Endothelial, inducible and neuronal nitric oxide synthase in congenital pulmonary lymphangiectasis.

Abnormal growth and development of lymphatic pulmonary structures leads to severe hypoxia in congenital pulmonary lymphangiectasis (CPL). This case study aims to determine the cellular source and topographical distribution of the nitric oxide synthases in CPL. It studies the post mortem tissue of a term newborn with the clinical course and histological findings of CPL and three controls without pulmonary pathology. It was found that endothelial cells of pulmonary arteries and lymphatic structures stained significantly more for endothelial nitric oxide synthase protein in the CPL patient compared to the controls. The authors conclude that synthesis of endothelial nitric oxide synthase is upregulated in vascular and lymphatic endothelial cells in congenital pulmonary lymphangiectasis.     

Bronchial casts in children with cardiopathies: the role of pulmonary lymphatic abnormalities.

Expectoration of bronchial casts, a condition also called plastic bronchitis, is very rare in children. Bronchial casts may be associated with bronchopulmonary diseases associated with mucus hypersecretion, bronchopulmonary bacterial infections, congenital and acquired cardiopathies, or pulmonary lymphatic abnormalities. A classification based on anatomy and pathology has been proposed which identifies an "acellular" group associated with congenital cardiopathies and palliative surgery. We report on 3 cases with bronchial casts associated with cardiopathy. Observations suggest that the formation of bronchial casts may result from lymphatic leakage into the bronchi. The 3 cases on which we report were immunodeficient and had pulmonary lymphatic abnormalities. The bronchial casts contained lymphocytes and lipids, as determined by histologic examination. In the absence of congenital pulmonary or diffuse lymphatic dysplasia associated with cardiopathy, the principal factors resulting in the formation of bronchial casts appear to be surgical trauma to the lymphatic channels surrounding the bronchi, pleural adhesions, and high systemic venous blood pressure. The prognosis for these patients is poor, and possibilities for treatment are limited.     

Pulmonary abnormalities in Klippel-Trenaunay syndrome. A histologic, ultrastructural, and immunocytochemical study.

Klippel-Trenaunay (KT) syndrome is a rare, sporadic, congenital vascular disease of unknown etiology. We describe pulmonary findings in an 18-year-old male patient followed up since birth with the KT syndrome. The patient developed pleural and pericardial serous effusions that led to an open lung biopsy. Previous pulmonary findings have been limited to thromboembolic phenomena and pulmonary vein varicosities. On the other hand, reports of lymphatic hyperplasia, aplasia, and hypoplasia in KT have been limited to the extremities. For the first time, we describe lymphatic involvement of the lung in KT. The plexiform hyperplasia of the lymphatic channels with smooth muscle hyperplasia leading to lymphatic obstruction, pleural and pericardial effusions are new findings. The lymphatic nature of the plexiform channels was confirmed by immunohistochemistry. Von Willebrand factor and QD-END/10 monoclonal antibodies either did not react or reacted poorly with lymphatic endothelium, features used to distinguish lymphatic and venous endothelium. Ultrastructurally, the absence of basement membrane continuity further substantiated the lymphatic nature of the channels. From our findings, the lymphatic abnormality in the syndrome appears to be more generalized than previously thought. This entity should be distinguished from lymphangioleiomyomatosis to which it bears a superficial morphologic appearance.     

Extravascular lung water in children immediately after operative closure of either isolated atrial septal defect or ventricular septal defect

Extravascular lung water (EVLW) was measured in 16 patients with congenital heart disease by the cold green dye, double indicator dilution technique. Five patients with optimally corrected tetralogy of Fallot served as controls, and EVLW in this group was 4.7 +/- 0.5 ml/kg (111 +/- 13 ml/m2) (mean +/- standard deviation). In 5 asymptomatic patients with atrial septal defect (ASD), normal pulmonary artery (PA) pressure and increased pulmonary blood flow, EVLW was 5.7 +/- 2.8 ml/kg (132 +/- 63 ml/m2), which was not significantly different from the value of control patients. However, in 6 patients with ventricular septal defect, PA hypertension, normal left atrial pressure and an equivalent left-to-right shunt to ASD patients, EVLW was 15.9 +/- 3.8 ml/kg (270 +/- 60 ml/m2). This was significantly different from values in both control and ASD patients (p less than 0.01). It is concluded that in the face of normal pulmonary vascular resistance, PA pressure is transmitted to the microvasculature, causing hydrostatic pulmonary edema. Other factors that may be implicated in the pathogenesis of pulmonary edema, such as increased pulmonary blood flow and relative lymphatic insufficiency in infants, cannot be excluded.     

