothelial growth factor-D (VEGF-D), angiotensin converting enzyme (ACE), matrix metalloproteinases (MMP) -2 and -9, clinical phenotype, thoracic and abdominal computerised tomography, lung function and quality of life were examined in a cohort of 58 patients. 32 healthy female controls had serum biomarkers measured. RESULTS: Serum VEGF-D, ACE and total MMP-2 levels were elevated in patients. VEGF-D was the strongest discriminator between patients and controls (median = 1174 vs. 332 pg/ml p < 0.0001 with an area under the receiver operating characteristic curve of 0.967, 95% CI 0.93-1.01). Application of European Respiratory Society criteria allowed a definite diagnosis without biopsy in 69%. Adding VEGF-D measurement to ERS criteria further reduced the need for biopsy by 10%. VEGF-D was associated with lymphatic involvement (p = 0.017) but not the presence of angiomyolipomas. CONCLUSIONS: Combining ERS criteria and serum VEGF-D reduces the need for lung biopsy in LAM. VEGF-D was associated with lymphatic disease but not lung function.

Evolution of coronary artery calcification in patients with chronic kidney disease Stages 3 and 4, with and without diabetes.

BACKGROUND: The purpose of this study was to report the evolution of coronary artery calcification (CAC) in subjects with chronic kidney disease Stages 3 and 4 comparing those with and without diabetes. We previously reported prevalence in the same population. METHODS: CAC was measured using multi-slice computer tomography. We prospectively followed up 103 patients for 2 years, 49 with diabetes and 54 without diabetes. Demographic, routine biochemistry, calcification inhibitors and bone mineral density data were collected and analysed. Evolution of CAC was defined as those with a difference of ≥ 2.5 U between baseline and final square root CAC scores. RESULTS: There were more progressors in the group with diabetes, 24 compared to 12 in the group without diabetes (P= 0.004). When diabetes was present, CAC progressed equally in men and women. Risk factors for evolution of CAC included age, baseline CAC score and serum phosphate levels. Baseline CAC score, phosphate and body mass index were independent predictors for the increase of CAC score during the study period. Severity of CAC was greater in the diabetes group (median CAC score at baseline in the group with diabetes 154 increased to 258 2 years later, P < 0.001). CONCLUSIONS: Evolution of CAC is greater in older patients and those with diabetes, where the gender advantage of being female is lost. Serum phosphate level, despite being within the normal range and virtually no use of phosphate binders, was also a risk factor. Further studies are required to determine the levels of serum phosphate required to minimize cardiovascular risk.

Left Atrial Enlargement on Non-Gated CT Is Associated with Large Vessel Occlusion in Acute Ischaemic Stroke.

BACKGROUND: Recent reports have suggested that atrial fibrillation (AF) is more prevalent in the large vessel occlusion (LVO) subgroup of acute ischaemic stroke patients. Given the association between left atrial enlargement (LAE) and AF, we sought to evaluate the feasibility of assessing LAE on non-gated CT and its association with LVO in the hyperacute stroke setting. METHODS: We analysed our prospectively collected database that included all stroke patients referred for consideration of endovascular treatment between April 14, 2020, and May 21, 2020. During this period, a CT chest was included in our regional stroke protocol to aid triage of patients suspected for COVID-19 from which cardiac measurements were obtained. Patients were dichotomized into LVO and no-LVO groups, and LA measurements were trichotomized into normal, borderline, and enlarged. Univariate analyses were performed between groups. RESULTS: Of the included 38 patients, 21 were categorized as LVO and 17 as no LVO. There was a statistically significant association between LAE and LVO (p = 0.028). No significant difference was demonstrated between groups for the baseline AF and other clinical characteristics, except for baseline NIHSS (p = 0.0005). There was excellent inter- and intra-rater reliability (ICC = 0.969) for LA measurements. CONCLUSION: Our study provides preliminary data to suggest LAE is more prevalent in the LVO stroke subgroup at presentation and can be reliably assessed on non-gated CT in the hyperacute setting. These findings have potential implications for stratifying secondary management and may prompt a more rigorous pursuit of occult AF or other cardiac causes of stroke.

Reporting radiographers and their role in thoracic CT service improvement: managing the pulmonary nodule.

OBJECTIVES: The use of cross-sectional imaging in clinical medicine has been a major step forward in the management of many conditions but with that comes the increasing demand on resources and the detection of other potentially significant findings. This, in the context of a shortage of skilled radiologists, means that new ways of working are important. In thoracic CT, pulmonary nodules are a significant challenge because they are so common. Poor and inconsistent management can both cause harm to patients and waste resources so it is important that the latest guidelines are followed. The latter mandate the use of semi-automated volumetry that allows more precise management but is time-consuming. METHODS: Reporting radiographers were iteratively trained in the use of semi-automated volumetry for pulmonary nodules by experienced thoracic radiologists. Once trained in this specific aspect, radiographers completed reporting of pulmonary nodules, checked by radiologists. RESULTS: Radiographer reporting reduced radiologist time in reporting nodules and measuring their volume. Most of the volumetry was completed prior to the multidisciplinary meeting. This facilitated an increase in the number of patients discussed in 60 min from 15 to 22. Radiographers failed to detect few nodules, although a second read by radiologists is required in any case for other aspects of the reporting. CONCLUSION: Reporting radiographers, working with radiologists in a supportive setting, can deliver the radiology in a lung nodule pathway, reducing the time commitment from radiologists and the pulmonary nodule multidisciplinary team members, whilst using this as an opportunity to conduct research.

Stridor in Crohn disease and the use of infliximab.

