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ARTICLE IN PRESS doi:10.1510/icvts.2009.207852 Editorial

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State-of-the-art - Transplantation

Department of Radiology X, Diagnostic Imaging Centre, Rigshospitalet, Copenhagen University Hospital, Denmark Department of Lung Transplantation, The Heart Centre, Rigshospitalet, Copenhagen University Hospital, Denmark

a b

Summary

Best Evidence Topic Nomenclature Historical Pages Brief Case Report Communication

䊚 2009 Published by European Association for Cardio-Thoracic Surgery

State-of-the-art

夞 This research project has not received any external funding. *Corresponding author. Department of Radiology X, Section 9641, Rigshospitalet, Blegdamsvej 9, Copenhagen 2100 OE, Denmark. Tel.: q45 35459800; fax: q45 35452058. E-mail address: [email protected] (E. Belmaati).

Follow-up Paper

In the early phase after lung transplantation, patients may develop both diffuse infiltrates that are visible on chest radiographs, and an impairment of the graft function. This may represent primary graft dysfunction (PGD). PGD occurs in 11–60% of transplant patients depending on the diagnostic criteria applied and reporting different degrees of severity w1x. PGD, defined by the presence of diffuse radiological infiltrate, was recorded in 63% of lung-transplanted patients w1, 2x. Development of PGD in the early postoperative period will negatively affect long-term survival of lung-transplanted patients, even in those patients who do not develop bronchiolitis obliterans syndrome (BOS), which is a sign of chronic rejection of the lung w1, 3x. Mortality rates of between 17% and 50% have been

reported w1, 4x. PGD also negatively affects the pulmonary function of recipients of bilateral lung transplants who survive the perioperative period w3x. In its most severe form, investigators have found transplant recipients to be at significantly higher risk for early mortality, longer intensive care unit (ICU) stays, and increased hospital staying w1, 3x. The International Society of Heart and Lung Transplantation (ISHLT) Working Group on PGD has recommended a definition of PGD based on radiological findings at chest X-ray examination and the gas exchange impairment measured by PaO2:FiO2 ratio (ratio of the partial pressure of oxygen in arterial blood to the fraction of inspired oxygen, also termed PyF ratio) w5–7x. This definition has limitations, as it is an operational definition, the description pertains to the symptoms of PGD only. A more detailed description of PGD could help refine diagnostic and therapeutic efforts in future lung-transplant patients. Evaluation and grading of disease using high resolution computed tomography (HRCT) scans have not been incorporated in the definition of PGD.

Negative Results

1. Introduction

Proposal for Bailout Procedure

Keywords: Lung transplantation; Tomography; X-ray computed; Lung disease

ESCVS Article

We have reviewed and discussed current knowledge on existing scoring systems regarding high resolution computed tomography (HRCT) images for the assessment of primary graft dysfunction (PGD) after lung transplantation. Adult respiratory distress syndrome (ARDS) has been more widely studied and appears to have many morphological features similar to what is found in PGD, and might, therefore, be usefully extrapolated to PGD. Principles of HRCT, scoring systems based on HRCT and various terms describing PGD were reviewed and summarized. The sensitivity, inter-intra observer variability, and reproducibility of these systems were discussed. Lastly, the future perspectives for 64-multi-slice computed tomography (MSCT) in relation to PGD were discussed. Few studies on scoring systems of lung tissue by HRCT in ARDS patients and idiopathic pulmonary fibrosis (IPF) patients were found. Most studies were performed on patients with cystic fibrosis (CF). Sensitivity of HRCT for the detection of parenchymal changes is superior to other imaging methods. High levels of reproducibility are achievable amongst observers who score HRCT lung images. Development of standardized criteria that specify the inclusionyexclusion criteria of patients, pilot testing, and training investigators through review of disagreements, were possibilities suggested for decreasing interyintra observer variability. Factors affecting the image attenuation (Hounsfield numbers) and thus, the reproducibility of CT densitometric measurements were of minimal influence. Studies have reported on how lung tissue images, derived by HRCT, can be scored and graded. There does not seem to be a golden standard for evaluating these images, which makes comparison between methods challenging. These scoring systems assess the presence, severity, and extent of parenchymal change in the lung. HRCT is considered relevant and superior in evaluating disease severity, disease progression, and in evaluating the effects of therapy regimes in the lung. It is, however, not clear to what extent these scoring methods may be implemented for grading PGD. Further efforts could be made to standardize scoring methods for lung tissue with regards to PGD. 䊚 2009 Published by European Association for Cardio-Thoracic Surgery. All rights reserved.