Lymphoscintigraphy in plastic bronchitis,A pediatric case report

Plastic bronchitis (PB) is an uncommon, potentially fatal disease, marked by endobronchial cast formation causing variable degrees of respiratory distress. Primary and secondary pulmonary lymphatic abnormalities have been identified among the underlying mechanisms of cast formation. We present a case of PB where lymphoscintigraphy demonstrated the underlying lymphatic defect. A 6‐year‐old Hispanic male with congenital heart disease (CHD; post‐Fontan) presented with recurrent pneumonia, respiratory distress. Bronchoscopy showed inflamed hypervascular mucosa and thick mucus plugs; no casts were seen. Later, PB was diagnosed after the patient expectorated a bronchial cast. Cast analysis showed lymphocytic aggregates with mucin and fibrin. Lymphoscintigraphy revealed abnormal lymphatic collaterals and retrograde trace reflux into the superior mediastinum, a picture consistent with thoracic duct lymph leakage into the tracheobronchial tree. The pathogenesis of PB is not fully understood, especially in patients with CHD. Chyle in bronchial casts suggests abnormal lymphatic flow. Reports of lymph flow abnormalities, especially endobronchial lymph leakage in CHD are limited. Lymphoscintigraphy in our case demonstrated clear evidence of retrograde lymph reflux and leakage into the bronchial tree. The case presented suggests that in some patients following Fontan surgery, high intrathoracic lymphatic pressure and retrograde lymph flow may contribute to recurrent cast formation. Finding the underlying lymphatic abnormality helps in specific case management. Lymphoscintigraphy is a safer and easier method than lymphangiography. Surgical lymphatic–venous shunting may be possible in select cases. Pediatr Pulmonol. 2013; 48:515–518. © 2012 Wiley Periodicals, Inc.     

Disorders of the pulmonary lymphatic system

The pulmonary lymphatic system plays an important role in lung perfusion homeostasis. Congenital errors of lymphatic vessel development lead to primary pulmonary lymphatic disorders (lymphangiomas, lymphangiectasis, lymphatic dysplasia syndromes). Acquired disorders of the pulmonary lymphatic system occur in a variety of clinical settings (ranging from trauma to cancer) and may lead to serious pulmonary disease. Because of their scarcity and confusing and inconsistent use of terminology, these conditions are often misdiagnosed. Their management is difficult.     

Abnormal endothelial factor VIII associated with pulmonary hypertension and congenital heart defects

In patients with pulmonary hypertension associated with congenital heart defects, ultrastructural abnormalities are observed in endothelial cells, which suggest heightened metabolic function. If endothelial production of the von Willebrand factor (vWF) is increased, this may be associated with abnormal interactions with platelets leading to worsening of the pulmonary hypertension. We therefore evaluated vWF in 30 patients with pulmonary hypertension (25 with congenital heart defects) and in 30 individuals with normal pulmonary arterial pressure (12 with congenital heart defects). We measured the antigenic (vWF: Ag) and biologic (VWF: rist) activity of vWF in plasma and assessed endothelial vWF: Ag directly by an immunoperoxidase stain applied to lung biopsy tissue. Because of considerable variance and small size, the group of five patients with pulmonary hypertension and without congenital heart defects were excluded from statistical analyses. Patients with pulmonary hypertension and congenital heart defects had significant higher vWF: Ag levels than individuals with normal pulmonary arterial pressure without congenital heart defects (p less than .05), whereas values in those with normal pressure and congenital heart defects were intermediate. In lung biopsy tissue available from 29 patients in this study and from 11 others we previously reported, immunostain of pulmonary arterial endothelium for vWF was intense (suggesting increased production) in 29 of 32 with pulmonary hypertension and congenital heart defects and in only one of eight with normal pulmonary arterial pressure and congenital heart defects (p less than .01). Only three patients with congenital heart defects and pulmonary hypertension and increased vWF: Ag, however, had increased vWF: rist. Compatible with this discrepancy was a loss of vWF high-molecular weight forms as determined by both crossed immunoelectrophoresis and multimeric analysis. Our results suggest that increased vWF in most patients with congenital heart defects and pulmonary hypertension is associated with increased production of a biologically deficient molecule lacking high-molecular weight forms.     

