Role of screening for uveitis in subjects with sarcoidosis.

BACKGROUND AND OBJECTIVES: Ocular involvement is common in sarcoidosis. Our study aimed to evaluate the role of screening for uveitis in subjects with sarcoidosis. METHODS: Retrospective case series of 88 subjects with a pre-existing diagnosis of sarcoidosis, with no previous diagnosis of uveitis, reviewed by Ophthalmology at Auckland District Health Board between January 2016 and May 2022. RESULTS: Among those undergoing a screening examination, uveitis was observed in 27.8% (15 out of 54 subjects). In those presenting with acute eye symptoms, uveitis was observed in 94.1% (32 out of 34 subjects). Sarcoid uveitis was diagnosed in a total of 50 out of 88 subjects (56.8%). 45 subjects required ocular treatment. Sarcoid uveitis was observed in 6 out of 27 subjects (22.2%) who were entirely asymptomatic at screening. On multivariate analysis, blurring of vision (OR 26.2 p < 0.001), eye pain (OR 7.3 p = 0.014) and respiratory disease (OR 7.1 p = 0.044) were associated with increased risk of sarcoid uveitis. In the 41 subjects with no uveitis at initial examination, 3 subjects (7.3%) subsequently developed uveitis. CONCLUSION: Our study highlights the importance of ophthalmic screening of all patients with systemic sarcoidosis, even in asymptomatic patients. With a high correlation of ocular symptoms in diagnosis of sarcoid uveitis, ophthalmologists should educate patients to look out for the development of symptoms of ocular inflammation, and clinicians who continue follow up for systemic sarcoidosis should remind patients to watch carefully for these symptoms to facilitate timely diagnosis and intervention.

Do Pulmonary Cavity Shapes Influence Lung Function?

Distribution of lung tissue within the chest cavity is a key contributor to delivery of both blood and air to the gas exchange regions of the lung. This distribution is multifactorial with influences from parenchyma, gravity, and level of inflation. We hypothesize that the manner in which lung inflates, for example, the primarily diaphragmatic nature of normal breathing, is an important contributor to regional lung tissue distribution. To investigate this hypothesis, we present an organ-level model of lung tissue mechanics, which incorporates pleural cavity change due to change in lung volume or posture. We quantify the changes using shape and density metrics in ten healthy subjects scanned supine at end-inspiratory and end-expiratory volumes and ten subjects scanned at both supine and prone end-inspiratory volumes. Comparing end-expiratory to end-inspiratory volume, we see primarily a change in the cranial-caudal dimension of the lung, reflective of movement of diaphragm. In the diaphragmatic region, there is greater regional lung expansion than in the cranial aspect, which is restricted by the chest wall. When moving from supine to prone, a restriction of lung was observed anteriorly, resulting in a generally reduced lung volume and a redistribution of air volume posteriorly. In general, we see the highest in lung tissue density heterogeneity in regions of the lung that are most inflated. Using our computational model, we quantify the impact of pleural cavity shape change on regional lung distribution and predict the impact on regional elastic recoil pressure.

Assessing the feasibility of a web-based registry for multiple orphan lung diseases: the Australasian Registry Network for Orphan Lung Disease (ARNOLD) experience.

BACKGROUND: We investigated the feasibility of using an online registry to provide prevalence data for multiple orphan lung diseases in Australia and New Zealand. METHODS: A web-based registry, The Australasian Registry Network of Orphan Lung Diseases (ARNOLD) was developed based on the existing British Paediatric Orphan Lung Disease Registry. All adult and paediatric respiratory physicians who were members of the Thoracic Society of Australia and New Zealand in Australia and New Zealand were sent regular emails between July 2009 and June 2014 requesting information on patients they had seen with any of 30 rare lung diseases. Prevalence rates were calculated using population statistics. RESULTS: Emails were sent to 649 Australian respiratory physicians and 65 in New Zealand. 231 (32.4%) physicians responded to emails a total of 1554 times (average 7.6 responses per physician). Prevalence rates of 30 rare lung diseases are reported. CONCLUSIONS: A multi-disease rare lung disease registry was implemented in the Australian and New Zealand health care settings that provided prevalence data on orphan lung diseases in this region but was limited by under reporting.

Bone density is normal and does not change over 2 years in sarcoidosis.