Institutional Report

Received 24 March 2009; received in revised form 23 June 2009; accepted 22 July 2009

Protocol

Esther Belmaatia,*, Claus Jensena, Klaus F. Kofoedb, Martin Iversenb, Ida Steffensenb, Michael B. Nielsena

Work in Progress Report

Primary graft dysfunction; possible evaluation by high resolution computed tomography, and suggestions for a scoring system夞

New Ideas

Interactive CardioVascular and Thoracic Surgery 9 (2009) 859–867

ARTICLE IN PRESS 860

E. Belmaati et al. / Interactive CardioVascular and Thoracic Surgery 9 (2009) 859–867

Several attempts at designing visual scoring systems to characterize lung disease from HRCT images have been made, especially in studies of cystic fibrosis (CF) and pulmonary fibrosis. However, there are no similar studies on PGD. We have, therefore, studied closely related syndromes like adult respiratory distress syndrome (ARDS) and other areas of lung disease like CF and idiopathic pulmonary fibrosis (IPF), in which scorings systems have been studied. 2. Method We searched the Pub Med database and included studies published from 1989 to 2007. We included published studies if: (a) study design was a randomised controlled trial, an observational study with historical controls or observational study; (b) study population included patients with interstitial lung disease; (c) study provided data on scoring systems of lung tissue. We searched Pub Med using the medical subject headings (MeSH) terms: lung, lung disease, lung transplantation, pathology, methods, complications, graft rejection, reperfusion injury, respiratory distress syndrome, adult; tomography, X-ray computed, diagnosis, and classification. A free text literature search was also carried out in Pub Med using the keywords: scoring systems, HRCT score, PGD, CT score, and post lung transplantation imaging. 3. HRCT Possibilities for non-invasive characterization of lung tissue have improved with current development in multi-slice computed tomography (MSCT). Very detailed HRCT images of lung tissue can be reconstructed using 64-MSCT scanners. The smallest airways can now be optimally visualized by the scanners ability to produce overlapping high-resolution 0.5 mm to 1–2 mm thick sections throughout the thorax in a single breath-hold. Advantages of HRCT are the fine detail available and the ability to distinguish areas of lung parenchyma showing different disease patterns. A potential disadvantage of this technique is the considerably greater radiation dose that patients could be exposed to. Use of low-dose scanning coupled with dose modulation techniques (like reducing milliamperage) available on newer CT scanners can be used to minimize the problem and should be routinely used especially when scanning younger patients and women w8, 9x. Effective dose equivalents reported for chest CT, vary from 3 to 9 mSv (milli Siverts) depending on the technique used w10x, as compared to a chest X-ray in two planes that results in a dose of 0.11 mSv only. New developments have been made which lower peak kilo voltage (KVp) settings that results in dose savings of over 40% and doses as low as 2 mSv are now possible w11– 13x. There are no studies in which 64-MSCT has been used to describe PGD in lung tissue. Thin-section CT provides images that are similar to gross pathological sections of the lung w14x. HRCT of the lung has proved to be a sensitive method for detecting emphysema, and scoring systems have correlated with disease severity as determined by clinical scoring systems, radiographic scoring systems and pulmonary function tests (PFT) w15x.