The G‐Allele of the PSMA6−8C>G polymorphism is associated with poor outcome in multiple myeloma independently of circulating proteasome serum levels

Introduction: The proteasome system plays a crucial role in several malignant disorders, especially in multiple myeloma (MM). The G‐allele of a single nucleotide polymorphism (SNP) ?8C>G in the gene PSMA6, one of seven α‐subunit genes of the 20S proteasome, was associated with myocardial infarction. Moreover, PSMA6 mRNA expression in human B‐cell lines depended on genotypes. We investigated a potential role of this novel SNP in patients with MM. Methods: PSMA6 genotypes of 116 patients with MM were associated with survival. Circulating proteasome levels (CPL) dependent on ?8C>G genotypes of 70 newly diagnosed patients were studied using an anti‐20S proteasome enzyme‐linked immunoabsorbant assay (ELISA). Results: Genotype distribution (69 CC, 44 CG, 3 GG) was compatible with Hardy–Weinberg equilibrium. Kaplan–Meier curves revealed a significant association of PSMA6?8C>G with 5‐yr survival (P = 0.014). Median survival time was 43 months for the GG genotype and 50 months for the CG genotype. It was not reached within follow‐up by the CC genotype (CC 5‐yr survival rate 61.2%). Following hazard ratio (HR) for overall survival was calculated: G‐allele vs. CC genotype: 2.038, 95% CI 1.14–3.65, P = 0.017. In multivariate analysis the G‐allele was an independent prognostic factor (HR 2.1, P = 0.014). CPL were not significantly different between genotypes [mean CPL: CC 284.9 ng/mL vs. 303.3 ng/mL G‐allele carriers (P = 0.709)]. Conclusions: These results suggest the G‐allele of the PSMA6?8C>G polymorphism as a possible survival prognosticator.     

Lymphatic Obstruction and Protein‐losing Enteropathy in Patients with Congenital Heart Disease

Objective. Protein‐losing enteropathy (PLE) is a known complication of surgical procedures for congenital heart disease. The pathogenesis and pathophysiology of PLE remain poorly understood. However, lymphatic insufficiency appears central to the disease process. We sought to investigate the role of lymphatic obstruction and central venous catheter‐related central venous thrombosis in patients with congenital heart disease and PLE. Design. A case‐control study design was constructed consisting of patients with congenital heart disease and PLE and 2:1 matched controls having undergone the same definitive surgical procedure. Obstruction to lymphatic return was considered present if the thoracic duct was ligated, or if there was complete central venous obstruction at the usual site of thoracic duct drainage. Results. Obstruction to lymphatic return was identified in 4 of 16 cases (25%) and 1 of 32 controls (4%), P = .06. There was no association between PLE and central venous catheter use or duration, and no discriminating characteristics between cases and controls with respect to anatomy, pre‐Fontan hemodynamic variables, operative or perioperative factors, or hemodynamic variables at the time of PLE diagnosis. Mortality for patients with PLE was 25% compared with 9% in controls (P = not significant). Long‐term resolution of PLE was obtained in six patients (38%). Conclusion. There is a high prevalence of apparent lymphatic obstruction in patients with congenital heart disease and PLE, suggesting that physical lymphatic obstruction may play an important, and previously unrecognized role in the development of PLE in patients with complex congenital heart disease.     

Isolated chylopericardium after intrapericardial procedures: possible role of inadvertent right efferent lymphatic trunk injury

Chylopericardium after an intrapericardial procedure is rare, and satisfactory explanations of its possible causes are lacking.Herein, we present 4 cases of chylopericardium that developed after intrapericardial surgery, and we review the literature.Our literature review revealed 29 cases of chylopericardium that complicated intrapericardial operations, to which we added our 4 cases for analysis. The 33 surgical procedures involved repair for congenital heart disease (n=21), valve surgery (n=5), coronary artery bypass grafting (n=6), and other (n=1). Causes were verified in 7 patients: small lymphatic injury in 3 and high venous pressure or venous thrombosis in 4. Of the 26 patients with chylopericardium of unknown origin, 15 had congenital heart disease. Ten of these 15 had chromosomal abnormalities, especially trisomy 21 (Down syndrome); these patients typically had increased lymphatic permeability, which raised the likelihood of chylopericardium. Five revascularizations for coronary artery disease required harvesting of the left internal thoracic artery for reconstruction, incurring a risk of damage to the drainage site of the right efferent lymphatic trunk. In addition, all 26 patients with chylopericardium of unknown origin underwent dissection of the ascending aorta and the main pulmonary artery, near the right efferent lymphatic trunk. Inadvertent injury to the trunk during the dissection would have increased the risk of chylopericardium. Accordingly, even though the overall incidence of chylopericardium during intrapericardial procedures is low, we recommend a meticulous dissection of the ascending aorta from the main pulmonary artery.     

