Sophie Maitre

Diagnostic strategy for patients with suspected pulmonary embolism: a prospective multicentre outcome study

BACKGROUND We designed a prospective multicentre outcome study to evaluate a diagnostic strategy based on clinical probability, spiral CT, and venous compression ultrasonography of the legs in patients with suspected pulmonary embolism (PE). The main aim was to assess the safety of withholding anticoagulant treatment in patients with low or intermediate clinical probability of PE and negative findings on spiral CT and ultrasonography. METHODS 1041 consecutive inpatients and outpatients with suspected PE were included. Patients with negative spiral CT and ultrasonography and clinically assessed as having a low or intermediate clinical probability were left untreated. Those with high clinical probability underwent lung scanning, pulmonary angiography, or both. All patients were followed up for 3 months. FINDINGS PE was diagnosed in 360 (34.6%) patients; 55 had positive ultrasonography despite negative spiral CT. Of 601 patients with negative spiral CT and ultrasonography, 76 were clinically assessed as having a high probability of PE; lung scanning or angiography showed PE in four (5.3% [95% CI 1.5-13.1]). The remaining 525 patients were assessed as having low or intermediate clinical probability, and 507 of them were not treated. Of these patients, nine experienced venous thromboembolism during follow-up (1.8% [0.8-3.3]). The diagnostic strategy proved inconclusive in 95 (9.1%) patients, and pulmonary angiography was done in 74 (7.1%). INTERPRETATION Withholding of anticoagulant therapy is safe when the clinical probability of PE is assessed as low or intermediate and spiral CT and ultrasonography are negative.

Pulmonary Veno-Occlusive Disease Clinical, Functional, Radiologic, and Hemodynamic Characteristics and Outcome of 24 Cases Confirmed by Histology

Pulmonary veno-occlusive disease (PVOD) is defined by specific pathologic changes of the pulmonary veins. A definite diagnosis of PVOD thus requires a lung biopsy or pathologic examination of pulmonary explants or postmortem lung samples. However, lung biopsy is hazardous in patients with severe pulmonary hypertension, and there is a need for noninvasive diagnostic tools in this patient population. Patients with PVOD may be refractory to pulmonary arterial hypertension (PAH)-specific therapy and may even deteriorate with it. It is important to identify such patients as soon as possible, because they should be treated cautiously and considered for lung transplantation if eligible. High-resolution computed tomography of the chest can suggest PVOD in the setting of pulmonary hypertension when it shows nodular ground-glass opacities, septal lines, lymph node enlargement, and pleural effusion. Similarly, occult alveolar hemorrhage found on bronchoalveolar lavage in patients with pulmonary hypertension is associated with PVOD. We conducted the current study to identify additional clinical, functional, and hemodynamic characteristics of PVOD. We retrospectively reviewed 48 cases of severe pulmonary hypertension: 24 patients with histologic evidence of PVOD and 24 randomly selected patients with idiopathic, familial, or anorexigen-associated PAH and no evidence of PVOD after meticulous lung pathologic evaluation. We compared clinical and radiologic findings, pulmonary function, and hemodynamics at presentation, as well as outcomes after the initiation of PAH therapy in both groups. Compared to PAH, PVOD was characterized by a higher male:female ratio and higher tobacco exposure (p < 0.01). Clinical presentation was similar except for a lower body mass index (p < 0.02) in patients with PVOD. At baseline, PVOD patients had significantly lower partial pressure of arterial oxygen (PaO2), diffusing lung capacity of carbon monoxide/alveolar volume (DLCO/VA), and oxygen saturation nadir during the 6-minute walk test (all p < 0.01). Hemodynamic parameters showed a lower mean systemic arterial pressure (p < 0.01) and right atrial pressure (p < 0.05), but no difference in pulmonary capillary wedge pressure. Four bone morphogenetic protein receptor II (BMPR2) mutations have been previously described in PVOD patients; in the current study we describe 2 additional cases of BMPR2 mutation in PVOD. Computed tomography of the chest revealed nodular and ground-glass opacities, septal lines, and lymph node enlargement more frequently in patients with PVOD compared with patients with PAH (all p < 0.05). Among the 16 PVOD patients who received PAH-specific therapy, 7 (43.8%) developed pulmonary edema (mostly with continuous intravenous epoprostenol, but also with oral bosentan and oral calcium channel blockers) at a median of 9 days after treatment initiation. Acute vasodilator testing with nitric oxide and clinical, functional, or hemodynamic characteristics were not predictive of the subsequent occurrence of pulmonary edema on treatment. Clinical outcomes of PVOD patients were worse than those of PAH patients. Abbreviations: BMPR2 = bone morphogenetic protein receptor II, CI = cardiac index, CT = computed tomography, DLCO = diffusing lung capacity of carbon monoxide, DLCO/VA = diffusing lung capacity of carbon monoxide/alveolar volume, FEV1 = forced expiratory volume in 1 second, HIV = human immunodeficiency virus, mPAP = mean pulmonary arterial pressure, mSAP = mean systolic arterial pressure, NO = nitric oxide, NYHA = New York Heart Association, PaCO2 = partial pressure of arterial carbon dioxide, PAH = pulmonary arterial hypertension, PaO2 = partial pressure of arterial oxygen, PCWP = pulmonary capillary wedge pressure, PVOD = pulmonary venoocclusive disease, PVRi = indexed pulmonary vascular resistance, SpO2 = pulse arterial oxygen saturation, TLC = total lung capacity, TPRi = indexed total pulmonary resistance, VC = vital capacity.