Chest HRCT scores and quantitative HRCT measurements have a greater sensitivity to detect early changes, and these methods also have the ability to effectively follow the progression of CF lung disease w16x. Biederer et al. w17x showed that HRCT was valuable in detecting the variable and discontinuously distributed pulmonary lesions in interstitial lung disease associated with rheumatoid arthritis. It was also superior in monitoring the progression of disease, or effectiveness of therapy, as compared to using PFT and bronchoalveolar lavage (BAL). Structural abnormalities on CT are closely linked to the severity of the disease w18–20x. It is, therefore, of relevance to consider using HRCT to evaluate PGD. 4. Definitions and grading severity of PGD Many terms have been used to describe the clinical entity of PGD in the literature. Most studies have employed variations of already developed ARDS classification schemes to define PGD in local patient populations. PGD has been variously referred to as severe ischemia-reperfusion injury, reperfusion oedema, early graft dysfunction or a re-implantation response w7x. To co-ordinate future research and facilitate the exchange of data, the ISHLT Working Group on PGD has recently suggested a definition and graded reperfusion oedema as PGD w7x. The proposed scheme takes two clinical parameters into consideration and timing is also included in the scheme as follows: T-zero (T0) within 6 h of final lung reperfusion, T24, T48 and T72. It was recognized that after 72 h other factors may confound the definition and the working group of ISHLT does not recommend grading beyond 72 h w6x. See Table 1. After lung transplantation, some patients develop early diffuse infiltrates (visible on chest radiographs) and a delay in graft function, which may represent reperfusion oedema. Reperfusion oedema is considered a non-immune mediated inflammatory process, which is clinically analogous to ARDS in the most severe cases. Reperfusion oedema has been associated with a high perioperative mortality, poorer longterm survival, and a more rapid progression to BOS, than in patients without clinical evidence of reperfusion oedema w2 x . Reperfusion oedema (now known as PGD) has also been described as a non-cardiogenic pulmonary oedema that typically occurs )24 h after transplantation, peaks in severity on postoperative day 4, and generally improves by the end of the first week w4x. Reperfusion oedema has many possible causes including surgical trauma, donor lung Table 1 Recommendations for grading primary graft dysfunction severity w7x Grade

PaO2 yFiO2

Radiographic infiltrates consistent with pulmonary edema

0 1 2 3

)300 )300 200–300 -200

Absent Present Present Present

PaO2:FiO2 (ratio of the partial pressure of oxygen in arterial blood to the fraction of inspired oxygen, also termed PyF ratio).

ARTICLE IN PRESS E. Belmaati et al. / Interactive CardioVascular and Thoracic Surgery 9 (2009) 859–867

Proposal for Bailout Procedure Negative Results Follow-up Paper State-of-the-art Best Evidence Topic Nomenclature

Table 2 Definitions of ARDS, CF and IPF

ESCVS Article

There have been no studies on scoring systems involving PGD. We have, therefore, studied closely the related syndrome, ARDS. We have also included other areas of lung disease, like CF and IPF, which are pathologically and radiologically quite different from PGD. This was done

Institutional Report

5.2. Studies on scoring systems in ARDS, CF and IPF

5.3.2. No ¨bauer-Huhmann et al. (2001). ARDS study No ¨bauer-Huhmann et al. w26x focused on changes in lung parenchyma after ARDS (assessed with HRCT), and revealed parenchymal abnormalities in patients with normal lung function tests. The study evaluated the appearance, the extent, and the distribution of parenchymal changes in the lung after ARDS, as a function of disease severity and therapeutic procedures, Table 4. HRCT scans, clinical examinations, and lung function tests were carried out in patients. For the radiological assessment of parenchymal

Protocol

A scoring system is a tool used to describe the abnormalities observed on diagnostic images like HRCT in a semiquantitative method of measurement. The scoring system used to convert the CT image to numeric data is an essential determinant of the performance of the CT scanning. The design of the scoring system determines the numerical value that is obtained from the CT images. Variations in the scoring system will likely have as much or more effect on the results obtained with CT scanning than with the technical aspects of obtaining the CT images. Multiple scorings systems have been proposed for other diseases. Evaluation of these systems identified limitations, suggesting that new scoring systems should be developed w21x.

5.3.1. Bhalla et al. (1991). CF study Bhalla et al. w24x were the first to publish a study on a thin-section CT scoring system for CF. Several modifications of this scoring system have since been published and they are based on a system of the reader identifying various abnormalities on the CT-scans, and assessing their severity. Abnormalities included in most scoring systems are bronchiectasis, parenchymal opacities, and airway wall thickening. Other abnormalities like mosaic attenuation, air-trapping, and nodules are only included in some systems. Expiratory images are included in more recent CT studies as they are thought to reflect small airway disease, which occurs early in the course of CF lung disease w25x. Important differences between scoring systems are the various compartmentalization methods (for example, lobar vs. segmental). Other scores are solely based on CT images while others are composite scores based on CT images and PFT w25x. In the Bhalla et al. publication w24x, airway disease was mainly assessed by the severity and extent, meaning the number of generations of bronchial divisions involved when evaluating morphological change, Table 3. In this study, thin-section CT was found to be superior to chest radiography for the evaluation of patients with CF w24x. The study suggested the possibility of generating a score that could be used clinically to determine the need for more aggressive therapy or to determine patients who would be candidates for lung transplantation.

