Clara Cell Protein CC16

accurate." Only the intensivist is well positioned to carry out these assessments and to repeat them as clinically indicated. Thus, intensivists now have the equipment to perform a broad range of ultrasound examinations and, motivated by the desire to help their patients, are beginning to do just that. Indeed, lately there has been an explosion of interest in ultrasound courses, lectures, texts, and other means of acquiring the necessary expertise. But, will this really prove beneficial? Or will well-meaning but inexperienced intensivists misinterpret, misdiagnose, and mistreat their fragile patients? For many reasons, it is essential that intensivists gain and nurture broad competence in ultrasound. First, they can provide more timely service than is practical from imaging consultants and do so without the need for transporting the unstable patient. Second, direct knowledge of the patient and the clinically relevant question should produce a more finely honed result. These advantages, however, rest on the assumption that intensivists can interpret sonographic images with sufficient expertise. Studies such as that of Melamed et al' show that modest training can be effective. Outside of clinical studies, such expertise will not develop without leadership, organization, and champions. Training programs must incorporate a formal ultrasound curriculum for their fellows, including supervised, hands-on guidance. In parallel, academic faculty must remediate their own discomfort in using, teaching, and supervising the use of a technique they did not grow up with. Challenges are no less outside of academic centers where practitioners often operate without the educational structures and critical mass typical of academic departments. Competencies must be defined, and ways to effectively assess whether trainees and practicing intensivists are qualified to perform ultrasonography should be studied and implemented. Fortunately, some of the professional societies have begun to organize in this regard. The Critical Care NetWork of the American College of Chest Physicians, working with the Societe de Reanimation de Langue Francaise, has just published a list of competencies in ICU ultrasound." This is a good start but, as we anticipate the coming boom in ICU ultrasound, it is essential to assure that skills spread as fast as the machines. Gregory A. Schmidt, MD, FCCP Iowa City, IA Dr. Schmidt is Professor of Medicine, University of Iowa. The author has reported to the ACCP that no significant conflicts ofinterest exist with any companies/organizations whose products or services may be discussed in this article. 1408

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. orgisite/miscireprints.xhtml). Correspondence to: Gregory A. Schmidt, MD, FCCP, 200 Hawkins Dr, C33-GH, Iowa City, IA 52246; e-mail: gregory-a-schmidt@ uiowa.edu DOl: lO.1378/chest.09-0502

REFERENCES 1 Melamed R, Sprenkle MD, Ulstad VK, et al. Assessment of left ventricular function by intensivists using hand-held echocardiography. Chest 2009; 135:1416-1420 2 Vignon P, Chastagner C, Francois B, et al. Diagnostic ability of hand-held echocardiography in ventilated critically ill patients. Crit Care 2003; 7:R84-R9I 3 Manasia AR, Nagaraj HM, Kodali RB, et al. Feasibility and potential clinical utility of goal-directed transthoracic echocardiography performed by noncardiologist intensivists using a small hand-carried device (SonolIeart) in critically ill patients. J Cardiothorac Vase Anesth 2005; 19:155-159 4 Vignon P, Dugard A, Abraham J, et al. Focused training for goal-oriented hand-held echocardiography performed by noncardiologist residents in the intensive care unit. Intensive Care Med 2007; 33:1795-1799 5 Brennan JM, Blair JEA, Hampole C, et al. Radial artery pulse pressure variation correlates with brachial artery peak velocity variation in ventilated subjects when measured by internal medicine residents using hand-carried ultrasound devices. Chest 2007; 131:1301-1307 6 Duraira] L, Schmidt GA. Fluid therapy in resuscitated sepsis: less is more. Chest 2008; 133:252-263 7 Barbier C, Loubieres Y, Schmit C, et al. Respiratory changes in inferior vena cava diameter are helpful in predicting fluid responsiveness in ventilated septic patients. Intensive Care Med 2004; 30:1740-1746 8 Mayo PH, Beaulieu Y, Doelken P, et al. American College of Chest Physicians/La Societe de Reanimation de Langue Francaise statement on competence in critical care ultrasonography. Chest 2009; 135:1050-1060

Clara Cell Protein CC16 A New Lung Epithelial Biomarker for Acute Lung Injury here has been considerable interest in the conT tribution of lung epithelial injury to the pathogenesis of acute lung injury (ALI). Injury to the alveolar epithelium leads to alveolar edema, a decrease in surfactant activity, a reduction in alveolar fluid clearance, and more procoagulant and antifibrinolytic activity in the distal airspaces of the lung. 1- 3 One approach to estimating the degree of lung epithelial injury has been to measure plasma and airspace biomarkers of alveolar epithelial injury in patients with ALL In addition to providing more insight into pathogenesis, biomarkers of lung epithelial injury may also have diagnostic value for differentiating cardiogenic edema from primary lung injury edema, particuEditorials