SUMMARY: Small studies have previously suggested that sarcoidosis may be associated with low bone mineral density. In this observational study of 64 patients with sarcoidosis, bone mineral density was within the normal range at baseline, and there was no evidence of accelerated bone loss over 1-2 years. INTRODUCTION: Several small studies have suggested that sarcoidosis may be associated with low bone mineral density (BMD). METHODS: We undertook a cross-sectional study of BMD in 64 patients with sarcoidosis. Of these, 27 with 25-hydroxyvitamin D<50 nmol/L entered a 1-year intervention study of vitamin D supplements, and 37 entered a 2-year longitudinal study of BMD, with the primary endpoint of the change in lumbar spine BMD. RESULTS: The mean age of participants was 58 years, 68% were female, and 8% were currently using oral glucocorticoids. At baseline, BMD for the entire cohort was greater than the expected values for the population at the lumbar spine (mean Z-score 0.7, P<0.001) and total body (0.5, P<0.001) and similar to expected values at the femoral neck (0.2, P=0.14) and total hip (0.2, P=0.14). BMD did not change at any of these four sites (P>0.19) over 2 years in the longitudinal study. In the intervention study, vitamin D supplements had no effect on BMD, and therefore we pooled the data from all participants. BMD did not change over 1 year at the spine, total hip, or femoral neck (P>0.3), but decreased by 0.7% (95% confidence interval 0.3-1.1) at the total body (P=0.019). CONCLUSIONS: BMD was normal at baseline, and there was no consistent evidence of accelerated bone loss over 1-2 years, regardless of baseline vitamin D status. Patients with sarcoidosis not using oral glucocorticoids do not need routine monitoring of BMD.

Hypoxic pulmonary vasoconstriction as a contributor to response in acute pulmonary embolism.

Hypoxic pulmonary vasoconstriction (HPV) is an adaptive response unique to the lung whereby blood flow is diverted away from areas of low alveolar oxygen to improve ventilation-perfusion matching and resultant gas exchange. Some previous experimental studies have suggested that the HPV response to hypoxia is blunted in acute pulmonary embolism (APE), while others have concluded that HPV contributes to elevated pulmonary blood pressures in APE. To understand these contradictory observations, we have used a structure-based computational model of integrated lung function in 10 subjects to study the impact of HPV on pulmonary hemodynamics and gas exchange in the presence of regional arterial occlusion. The integrated model includes an experimentally-derived model for HPV. Its function is validated against measurements of pulmonary vascular resistance in normal subjects at four levels of inspired oxygen. Our results show that the apparently disparate observations of previous studies can be explained within a single model: the model predicts that HPV increases mean pulmonary artery pressure in APE (by 8.2 ± 7.0% in these subjects), and concurrently shows a reduction in response to hypoxia in the subjects who have high levels of occlusion and therefore maximal HPV in normoxia.

Lack of functional information explains the poor performance of 'clot load scores' at predicting outcome in acute pulmonary embolism.

Clot load scores have previously been developed with the goal of improving prognosis in acute pulmonary embolism (PE). These scores provide a simple estimate of pulmonary vascular bed obstruction, however they have not been adopted clinically as they have poor correlation with mortality and right ventricular (RV) dysfunction. This study performed a quantitative analysis of blood flow and gas exchange in 12 patient-specific models of PE, to understand the limitations of current clot load scores and how their prognostic value could be improved. Prediction of hypoxemia in the models when using estimated baseline (non-occluded) minute ventilation and cardiac output correlated closely with clinical metrics for RV dysfunction, whereas the clot load score had only a weak correlation. The model predicts that large central clots have a greater impact on function than smaller distributed clots with the same total clot load, and that the partial occlusion of a vessel only has a significant impact on pulmonary function when the vessel is close to completely occluded. The effect of clot distribution on the redistribution of blood from its normal pattern - and hence the magnitude of the potential effect on gas exchange - is represented in the model but is not included in current clot load scores. Improved scoring systems need to account for the expected normal distribution of blood in the lung, and the impact of clot on redistributing the blood flow.

Pulmonary embolism: predicting disease severity.

Pulmonary embolism (PE) is the most common cause of acute pulmonary hypertension, yet it is commonly undiagnosed, with risk of death if not recognized promptly and managed accordingly. Patients typically present with hypoxemia and hypomania, although the presentation varies greatly, being confounded by co-morbidities such as pre-existing cardio-respiratory disease. Previous studies have demonstrated variable patient outcomes in spite of similar extent and distribution of pulmonary vascular occlusion, but the path physiological determinants of outcome remain unclear. Computational models enable exact control over many of the compounding factors leading to functional outcomes and therefore provide a useful tool to understand and assess these mechanisms. We review the current state of pulmonary blood flow models. We present a pilot study within 10 patients presenting with acute PE, where patient-derived vascular occlusions are imposed onto an existing model of the pulmonary circulation enabling predictions of resultant haemodynamic after embolus occlusion. Results show that mechanical obstruction alone is not sufficient to cause pulmonary arterial hypertension, even when up to 65 per cent of lung tissue is occluded. Blood flow is found to preferentially redistribute to the gravitationally non-dependent regions. The presence of an additional downstream occlusion is found to significantly increase pressures.