Work in Progress Report

5.1. Scoring systems

5.3. The various scoring systems

New Ideas

5. HRCT and the various scoring systems

solely for the purpose of comparing principles of constructing scoring systems, for these lung diseases, to pave the way for creating a scoring system for PGD. For definitions of ARDS, CF and IPF, see Table 2.

Editorial

ischemia, interruption of the bronchial circulation or lymphatic flow, and denervation of the donor lung. Radiographic CT features are non-specific and may include peri-hilar ground glass opacities, peri-bronchial and peri-vascular thickening, and reticular interstitial or airspace opacities located predominantly in the middle lower lobes w4x. PGD after lung transplantation has many clinical features in common with other forms of acute lung injury like ARDS, including severe hypoxemia in the first 72 h after surgery, lung oedema and radiographic evidence of diffuse pulmonary infiltration without identifiable cause. Reliability of X-ray interpretation in PGD is an important concern, given the experience with X-ray inconsistency in ARDS w7x. In addition, gas exchange impairment has been assessed by using the PyF ratio. Although this is a widely accepted parameter, it can be problematic at the extremes of the range of FiO2, or with the application of partial endexpiratory pressure (PEEP). For example, an individual with a FiO2 of 0.24, PaO2 of 65 and a PayFiO2 score of 271 would meet the criteria for PGD in some studies w7x.

861

ARDS is an advanced form of acute lung injury characterized by diffuse pathological changes of inflammation, increased capillary permeability, and tissue repair. The clinical syndrome includes a triad of hypoxemia, chest radiographic abnormalities and decreased lung compliance w22x.

ARDS, adult respiratory distress syndrome; CF, cystic fibrosis; IPF, idiopathic pulmonary fibrosis; HRCT, high resolution computed tomography.

Brief Case Report Communication

IPF is defined as a specific form of chronic fibrosing interstitial pneumonia limited to the lung and associated with the histological appearance of usual interstitial pneumonia (UIP) on surgical (thoracoscopic or open) lung biopsy w23x. The etiology is unknown. The definite diagnosis of IPF in the presence of a surgical biopsy showing UIP includes the following: 1. Exclusion of other known causes of interstitial lung disease such as; drug toxicities, environmental exposure and collagen disease. 2. Abnormal pulmonary function studies that include evidence of restriction andyor impaired gas exchange with rest or exercise or decreased diffusion capacity of the lung for CO (DLco). 3. Abnormalities on conventional chest radiographs and HRCT scan w23x.

Historical Pages

CF on the other hand, is a genetic disorder causing progressive lung disease that in the first months of life and leads to progressive structural damage to the lungs. In the early stages, there is submucosal gland hypertrophy, depletion of airway surface liquid and ineffective clearance of mucous. These changes foster airway obstruction, airway inflammation and infection, which then lead to increased airway wall thickness, bronchiectasis, mucous plugging, air-trapping, peribronchial thickening, and parenchymal abnormalities w16, 18, 21x.

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Table 3 The components of various scoring systems involving the use of CT, for interstitial lung disease

Compartmentalization method Ground glass opacities Consolidations Septal thickening Peribronchial thickening Mosaic attenuation Air-trapping Bronchiectasis Emphysema Mucous plugging Centrilobular (acinar) nodules Bullae Overinflation Sacculation or abscess

Bhalla et al., 1991

Robinson et al., 2001

No ¨bauerHuhmann et al., 2001

Robinson, 2004

Brody, 2004

Brody et al., 2006

CF study ns14

CF study ns17

ARDS study ns15

CF study ns25

CF study ns60

CF study ns31

Thin-section CT

HRCT

HRCT

HRCT

HRCT

HRCT

BPS

Lobes

24 zones

Lobes

Lobes

Lobes

*

* * *

* * * *

* * * *

* *

* *

*

*

* *

* * * * * *

* *

* *

* *

*

*

* * *

* * * *

* *

* * *

* *

*

*Included in the scoring system. CT, computed tomography; CF, cystic fibrosis; ARDS, adult respiratory distress syndrome; HRCT, high resolution computed tomography; BPS, bronchopulmonary segments.