Role of CT in chronic pulmonary embolism: comparison with pulmonary angiography.

To assess the value of CT in chronic pulmonary embolism (CPE), CT scans and pulmonary angiograms of 21 consecutive patients were reviewed. Computed tomography was better than angiography in assessing proximal clots (three thrombi not seen by angiography, three angiographic false-positives confirmed by surgery). Furthermore, CT was able to analyze pulmonary arteries distal to angiographic amputations. Computed tomography was less sensitive than angiography for vascular distortions (38 vs. 50%) and stenosis (35 vs. 71.8%). Pulmonary infarctions were better detected and characterized by CT than by angiography. Isolated parenchymal ground-glass opacities were seen by CT in 18 patients, especially in those with right cardiomegaly. High resolution CT delineated them better than did standard CT. Computed tomography may be a useful adjunct to angiography in the assessment of CPE.

Computed tomography findings of pulmonary venoocclusive disease in scleroderma patients presenting with precapillary pulmonary hypertension

OBJECTIVE Pulmonary venoocclusive disease (PVOD) is an uncommon form of pulmonary hypertension (PH) characterized by obstruction of small pulmonary veins. Pulmonary venous involvement has been reported in pathologic assessment of patients with systemic sclerosis (SSc) presenting with precapillary PH. High-resolution computed tomography (HRCT) of the chest is a noninvasive diagnostic tool used to screen for PVOD. No HRCT data are available on SSc patients with precapillary PH. We undertook this study to evaluate the frequency and effect on prognosis of HRCT signs of PVOD in SSc patients with precapillary PH. METHODS We reviewed chest HRCT data from 26 SSc patients with precapillary PH and 28 SSc patients without pulmonary arterial hypertension (PAH) or interstitial lung disease (ILD). RESULTS The radiographic triad of HRCT signs of PVOD (lymph node enlargement [57.7% versus 3.6%], centrilobular ground-glass opacities [46.2% versus 10.7%], and septal lines [88.5% versus 7.1%]) was significantly more frequent in SSc patients with precapillary PH than in SSc patients without PAH or ILD (all P < 0.005). Indeed, 61.5% of SSc patients with precapillary PH had ≥ 2 of these signs. Cardiomegaly (P < 0.0001), pulmonary artery enlargement (P < 0.0001), and pericardial effusion (P < 0.0005) were also significantly more frequent in SSc patients with precapillary PH. Pulmonary venous involvement was histologically confirmed in 2 patients with radiographic signs of PVOD. The presence of ≥ 2 radiographic signs of PVOD was associated with the occurrence of pulmonary edema after initiation of PAH-specific therapy (in 8 of 16 patients) and with more rapid progression from diagnosis of PH to death. CONCLUSION HRCT signs of PVOD are frequently observed in SSc patients with precapillary PH, correlated with histologic assessment, and were associated with a high risk of pulmonary edema.