Perceptions and beliefs in sarcoidosis.

BACKGROUND: Sarcoidosis is a chronic multisystem disease with a high prevalence of depression although this is often not recognised. It is not known how patients perceive their disease or the medications required for treatment. We hypothesised that perceptions of illness and beliefs about medications may relate to psychological distress in this condition. METHODS: 81(42 female) patients with sarcoidosis completed the following: Hospital Anxiety and Depression Scale, Illness Perception Questionnaire, Beliefs about Medications Questionnaire. Demographic and clinical data were collected and the physician's perception of symptom severity and relationship to sarcoidosis recorded. RESULTS: The prevalence of depression (23%) and anxiety (33%) was high and related to self reported symptoms of sarcoidosis. Those on current treatment reported different illness perceptions than those not, and illness perceptions related to anxiety and depression scores. The majority of the sample felt that sarcoid medications were unnecessary but few patients reported concerns about potential adverse consequences of taking them. Beliefs about medications were related to illness perceptions but not associated with anxiety or depression scores or with clinical perception of disease state. There were significant gender differences in perceptions of illness and beliefs about medications. CONCLUSIONS: These data confirm earlier reports that anxiety and depression are common in patients with sarcoidosis and in turn perceptions of illness impact on emotional wellness in this disorder. Use of the Illness Perceptions Questionnaire in clinical practice may help to identify those patients who would benefit from interventions to change their perceptions of illness.

Use of the 'CURB 65' score in hospital practice.

BACKGROUND: The 'CURB 65' score is a simple well-validated tool for the assessment of severity in community acquired pneumonia (CAP). Whether it is used routinely is unknown. The aim of this study was to determine the frequency of use of the score in routine hospital practice and correlate this with clinical decision making and patient outcome. METHODS: Retrospective cohort study of all patients with CAP (n=174) presenting in three winter months. Demographic and clinical outcome data were recorded and comparisons were made between those patients who had score applied on admission with those that did not. A CURB 65 score was assigned to all patients using data from the patient record, and admission decisions were compared. RESULTS: Only 9 (5.2%) CAP patients had the 'CURB 65' score applied at admission. The overall mortality rate was 3.4%. On applying a score to all cases retrospectively, appropriate admission decisions were made for patients with moderate or severe pneumonia and outcome was in accordance with published results. However, 23 (13%) patients age<65 with mild CAP and no comorbidities were admitted in spite of guideline recommendation for community care. CONCLUSIONS: These data demonstrate that clinical decision making in respect of moderate or severe CAP is the same whether or not a pneumonia severity score is applied. However, routine use of the score will identify patients with mild CAP thus potentially reducing unnecessary admission.

Does CT scanning predict the likelihood of a positive transbronchial biopsy in sarcoidosis?

BACKGROUND: Transbronchial lung biopsy (TBB) has a variable diagnostic yield in sarcoidosis. It was hypothesised that the extent and pattern of parenchymal disease on CT scanning would predict the likelihood of a positive TBB result. METHODS: Patients with sarcoidosis (n = 77) were included if they had undergone a CT scan within 6 weeks of TBB. Ethnicity, symptoms, pulmonary function and site and results of TBB and bronchoalveolar lavage (BAL) were recorded. CT scans were scored quantitatively for patterns of parenchymal disease (nodular, reticular, consolidation and ground glass) on a lobar basis. RESULTS: 39 patients (50.6%) had a positive TBB. Symptoms, ethnicity, treatment, lung volumes and chest radiographic stage were not predictors of a positive biopsy. Female gender, reduced percentage predicted carbon monoxide transfer factor and a higher percentage of lymphocytes in the BAL fluid were associated with a positive biopsy, as were higher total lung score, reticular pattern and ground-glass opacity. The associations were more significant for the total lobar score and the lobar ground-glass score of the lobe biopsied. On multivariate analysis gender, percentage of lymphocytes in the BAL fluid and total lung score were independent predictors of a positive TBB. CONCLUSION: The total extent of parenchymal disease on the CT scan in addition to the pattern and lobar distribution predicts the likelihood of a positive TBB at bronchoscopy.

WT1 as a complementary marker of malignant melanoma: an immunohistochemical study of whole sections.