larly since the diagnostic criteria for ALI,4 bilateral chest radiographic infiltrates with arterial hypoxemia (Pa02/Fi02 ratio, < 300), are often present in patients with acute respiratory failure from cardiogenic edema as well as in patients with ALI:'5 Also, elevated lung microvascular pressure often coexists in patients with ALI, as has been reported in the ARDS Network Fluid and Catheter Treatment Trial,6 in which 29% of patients in whom ALI had been diagnosed had a pulmonary artery wedge pressure of > 18 mm Hg. Thus, a biomarker that helps to make the diagnosis of ALI would be valuable to both guide clinical management as well as to define a more homogenous patient cohort for clinical trials of ALI. In this issue of CHEST (see page 1440), Kropski et al? have studied CCI6, a protein secreted predominantly from Clara cells of the distal lung airway epithelium, as a potential diagnostic biomarker in ALI. Plasma and pulmonary edema fluid samples were collected from 32 ventilated patients with pulmonary edema early in their clinical course. Compared to patients with cardiogenic pulmonary edema, both plasma and pulmonary edema fluid levels of CC16 were Significantly decreased in patients with ALI. These interesting results suggest that reduced levels of CC16 may help to differentiate lung injury edema from hydrostatic edema. The strengths of this current study include the measurement of CC16 levels in both plasma and the alveolar compartments, as well as comparison with patients with cardiogenic pulmonary edema. Although there was no relationship to clinical outcomes in this 32-patient, single-center study, larger studies will be needed to test the prognostic value of CC16 in patients with ALI. Other lung epithelial cell-associated biomarkers have been studied in the plasma of patients with lung injury. Elevated levels of the soluble receptor of advanced glycation end products (RAGE) is an indication in part of type I alveolar cell injury in patients with ALP In plasma samples from 676 patients from the ARDS Network low-tidal volume study," higher baseline RAGE levels were associated with higher indexes of lung injury severity. Also, in the group randomized to receive the higher tidal volume ventilation, higher baseline RAGE levels were associated with increased mortality and fewer ventilator-free and organ failurefree days compared to patients who received ventilation with the lower tidal volume strategy, suggesting that ALI patients with alveolar epithelial injury may be particularly susceptible to the injurious effects of higher tidal volume ventilation. Plasma RAGE levels decreased in the 3 days after study enrollment, but by 15% more in the patients www.chestjoumal.org

treated with low tidal volume and lower airway pressure. Furthermore, plasma samples from 565 patients in the same trial found that higher baseline plasma surfactant protein-D, a type II alveolar epithelial cell-associated protein, was associated with increased mortality, and that the lower tidal volume strategy was associated with a significant decrease in surfactant protein- D levels by study day 3. 10 Taken together, these studies provide biochemical evidence of lung epithelial cell injury in the pathogenesis of ALI and ventilator-associated lung injury. The current data implicate a largely unrecognized role for the distal airway epithelium in the pathophysiology of ALI. In regions of alveolar injury, clusters of cuboidal epithelial cells commonly in acinar or papillary formations have been identified, a pattern that has been called alveolar bronchiolization.These bronchiolized alveolarcells and the adjacent distal airway epithelial cells have a complex phenotype, showing coexpression of markers of both alveolar type II cells and Clara cells. These data suggest that distal lung epithelial cells may be important in alveolar epithelial injury and repair.l! In the setting of ALI, the decrease in CC16 levels could reflect the differentiation of distal lung epithelial cells into alveolar epithelial cells as part of a repair process. Other potential mechanisms for a reduction in CC16 levels in patients with lung injury, as discussed by Kropski et a1,7 include Clara cell death, alterations in alveolar epithelial permeability, and changes in transcriptional activity within the remaining Clara cells. Mechanical ventilation is known to cause epithelial injury,12 and reducing tidal volume and lowering plateau airway pressure are the only interventions that have reduced the mortality of patients with ARDS. However, it has become evident that even the best mechanical ventilation strategy may further damage the injured lung. Furthermore, low-tidal volume ventilation itself may increase the amount of collapsed lung and exacerbate atelectotrauma. Therefore, another important potential role for a diagnostic biomarker such as CC16 might be to identify a threshold for the presence of ventilator-associated lung injury to allow an optimum ventilatory strategy to be tailored to the needs of an individual patient. Additional studies will be required to determine the utility of CC16 measurement in the diagnosis of ventilator-associated lung injury. The measurement of soluble CC16 joins an increasing and impressive list of candidate biomarkers for ALI. In the absence of an ideal single biomarker.P it is possible that a panel of biomarkers will emerge to guide the management of individual patients as well as to advance clinical research by the selection of patients for clinical CHEST /135/6/ JUNE, 2009

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trials.l- Plasma levels of CCI6, in addition to other lung epithelial biomarkers, may help to confirm the diagnosis and to define the prognosis in critically ill patients with ALI. Danny F. McAuley, MD Belfast, UK Michael A. Matthay, MD, FCCP San Francisco, CA Dr. McAuley is Senior Lecturer and Consultant in Intensive Care Medicine, Centre for Infection and Immunity, School of Medicine, Dentistry and Biomedical Sciences, Microbiology Building, Queen's University of Belfast. Dr. Matthay is Professor of Medicine and Anesthesia and is Senior Associate at the Cardiovascular Research Institute, University of California at San Francisco. The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. orglsite/misc/reprints.xhtml). Correspondence to: Michael A. Mattha'./., MD, FCCP, Cardiovascular Research Institute, University oJ California at San Francisco, 505 Parnassus Ave, M-9I7, San Francisco, CA 94143-0624; e-mail: michael. matthay@ucsfedu DOl: 1O.1378/chest.09-0304