changes, the lung was divided into 12 compartments on each side (24 in all), namely the apical, middle, and basal zones, each consisting of a central, ventral, lateral, and dorsal compartment. Changes were considered ‘localized’ when they were present in less than one-third of each compartment. The presence and extent of morphological changes were separately assessed and grouped into three severity classes of parenchymal destruction, namely minor, moderate and severe. An overall HRCT score for each patient was calculated by averaging all compartment scores. The distribution of the findings was assessed, by calculating the mean score of the compartments according to the anatomic location. 5.3.3. Robinson (2004). CF study Robinson summarizes developments in HRCT and volumetric CT imaging and concludes that chest HRCT scores and quantitative HRCT measurements can detect regional CF lung disease before changes seen in global pulmonary function measurements w16, 27x. The parenchymal components that were scored are listed in Table 3. An actual scoring method was not described, however, potential reversible components were marked as follows: *, atelectasis minimal or not seen; q, improvement in scores; –, no change in score. 5.3.4. Brody et al. (2004, 2006). CF study Brody et al. carried out a study of scoring systems for CT on children in the Wisconsin CF Neonatal Screening Project, and demonstrated that the overall score was both sensitive to variation in the severity of lung disease, and reproducible w21x. This study evaluated and scored the presence and

severity of the findings of CF lung disease in each lobe, (the lingual lobe was counted as a separate lobe), a total of six lobes. Sub-scores for each lobe and each abnormality were added to produce an overall lung disease severity score. Each lobe was evaluated centrally and peripherally. The clinical relevance of the scoring system as an end point in intervention or natural history was not established in this study. An earlier study by Alan S. Brody w28x using a very similar scoring system, as the one just described, correlated HRCT scans of the lungs with spirometry and suggested that HRCT could identify lung disease in children whose lungs were evaluated as normal by using spirometry. HRCT often showed more lung disease than suggested by spirometry. 5.3.5. Lynch et al. (2005). IPF study Lynch aimed at shedding light on the HRCT features of patients with IPF that had mild to moderate physiological impairment, the usefulness of HRCT findings as predictors of mortality in such patients, and the reliability of the HRCT interpretation among radiologist. HRCT was an integral aspect of the evaluation of patients with suspected IPF. The combined extent of reticulation and honeycombing, which represents the extent of fibrosis, is a strong independent predictor of mortality in patients with IPF w29x. The diagnosis of IPF was confirmed by a panel of radiologists using HRCT. 6. Methodological problems in CT indexes Most studies compare lung X-ray with CT while there are only few studies on CT-CT comparison. Lung X-ray images

ARTICLE IN PRESS E. Belmaati et al. / Interactive CardioVascular and Thoracic Surgery 9 (2009) 859–867

863 Editorial

Table 4 An overview of various studies on scoring systems and their clinical relevance

Severity and extent of all morphological change in lungs of CF patients

Severity and extent of lung disease in CF patients

Changes in lung parenchyma after ARDS assessed with HRCT

HRCT of parenchyma. No actual method described

Presence and severity of CF lung disease findings in each lobe

Presence and severity of CF lung disease findings in each lobe

Conclusions

CT is superior to chest X-ray in CF disease detection and facilitates evaluation of therapeutic regimens

Spirometertriggered HRCT and PFTs were sensitive to change after treatment

HRCT detects parenchymal change in ARDS survivors. Changes were localized and had ventral predominance

HRCT detects regional CF lung disease before changes seen in global pulmonary function measurements

HRCT shows pulmonary abnormalities in patients with mildy moderate CF disease and normal PFTs

Numerical value obtained from CT images measures disease severity

Inter-observer variability

S.D. of 1.02

None

None

None

PCPA method. 83, 93 and 82% for bron, mp, and at, respectively

MELMA method 0.28 variation

Intra-observer variability

None

SBPF (0.97)

None

None

PCPA was used. No results

MELMA method 0.45 variation

Reproducibility

None

None

None

None

None

MELMA method Result: 95%

Sensitivity

None

No actual measure. HRCT is able to detect change after treatment for pulmonary exacerbation

Significant correlation between severity of CT findings and severity of ARDS (Murray score; P-0.05) 0.03

No actual measure. HRCT detects early changes and has the ability to follow progression of CF lung disease

None

MELMA Result: 3.81

Clinical relevance

May facilitate objective evaluation of therapeutic regimens and be valuable as a tool to assess lung patients preoperatively

HRCT imaging can be used in combination with, and standardized by PFTs for assessing short-term treatment changes in CF

Assessing lung damage after ARDS due to ventilation treatment (highly aggressive and prolonged mechanical ventilations with high pressure and high oxygen)

Study proposes that chest HRCTy CT outcome measures should be used during clinical intervention studies to evaluate treatment effects