Aberrant mural cell recruitment to lymphatic vessels and impaired lymphatic drainage in a murine model of pulmonary fibrosis

Pulmonary fibrosis is a progressive disease with unknown etiology that is characterized by extensive remodeling of the lung parenchyma, ultimately resulting in respiratory failure. Lymphatic vessels have been implicated with the development of pulmonary fibrosis, but the role of the lymphatic vasculature in the pathogenesis of pulmonary fibrosis remains enigmatic. Here we show in a murine model of pulmonary fibrosis that lymphatic vessels exhibit ectopic mural coverage and that this occurs early during the disease. The abnormal lymphatic vascular patterning in fibrotic lungs was driven by expression of platelet-derived growth factor B (PDGF-B) in lymphatic endothelial cells and signaling through platelet-derived growth factor receptor (PDGFR)-β in associated mural cells. Because of impaired lymphatic drainage, aberrant mural cell coverage fostered the accumulation of fibrogenic molecules and the attraction of fibroblasts to the perilymphatic space. Pharmacologic inhibition of the PDGF-B/PDGFR-β signaling axis disrupted the association of mural cells and lymphatic vessels, improved lymphatic drainage of the lung, and prevented the attraction of fibroblasts to the perilymphatic space. Our results implicate aberrant mural cell recruitment to lymphatic vessels in the pathogenesis of pulmonary fibrosis and that the drainage capacity of pulmonary lymphatics is a critical mediator of fibroproliferative changes.     

The right heart in congenital heart disease

The clinical presentation of right ventricular (RV) dysfunction due to congenital heart disease (CHD) is similar to that of cor pulmonale. RV volume and pressure loads, and primary RV myocardial dysfunction are mechanisms by which CHD affects right heart function. RV volume load may arise from pre-tricuspid left to right shunts (e.g., atrial septal defect) or regurgitant lesions in the right heart (e.g., Ebstein's anomaly of the tricuspid valve and pulmonary insufficiency after repair of tetralogy of Fallot). RV pressure load may be caused by anatomic obstruction to RV outflow and by pulmonary arteriolar hypertension. The latter can result from Eisenmenger syndrome secondary to congenital and postoperative left to right shunts or from defects that cause pulmonary venous hypertension (e.g., pulmonary vein stenosis, cor triatriatum, or mitral stenosis). The RV myocardium may be affected by a primary cardiomyopathy or by congenital abnormalities of the coronary vessels. Finally, CHD may be associated with airway obstruction, scoliosis, or pulmonary emboli, which, in turn, may lead to the development of cor pulmonale. Congenital heart disease, therefore, must be included in the differential diagnosis of patients who present with right ventricular dysfunction.     

Choledochal cysts: Similarities and differences between Asian and Western countries

Choledochal cysts(CCs)are rare bile duct dilatations,intra-and/or extrahepatic,and have higher prevalence in the Asian population compared to Western populations.Most of the current literature on CC disease originates from Asia where these entities are most prevalent.They are thought to arise from an anomalous pancreaticobiliary junction,which are congenital anomalies between pancreatic and bile ducts.Some similarities in presentation between Eastern and Western patients exist such as female predominance,however,contemporary studies suggest that Asian patients may be more symptomatic on presentation.Even though CC disease presents with an increased malignant risk reported to be more than 10%after the second decade of life in Asian patients,this risk may be overstated in Western populations.Despite this difference in cancer risk,management guidelines for all patients with CC are based predominantly on observations reported from Asia where it is recommended that all CCs should be excised out of concern for the presence or development of biliary tract cancer.     

Nanosecond time-resolved circular polarization of fluorescence: study of NADH bound to horse liver alcohol dehydrogenase.