REFERENCES 1 Matthay MA, Zimmerman GA. Acute lung injury and the acute respiratory distress syndrome: four decades of inquiry into pathogenesis and rational management. Am J Respir Cell Mol Bioi 2005; 33:319-327 2 Wang L, Bastarache JA, Wickersham N, et al. Novel role of human alveolar epithelium in regulating intra-alveolar coagulation. Am J Respir Cell Mol BioI 2007; 293:364-374 3 Ware LB, Matthay MA, Parsons PE, et al. Pathogenetic and prognostic significance of altered coagulation and fibrinolysis in acute lung injury/acute respiratory distress syndrome. Crit Care Med 2007; 35:1821-1828 4 Bernard GR, Artigas A, Brigham KL, et al. The AmericanEuropean Consensus Conference on ARDS: definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med 1994; 149:818-824 5 Ware LB, Kaner RJ, Crystal RG, et al. VEGF levels in the alveolar compartment do not distinguish ARDS and pulmonary oedema. Eur Respir J 2005; 26:101-105 6 ARDS Network. Pulmonary-artery versus central venous catheter to guide treatment of acute lung injury. N Engl J Med 2006; 354:2213-2224 7 Kropski JA, Fremont RD, Calfee CS, et al. Clara cell protein (CCI6), a marker of lung epithelial injury, is decreased in plasma and pulmonary edema fluid from patients with acute lung injury. Chest 2009; 135:1440-1447 8 Uchida T, Shirasawa M, Ware LB, et al. Receptor for advanced glycation end-products is a marker of type I cell injury in acute lung injury. Am J Respir Crit Care Med 2006; 173:1008-1015 9 Calfee CS, Ware LB, Eisner MD, et al. Plasma receptor for advanced glycation end products and clinical outcomes in acute lung injury. Thorax 2008; 63:1083--1089 10 Eisner MD, Parsons P, Matthay MA, et al. Plasma surfactant protein levels and clinical outcomes in patients with acute lung injury. Thorax 2003; 58:983-988 11 Betsuyaku T, Fukuda Y, Parks WC, et al. Gelatinase B is required for alveolar bronchiolization after intratracheal bleomycin. Am J Pathol 2000; 157:525-535 1410

12 Frank JA, Gutierrez JA, Jones KD, et al. Low tidal volume reduces epithelial and endothelial injury in acid-injured rat lungs. Am J Respir Crit Care Med 2002; 165:242-249 13 Bucher HC, Guyatt GH, Cook DJ, et al. Users' guides to the medical literature: XIX. Applying clinical trial results: a how to use an article measuring the effect of an intervention on surrogate end points; Evidence-Based Medicine Working Group. JAMA 1999; 282:771-778 14 McClintock D, Zhuo H, Wickersham N, et al. Biomarkers of inflammation, coagulation, and fibrinolysis predict mortality in acute lung injury. Crit Care 2008; 12:R41

Sarcoidosis-Associated Pulmonary Hypertension One Size Does Not Fit All is a multisystem disease of unknown Sarcoidosis etiology that is characterized pathologically by noncaseating granulomatous inflammation with a particular predilection for the lungs. Its clinical course is highlyvariable, with a sizable proportion of patients experiencing spontaneous regression, while in others chronic disease develops.' Pulmonary hypertension (PH) is a hemodynamic state defined as a mean pulmonary artery pressure of > 25 mm Hg at rest or > 30 mm Hg with exercise. PH is seen in a variety of clinical settings, notably left-sided valvular and myocardial disease, chronic lung disease with hypoxemia, and chronic pulmonary embolism (Table 1).2 PH with a pulmonary capillary wedge pressure of < 15 mm Hg is called pulmonary arterial hypertension (PAH), and is seen in association with connective tissue disorders, congenital heart disease, and HIV infection, among other conditions. When no clear etiology can be identified in patients with PAH, the disease is classified as idiopathic PAH (IPAH).2.3 While IPAH is less common than other forms of PH, it is the best studied mainly because it is a well-defined subset of the disease.w' Sarcoidosis-associated PH is one of the harder to define PH subsets and falls into the "miscellaneous" category in the current classification, highlighting its heterogeneity and our lack of complete understanding of this condition. Several different mechanisms could account for PH in sarcoidosis. Left heart disease in the form of cardiac sarcoidosis needs to be ruled out, as elevated pulmonary capillary wedge pressure was seen 11% of the time in one study." The need for oxygen correlates with PH,6 and the majority of cases have radiographic stage IV disease," suggesting that parenchymal lung disease and hypoxemia play major roles in some patients. However, the relationship between lung volumes or hypoxemia and PH is far Editorials