Extraintestinal manifestations of Crohn disease are well recognized. Upper airway obstruction is a very rare but important complication that usually responds to high-dose steroids. We report a case of Crohn disease initially presenting with respiratory symptoms and subsequently resulting in acute severe upper airway obstruction, which failed to respond to steroids but dramatically responded to the first documented use of infliximab in this context.

How successful is lung-preserving radical surgery in the mesothelioma and radical surgery-trial environment? A case-controlled analysis.

OBJECTIVE: To determine whether there is a survival benefit from open-lung-preserving surgery (radical decortication) for malignant mesothelioma, when compared with the non-radical approach in the mesothelioma and radical surgery (MARS)-trial era. METHODS: We compared outcomes between 13 patients with malignant mesothelioma, who underwent radical decortication (group RD, n = 13) with 13 case-matched patients, who had palliative surgery (group non-radical decortication (NRD), n = 13) over a period of 2 years from June 2006 onwards. Patients were matched for age, sex, histology, computed tomography (CT) stage, haematological indices, body mass index (BMI) and adjuvant chemotherapy. We compared perioperative and postoperative courses and long-term survival. RESULTS: Histology was 25% biphasic and 75% epithelioid in both the groups. There was no significant difference in the proportions receiving adjuvant chemotherapy (54%, p = 1.00), but more patients in the RD group received adjuvant radiotherapy (46% vs 15%, p = 0.20). Median survival was higher for all cell types in the RD group (16.9 months vs 6.8 months, p = 0.001). CONCLUSION: Radical open-lung-sparing surgery may confer a survival advantage to patients with malignant mesothelioma, who are fit to undergo radical decortication followed by chemotherapy and radiotherapy. Trials of radical surgery versus no surgery should include lung-sparing operations.

Sirolimus therapy for angiomyolipoma in tuberous sclerosis and sporadic lymphangioleiomyomatosis: a phase 2 trial.

PURPOSE: Renal angiomyolipomas are a frequent manifestation of tuberous sclerosis and sporadic lymphangioleiomyomatosis (LAM). These disorders are associated with mutations of TSC1 or TSC2 that lead to overactivation of mTOR complex 1 (mTORC1), suggesting an opportunity for targeted therapy by using mTORC1 inhibitors. This study investigated the efficacy and safety of the mTORC1 inhibitor sirolimus for treatment of renal angiomyolipomas in patients with these disorders. EXPERIMENTAL DESIGN: In this multicenter phase 2 nonrandomized open label trial, 16 patients with tuberous sclerosis or sporadic LAM and renal angiomyolipoma(s) were treated with oral sirolimus for up to 2 years. Steady-state blood levels were 3 to 10 ng/mL. The primary outcome was change in size of renal angiomyolipomas measured by MRI and assessed by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Secondary outcomes included safety, neurocognitive function, and pulmonary function. RESULTS: The response rate, by RECIST criteria, was 50%. Summated angiomyolipoma diameters were reduced in all 16 patients and by 30% or more in eight (all from the per protocol group of 10). Forty-one of 48 angiomyolipomas were smaller at the last measurement than at baseline. Most shrinkage occurred during the first year of treatment. There was little change in pulmonary function. Recall memory improved in seven of eight patients with tuberous sclerosis. Adverse events were consistent with the known toxicities of sirolimus. CONCLUSIONS: This study showed sustained regression of renal angiomyolipomas in patients with tuberous sclerosis or sporadic LAM receiving 2 years of sirolimus treatment. Possible effects on pulmonary function and neurocognition require further investigation.

Pulmonary thromboembolism with floating thrombus trapped in patent foramen ovale.

A 39-year-old man was hospitalized with symptoms of acute deep vein thrombosis, and computed tomography showed that he had pulmonary thromboembolism. Transthoracic echocardiography showed a large, right atrial thrombus and transesophageal echocardiography showed migrating thrombus trapped in a patent foramen ovale and extending all the way up to the ascending aorta. He underwent surgical embolectomy under cardiopulmonary bypass. At the conclusion of the operation, repeat transesophageal echocardiography examination revealed fresh but small thrombus in the right atrium. This continued entry of thrombi into the heart was further managed with fluoroscopy-guided insertion of a retrievable inferior vena cava filter through the internal jugular vein in the operating room itself.

Detection of coronary and peripheral artery calcification in patients with chronic kidney disease stages 3 and 4, with and without diabetes.

BACKGROUND: The purpose of this study was to describe the prevalence and extent of coronary artery calcification (CAC) in subjects with chronic kidney disease (CKD) stages 3 and 4 comparing those with and without diabetes. We also wished to determine if the presence of peripheral artery calcification (PAC) would assist in identifying patients positive for CAC. METHODS: CAC was detected by multi-slice computed tomography and PAC was detected by plain foot radiography. Study population was 112 patients, 54 with diabetes and 58 without, all asymptomatic for heart disease. Demographic and laboratory data were collected and analysed. RESULTS: The prevalence of CAC in CKD patients was 76 and 46.5% with and without diabetes, respectively. Patients with diabetes had higher CAC scores with more vessels affected, and in the presence of diabetes men and women had the same risk for CAC. In patients with diabetes, age was the unique explanatory variable for detecting the presence of CAC, while age and smoking history predicted severity. In patients without diabetes, age, male gender, body mass index, estimated glomerular filtration rate and serum phosphate levels predicted the presence of CAC, while parathyroid hormone predicted severity. Prevalence of PAC was 63 and 12% in subjects with and without diabetes. PAC detected by foot radiography was not an adequate alternative-screening marker for identifying patients with CAC. CONCLUSIONS: CAC is common in CKD stages 3 and 4 patients, especially in men and women with diabetes.