Circularly polarized luminescence (CPL) spectroscopy provides information on the excited-state chirality of a lumiphore analogous but complementary to information regarding the ground-state chirality derived from circular dichroism. The sensitivity of CPL spectra to molecular conformation makes this technique uniquely suited for the study of biomolecular structure, as extensively demonstrated in earlier studies. Unfortunately, the CPL spectra of many biomolecules often contain significantly overlapping contributions from emitting species either because multiple lumiphores are present (e.g., tryptophan residues in a protein) or because multiple conformations of the biomolecule simultaneously exist, each with a unique CPL spectrum. Increased resolution between individual contributions to the CPL may be achieved by time-resolving this signal, thus taking advantage of the fact that, as a rule, each of the emitting species also has a characteristic decay time associated with its electronically excited state. In addition, the time resolution provides information regarding dynamics associated with the different chiral states of the system. The present study describes an instrument for the determination of time-resolved CPL (TR-CPL) with subnanosecond resolution and its application to several chiral systems. The technique was first demonstrated on a model system with a strong time-dependent CPL signal. Subsequently, the circularly polarized component in the fluorescence of reduced nicotinamide adenine dinucleotide (NADH) bound to liver alcohol dehydrogenase was time-resolved. The CPL of NADH in the binary enzyme-coenzyme complex is time-dependent, reflecting structural differences around the reduced nicotinamide possibly due to a dynamic restructuring. In contrast, the CPL of the coenzyme in the ternary complex formed with enzyme and the substrate analog isobutyramide is essentially time-independent, likely reflecting a more rigid binding domain. Since the linear polarization of the fluorescence of the two complexes did not show any local flexibility of the NADH chromophore, the excited-state conformational rearrangement of the binary complex indicates a subtle change in its interactions with group(s) in direct contact with it.     

Cross sectional echocardiographic diagnosis of total anomalous pulmonary venous connection

Total anomalous pulmonary venous connection can be diagnosed by cross sectional echocardiography. Information is, however, lacking concerning the diagnostic accuracy of this imaging method and any factors which may influence it. To predict the pulmonary venous connection 463 patients with congenital heart disease who had angiographic confirmation were prospectively examined. Total anomalous pulmonary venous connection was present in 34 (7%) patients and correctly detected in 33 (97% sensitivity). There were two false positive results (99% specificity). All 23 patients with atrial situs solitus with or without associated congenital heart defects were correctly detected. One false negative result occurred in a patient with right atrial isomerism and complex congenital heart disease with decreased pulmonary blood flow. Diagnosis of the type of total anomalous pulmonary venous connection, including the site and other anatomical details, was analysed and was correct in 24 of 34 (71%) patients. Errors included incorrect prediction of the site of total anomalous pulmonary venous connection in five patients with right atrial isomerism, atrioventricular canal defect, and pulmonary atresia, details of confluence interconnection in three of four patients with the mixed type of connection, undiagnosed pulmonary venous obstruction in three of the patients with right atrial isomerism, and failure to predict common pulmonary vein atresia in one patient. Factors which were related to incorrect echocardiographic diagnosis were abnormal atrial situs, mixed total anomalous pulmonary venous connection, and associated congenital cardiac defects, whereas age, weight, sex, clinical condition, and time during the study were not related. It is concluded that cross sectional echocardiography can be used to diagnose accurately total anomalous pulmonary venous connection. This method can be the definitive imaging and diagnostic method in symptomatic infants with total anomalous pulmonary venous connection who have atrial situs solitus, unifocal pulmonary venous connection, and no evidence of other major congenital cardiac defect.     

Pathological aspects of cholangiocarcinoma

Cholangiocarcinoma (CC) arises from the biliary epithelium and in most cases represents adenocarcinoma. Pathomorphological evaluation is of decisive impact for the prognosis and management of CC. Morphological subtyping (histotype; hilar vs peripheral type), TNM classification, lymphatic spread, and resection margin status are of prognostic relevance. Distinction from hepatic metastases may be aided by immunohistology and clinico-pathological correlation. There is convincing evidence of the development of CC via premalignant lesions, especially biliary intraepithelial neoplasia, although further knowledge about the biology and diagnostic definition of these lesions has to be accumulated. Currently, there are no established molecular markers of prognosis or therapeutic target structures to be evaluated at the tissue level. Future progress is needed and expected in novel differential diagnostic and predictive markers, in uniform definition of resection margin status and further understanding of molecular and morphological changes in the development of CC.     

Dehiscence of a pulmonary bioprosthesis with a focal dissection of the pulmonary artery in a patient with congenital pulmonic stenosis

Pulmonary valve replacement (PVR) is the most common adult congenital cardiac operation performed. Valve degeneration leading to prosthetic stenosis and/or regurgitation is a long‐term risk in this population and may be associated with paravalvular leak (PVL). Complications involving the proximal pulmonary artery, including dissection, are less clearly defined. Herein, we report the case of a 30‐year‐old patient with a history of multiple pulmonary valve interventions secondary to congenital pulmonic stenosis, who developed dehiscence of a bioprosthetic PVR associated with significant paravalvular leak (PVL) and further complicated by a focal dissection of the proximal pulmonary artery.     