HRCT-PFT data combined may be best in assessing CF. HRCT could confirmyevaluate disease severityy progression with normalyworsening PFTs

This study did not establish the clinical relevance of the scoring system nor the value of the scoring system as an end point in intervention or natural history trials

Negative Results

Scoring and evaluation methods

Best Evidence Topic Nomenclature Historical Pages Brief Case Report Communication

The sensitivity of HRCT for the depiction of parenchymal changes is known to be superior to other imaging methods and HRCT has been shown to reveal parenchymal abnormalities in patients with normal lung function tests w26x (Table 4). CT scoring was highly likely to be more sensitive than spirometric parameters to detect relevant disease progression in CF w18x. PFTs have been the mainstay of clinical evaluation of lung disease in CF. Severity of lung disease in

State-of-the-art

6.1. Sensitivity

CF is usually evaluated with measurement of the FEV1. This approach is limited in patients with mild lung disease in whom the FEV1 value is normal despite the presence of abnormal airways and an exaggerated inflammatory response. Numerous investigators have found that in patients with abnormal PFT results, correlation between PFT results and the morphological abnormalities identified with imaging is limited. This could be because PFTs are effort dependant and because the presence of bronchiectasis has little effect on PFT results. PFTs reflect the overall status of the lungs whereas CT provides excellent anatomic localization w30x. It is important to be aware of limitations in the accuracy of thin-section CT for the diagnosis of acute rejection. Gotway et al. have shown limited sensitivity,

Follow-up Paper

CF, cystic fibrosis; ARDS, adult respiratory distress syndrome; HRCT, high resolution computed tomography; CT, computed tomography; PFT, pulmonary function test; S.D., standard deviation; PCPA, Pearson correlations and percent agreement; bron, bronchiectasis; mp, mucous plugging; at, air-trapping; MELMA, mixed effects linear model analysis; SBPF, Spearman Brown prediction formula.

have the disadvantage of being difficult to quantify, whereas CT scan, to a large extent, be quantified in inter-intra observer studies.

Proposal for Bailout Procedure

Brody et al., 2006

ESCVS Article

Brody, 2004

Institutional Report

Robinson, 2004

Protocol

No ¨bauer-Huhmann et al., 2001

Work in Progress Report

Robinson et al., 2001

New Ideas

Bhalla et al., 1991

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specificity, positive and negative predictive values, and accuracy for the detection of acute rejection shortly following lung transplantation w31, 32x. Thin-section CT is, however, useful as an aid in diagnosing chronic rejection, as it reveals early changes in the lung w33x. 6.2. Inter-intra observer variability Visual screening is subjective and HRCT has shown various intra- and inter-observer k-values in several chronic lung parenchymal diseases w15x. To evaluate the variability of a scoring system, one should evaluate the inter-intra variability of both the composite CT score (total score) and of its component score (score of each parameter) w25x. A review of several studies on scoring systems were evaluated for inter-intra variability in a cross sectional study. The studies were by Brody et al. w30x, Bhalla et al. w24x, Helbich et al. w34x and Santamaria et al. w35x. A total of 25 CT-scans from children with CF, ages 5–18 years, were

scored and re-scored by three observers after an interval of 1–2 weeks to 1–2 months. Inter-intra observer variability was low, with intra-class correlation coefficients generally )0.8. After this validation, the systems were used in a 2-year longitudinal study of 48 children with CF. Again, there was no difference in the ability to track disease progression between the scoring systems. The study concluded that overall scoring systems had good inter-intra observer variability for the composite CT scores. Inter-intra observer variability was reasonable for component scores, but inter-observer variability was poor for some components. The reason for the high variability of some component scores was related to the lack of unambiguous definitions and of reference images. Inter-intra observer variability could possibly be reduced by improving definitions of components, using reference images, and standardizing training of observers w25x. Limited inter-observer levels of agreement in assessing diagnostic images of patients with ARDS, suggests a need to attend to this issue.