Pulmonary veno-occlusive disease: Recent progress and current challenges

Pulmonary veno-occlusive disease (PVOD) is an uncommon form of pulmonary arterial hypertension characterised by a progressive obstruction of small pulmonary veins that leads to elevation in pulmonary vascular resistance and right ventricular failure. Despite improved understanding and more efficacious treatment options for PAH overall, the prognosis of PVOD remains dismal. Without therapeutic intervention few patients would be expected to survive more than two years. PVOD may occur in both idiopathic and heritable forms, or develop in association with connective tissue disease, chronic respiratory disease, malignancy or bone marrow transplantation, among other causes. A widespread fibrous intimal proliferation that predominantly involves the pulmonary venules and small veins is the key histopathological hallmark. Surgical lung biopsy is considered the definitive diagnostic test but is associated with significant risk and is not recommended. Distinguishing PVOD from PAH on clinical grounds alone is generally not possible, although PVOD is characterised by a higher male/female ratio and higher tobacco exposure. Instead, non-invasive tests may be helpful and the diagnosis is usually based on an integrated assessment that incorporates high resolution computed tomography (septal lines, ground-glass opacities and lymph node enlargement), pulmonary function testing (lower DLCO), arterial blood gas analysis (lower PaO(2) at rest) and bronchoalveolar lavage (occult alveolar haemorrhage). Treatment of PVOD remains challenging as exposure to pulmonary vasodilators and PAH-specific agents may precipitate acute pulmonary oedema. Nonetheless, a number of successful outcomes describing cautious use of prostanoids, endothelin antagonists and phosphodiesterase type-5 inhibitors have been described. Unfortunately, the long term effects of these agents are variable and lung transplantation remains the treatment of choice.

Harmful effect of adipose tissue on liver lesions in patients with alcoholic liver disease.

BACKGROUND & AIMS Adipose tissue is an important source of cytokines. Excess weight is an independent risk factor for steatosis, acute alcoholic hepatitis (AAH), and cirrhosis in patients with alcoholic liver disease (ALD). In this study, we investigated the role of adipose tissue in human ALD. PATIENTS AND METHODS Fifty patients with ALD underwent liver and abdominal subcutaneous adipose tissue biopsies and supplied blood samples for the investigation of cytokine gene expression and secretion, as well as liver histology. RESULTS The levels of TNF-alpha and IL-10 in adipose tissue were higher in patients with AAH. IL-10 level in adipose tissue was also correlated with fibrosis score. TNF-alpha gene expression in adipose tissue was correlated with Maddrey score, blood C-reactive protein (CRP) concentration and liver IL-6 concentration. IL-6 production levels in the liver were higher in patients with AAH and correlated with AAH score, liver histological lesions, liver TNF-alpha concentration, Maddrey score, and blood CRP concentration. Plasma concentrations of soluble forms of TNF-receptor were correlated with inflammatory lesions in the liver, Maddrey score and fibrosis score. CONCLUSION In patients with ALD, inflammation occurs not only in the liver, but also in the adipose tissue. Adipose tissue inflammation is correlated with the severity of pathological features in the liver. Our findings may account for the harmful interactions between body mass index, AAH, fibrosis, and cirrhosis in alcoholic patients.

Housekeeping gene variability in the liver of alcoholic patients.

BACKGROUND Quantification of gene expression using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) requires normalization to an endogenous reference gene termed housekeeping gene (HKG). Many of the commonly used HKGs are regulated and vary under experimental conditions and disease stages. Alcoholic liver disease (ALD) is associated with several different liver histological lesions that may modulate HKG expression. We investigated the variability of commonly used HGKs (18S, β-actin, glyceraldehyde-3-phosphate [GAPDH], and arginine/serine-rich splicing factor [SFRS4]) in the liver of patients with ALD. METHODS Fifty consecutive patients at different stages of ALD underwent liver biopsy. The stability of HKG was assessed according to liver histological lesions. RESULTS β-actin had the highest coefficient of dispersion (COD) (23.9). β-actin tended to decrease with steatosis and to increase with alcoholic hepatitis; β-actin also increased in patients with both alcoholic hepatitis and cirrhosis. GAPDH and SFRS4 COD were 2.8 and 2.1, respectively. GAPDH was decreased with steatosis and increased with alcoholic hepatitis and fibrosis. 18S had the lowest COD (1.4). Both 18S and SFRS4 levels were not significantly modified with respect to all alcohol-induced liver histological lesions. CONCLUSIONS In patients with ALD, the most constantly expressed HKGs are 18S and SFRS4. These genes are appropriate reference genes for normalization of RT-qPCR in the liver of patients with ALD. The use of other HKGs such as β-actin or GAPDH would lead to misinterpretation of the results.