香烟烟熏对COPD大鼠血清及肺组织中CC16水平的影响

目的通过测定COPD大鼠血清及肺组织中CC16的水平,探讨烟熏在COPD形成中的作用。方法采用烟熏加气管内注入内毒素法建立大鼠COPD模型。HE染色观察大鼠肺、支气管的病理改变。ELISA法检测血清中CC16的含量。免疫组化法检测肺组织中CC16的含量变化。结果 COPD组大鼠血清及肺组织中CC16含量与对照组相比均明显降低(P<0.01);内毒素组大鼠血清及肺组织中CC16含量较对照组低,但差别无统计学差异。结论香烟烟熏造成COPD大鼠血清及肺组织中CC16的含量降低,这一改变可能是吸烟所致COPD形成的机制之一。     

Cross sectional echocardiographic diagnosis of total anomalous pulmonary venous connection.

Total anomalous pulmonary venous connection can be diagnosed by cross sectional echocardiography. Information is, however, lacking concerning the diagnostic accuracy of this imaging method and any factors which may influence it. To predict the pulmonary venous connection 463 patients with congenital heart disease who had angiographic confirmation were prospectively examined. Total anomalous pulmonary venous connection was present in 34 (7%) patients and correctly detected in 33 (97% sensitivity). There were two false positive results (99% specificity). All 23 patients with atrial situs solitus with or without associated congenital heart defects were correctly detected. One false negative result occurred in a patient with right atrial isomerism and complex congenital heart disease with decreased pulmonary blood flow. Diagnosis of the type of total anomalous pulmonary venous connection, including the site and other anatomical details, was analysed and was correct in 24 of 34 (71%) patients. Errors included incorrect prediction of the site of total anomalous pulmonary venous connection in five patients with right atrial isomerism, atrioventricular canal defect, and pulmonary atresia, details of confluence interconnection in three of four patients with the mixed type of connection, undiagnosed pulmonary venous obstruction in three of the patients with right atrial isomerism, and failure to predict common pulmonary vein atresia in one patient. Factors which were related to incorrect echocardiographic diagnosis were abnormal atrial situs, mixed total anomalous pulmonary venous connection, and associated congenital cardiac defects, whereas age, weight, sex, clinical condition, and time during the study were not related. It is concluded that cross sectional echocardiography can be used to diagnose accurately total anomalous pulmonary venous connection. This method can be the definitive imaging and diagnostic method in symptomatic infants with total anomalous pulmonary venous connection who have atrial situs solitus, unifocal pulmonary venous connection, and no evidence of other major congenital cardiac defect.     

Study of Clara cell 16, KL-6, and surfactant protein-D in serum as disease markers in pulmonary sarcoidosis

STUDY OBJECTIVES: To determine the discriminative value of serum Clara cell 16 (CC16), KL-6, and surfactant protein (SP)-D as markers of interstitial lung diseases, and their ability to reflect pulmonary disease severity and prognosis in sarcoidosis. SUBJECTS: Seventy-nine patients with sarcoidosis and 38 control subjects. MEASUREMENTS: Serum CC16, KL-6, and SP-D concentrations at disease presentation were measured. Pulmonary function tests and chest radiographs were analyzed at presentation and 2-year follow-up. RESULTS: All markers co-correlated, and a significant difference was found between CC16, KL-6 (Krebs von den Lungen-6), and SP-D levels in patients with sarcoidosis and control subjects (p < 0.0001). Receiver operating characteristic curve analysis revealed largest area under the curve for KL-6. Significantly higher levels of CC16 and KL-6 were found in patients with parenchymal infiltration (stage II, III) compared to patients without parenchymal infiltration (stage I). In concordance, CC16 and KL-6 levels inversely correlated with diffusion capacity and total lung capacity, and KL-6 also with inspiratory vital capacity. Moreover, higher KL-6 levels were weakly but significantly associated with persistence or progression of parenchymal infiltrates at 2-year follow-up. CONCLUSION: In this study, KL-6 appears to be the best discriminative marker in differentiating patients with sarcoidosis from healthy control subjects; however, as it is not a specific marker for this condition, this quality is unlikely to be useful as a diagnostic tool. Both CC16 and KL-6 may be of value in reflecting disease severity, and KL-6 tends to associate with pulmonary disease outcome.