AIMS: To test the usefulness of WT1 as a diagnostic aid in melanoma diagnosis and prognostication. METHODS AND RESULTS: Benign naevi, Spitz naevi, dysplastic naevi and melanoma in situ, primary epithelioid, spindle cell and desmoplastic melanoma, and metastatic melanoma biopsy specimens were collected. Primary melanoma cases were grouped using the 2003 Tumour Node Metastasis classification. Cases were examined using haematoxylin and eosin and WT1-stained sections. The presence and pattern of WT1 expression were recorded. Benign naevi were uniformly negative with WT1. The majority of Spitz naevi expressed WT1 (83%). The dysplastic naevi/in situ group showed expression of WT1 in 35% of cases. The majority of primary epithelioid melanoma cases showed WT1 expression (88%). The prevalence of expression by each T category was similar, with T1 = 90%, T2 = 75%, T3 = 95% and T4 = 90%. All spindle cell and desmoplastic melanoma cases showed WT1 expression (100%). Ninety per cent of metastatic melanoma cases expressed WT1. CONCLUSIONS: WT1 is a useful ancillary diagnostic tool in routine melanoma diagnosis. WT1 expression in primary melanoma is unrelated to tumour depth. Its usefulness is limited by the fact that most Spitz naevi express WT1, up to one-third of dysplastic naevi can express WT1 and not all melanomas demonstrate its expression.

Pulmonary rheumatoid nodules demonstrating features usually associated with rheumatoid synovial membrane.

OBJECTIVES: To describe the unusual immunohistological characteristics of two pulmonary rheumatoid nodules showing ectopic lymphoid follicles and the features normally associated with rheumatoid synovial membrane, and to discuss the implications of this novel observation. METHODS: Two formalin-fixed wax-embedded pulmonary rheumatoid nodules were processed for immunohistology. RESULTS: The central structure of the pulmonary nodules was typical of that uniformly expected in a rheumatoid nodule with central necrosis surrounded by a palisade of macrophages. However, a feature not previously observed in nodules was the presence of lymphoid aggregates containing B lymphocytes and, in some cases, showing characteristic features of lymphoid follicles. CONCLUSIONS: The presence of B lymphocytes and the development of ectopic lymphoid follicles in rheumatoid nodules have not been described previously. It is similar to synovial membrane, and contrasts with the expected structure of subcutaneous nodules where B cells and lymphoid follicles are normally absent. These observations establish that the morphology of rheumatoid nodules can vary in different tissues. They further suggest that the inflammatory process in the nodule and synovial membrane are likely to be similar, and that the characteristics of different tissues may be an important determinant of apparent differences between inflammatory lesions in synovial membrane and extra-articular nodules in rheumatoid arthritis.

Exhaled nitric oxide in sarcoidosis.

BACKGROUND: Increased production of nitric oxide (NO) by the lower respiratory tract is viewed as a marker of airway inflammation in asthma and bronchiectasis. NO is a potentially important immune modulator, inhibiting the release of several key pro-inflammatory cytokines. As sarcoidosis is characterised by granulomatous airway inflammation, we hypothesised that exhaled NO levels might be raised in sarcoidosis and correlate with the morphological extent and functional severity of disease. METHODS: Fifty two patients with sarcoidosis (29 men) of mean age 42 years underwent thin section computed tomography (CT), pulmonary function tests, and measurement of exhaled NO. RESULTS: Exhaled NO levels (median 6.8 ppb, range 2.4-21.8) did not differ significantly from values in 44 control subjects, and were not related to the extent of individual CT abnormalities or the level of pulmonary function impairment. CONCLUSION: Exhaled NO levels are not increased in pulmonary sarcoidosis.

Determinants of plasma D-dimer levels in a traveling population.

BACKGROUND: Plasma D-dimer measurement is a widely used diagnostic test for assessing individuals with suspected venous thromboembolism (VTE). Whilst a negative test is helpful in ruling out thrombosis, the significance and determinants of an elevated plasma D-dimer level in otherwise healthy subjects are poorly understood. OBJECTIVES: To determine the association between recognized risk factors for VTE and plasma D-dimer levels in an adult population. SUBJECTS AND METHODS: Blood samples for measurement of plasma D-dimer levels were obtained from 1000 adults aged <70 years who were participating in a study investigating the incidence of VTE in long distance air travellers. The relationship between D-dimer levels and selected risks factors for VTE including thrombophilia status was investigated. RESULTS: The median (Inter-quartile range) D-dimer level was 243 ng mL(-1) (175-345). Multivariate analysis showed that plasma D-dimer levels were positively associated with increasing age, larger body mass index, female gender, the use of hormone therapy, thrombophilia state, and the presence of co-morbid conditions. CONCLUSION: Plasma D-dimer levels vary markedly between individuals and are associated with known risk factors for VTE, including the presence of thrombophilia conditions. The potential role for the measurement of plasma D-dimer as a marker for thrombosis risk requires further investigation.