Alcohol withdrawal alleviates adipose tissue inflammation in patients with alcoholic liver disease

Patients with alcoholic liver disease (ALD) display inflammation of the subcutaneous adipose tissue (SAT) which correlates with liver lesions. We examined macrophage markers and polarization in the SAT of alcoholic patients and adipokine expression according to liver inflammation; we studied the consequences of alcohol withdrawal.

Maladie veino-occlusive et hémangiomatose capillaire pulmonaire

The new classification of pulmonary hypertension proposed in the joint European Society of Cardiology (ESC) and European Respiratory Society (ERS) guidelines, combines pulmonary veno-occlusive disease (PVOD) and pulmonary capillary hemangiomatosis (PCH) from separate categories into a single subcategory within pulmonary arterial hypertension (PAH) because of specific similarities in their diagnosis, prognosis, and management. These diseases are characterized histologically by their predominant involvement of small pulmonary veins (PVOD) and capillaries (PCH). Their precise prevalence is not known, but they are thought to account for 5 to 10% of the forms of PAH initially considered idiopathic. They cannot be distinguished from idiopathic PAH by their clinical or hemodynamic presentation. Only pathology examination can confirm the diagnosis, but lung biopsies are high-risk procedures and not recommended. A less invasive approach combining chest CT (centrilobular ground-glass opacities, septal lines, and mediastinal adenopathy), blood gases (resting hypoxemia), lung function tests [collapse in carbon monoxide diffusion (DLCO)] and bronchoalveolar lavage (occult intra-alveolar hemorrhage) makes it possible to screen the patients at risk of PVOD or HCP and thus avoid a lung biopsy. These patients have a poor prognosis and are at risk of developing severe pulmonary edema after the initiation of specific treatment for PAH. In view of their limited response to specific treatment and poor prognosis, pulmonary transplantation remains the treatment of choice for PVOD and HCP. In patients with the most severe disease, the prudent use of continuous intravenous epoprostenol, can serve as bridge-therapy while awaiting a lung transplant.

Mise au pointMaladie veino-occlusive et hémangiomatose capillaire pulmonairePulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis

The new classification of pulmonary hypertension proposed in the joint European Society of Cardiology (ESC) and European Respiratory Society (ERS) guidelines, combines pulmonary veno-occlusive disease (PVOD) and pulmonary capillary hemangiomatosis (PCH) from separate categories into a single subcategory within pulmonary arterial hypertension (PAH) because of specific similarities in their diagnosis, prognosis, and management. These diseases are characterized histologically by their predominant involvement of small pulmonary veins (PVOD) and capillaries (PCH). Their precise prevalence is not known, but they are thought to account for 5 to 10% of the forms of PAH initially considered idiopathic. They cannot be distinguished from idiopathic PAH by their clinical or hemodynamic presentation. Only pathology examination can confirm the diagnosis, but lung biopsies are high-risk procedures and not recommended. A less invasive approach combining chest CT (centrilobular ground-glass opacities, septal lines, and mediastinal adenopathy), blood gases (resting hypoxemia), lung function tests [collapse in carbon monoxide diffusion (DLCO)] and bronchoalveolar lavage (occult intra-alveolar hemorrhage) makes it possible to screen the patients at risk of PVOD or HCP and thus avoid a lung biopsy. These patients have a poor prognosis and are at risk of developing severe pulmonary edema after the initiation of specific treatment for PAH. In view of their limited response to specific treatment and poor prognosis, pulmonary transplantation remains the treatment of choice for PVOD and HCP. In patients with the most severe disease, the prudent use of continuous intravenous epoprostenol, can serve as bridge-therapy while awaiting a lung transplant.