Table 5 MSCT scan plan First MSCT: Third day post-lung transplantation: maximal changes in the lung are expected at this time. Most patients ()90%) will be extubated at this time, which means that there are fewer practical problems compared to an earlier scan. Second MSCT: Fourteenth day post-lung transplantation: this is when the first biopsy will be taken. The biopsies will be taken before the scan to avoid artefacts. Most patients with PGD will have a normal chest X-ray, whereas, we expect to find clear morphological changes in the lung tissue with MSCT at this stage. The morphological changes at this time can be correlated to the first trans-bronchial biopsy. Third MSCT: Three months post lung-transplantation: most patients have achieved stable lung function, close to the maximum obtainable after transplantation. The morphological changes found will be correlated to the lung biopsies, which are taken at this time. All patients will also be routinely assessed with a ventilationyperfusion scanning taken at three months post transplantation, which can also be correlated with the CT-scans. Fourth MSCT: Twelve months post lung-transplantation. We expect that patients are quite stabile and that any lung changes found at this time, will most likely be chronic. MSCT, multi-slice computed tomography; PGD, primary graft dysfunction; CT, computed tomography. Table 6 Definitions of parameters used in the scoring system w9x Changes on CT

Definitions

Ground glass opacities

A hazy increase in the lung opacity on HRCT that is not associated with obscuration of underlying vessels and can, therefore, be differentiated from air space consolidation. An increase in lung opacity, discernible on plain radiographs or HRCT, that results in obscuration of underlying vessels. Abnormal thickening of interlobular septa usually resulting from fibrosis, edema, or infiltration by cells or other material. Thickening can be smooth, nodular, or irregular in different diseases. Septal fortykkelser scores som 1 selv om der kun er lidt. Thickening of the peribronchovascular interstitium that surrounds the perihilar bronchi and vessels. This is recognizable by an apparent thickening of the bronchial wall and an apparent increase in size or nodular appearance of pulmonary arteries. Note that on the 3rd day, peribronchial thickening should be assesed from the first point of division of the main bronchus, due to cuffing (swelling) around the hilus, seen in all patients just after the operation. An accumulation of fluid between the layers of the membranes that line the lungs and chest cavity. A collection of gas in the space around the lungs. The sudden obstruction of a pulmonary artery due to a clot (embolus). A clot in a pulmonary vein. Regional differences in lung perfusion resulting in visible attenuation differences on inspiratory HRCT. Abnormal retention of air within a lung or part of lung, especially during or after inspiration as a result of airway obstruction or abnormalities in lung compliance. Lung parenchyma remains lucent after post expiratory CT-scans. Localized or diffuse, irreversible bronchial dilation. A rupture or splitting open, as of a surgical wound or of an organ or structure to discharge its contents. Occurs when air gets into tissues under the skin covering the chest wall or neck. Increased lymph node size or heterogenecity of lymph nodes.

Consolidation Septal thickening

Peribronchial (peribronchovascular) thickening

Pleural effusion Pneumothorax Arterial lung emboli Venous lung emboli Mosaic attenuation Air-trapping

Bronchietasis Dehiscense Subcutaneous emphysema Lymph nodes

The central part of the lobe is defined as the anatomical half of the lobe closest to the hilus. The peripheral part of the lobe is defined as the outer half of the lobe around the central part of the lobe. CT, computed tomography; HRCT, high resolution computed tomography.

ARTICLE IN PRESS E. Belmaati et al. / Interactive CardioVascular and Thoracic Surgery 9 (2009) 859–867

865 Editorial New Ideas Work in Progress Report Protocol Institutional Report ESCVS Article Proposal for Bailout Procedure Negative Results Follow-up Paper State-of-the-art Best Evidence Topic Nomenclature Brief Case Report Communication

(AECC) radiographic criterion for acute lung injury-ARDS (ALI-ARDS) w37x. It was suggested that the variability in the reports of the incidence, risk factors, and outcomes of ARDS were due, in part, to poorly characterized definitions, and to a heterogeneous patient population. Definitions were not specific enough to lead readers to a reliable and reproducible interpretation of chest radiographs. To standardize these definitions, AECC defined ALI as the acute onset of arterial hypoxemia (PaO2 :FiO2 ratio, F300), a pulmonary artery wedge pressure of F18 mmHg with no

Historical Pages

Diagnosing ARDS depends, in part, on identifying characteristic radiographic abnormalities. To be consistently useful, interpretation of a radiological investigation must be reliable. Development of standardized criteria that specify the inclusionyexclusion criteria of patients, pilot testing, and training investigators through review of disagreements, are possibilities for decreasing interyintra observer variability. Rubenfeld et al. w36x studied the inter-observer variability in applying American European Consensus Conference

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clinical evidence of left arterial hypertension, and bilateral infiltrates with pulmonary oedema on frontal chest radiograph. ARDS is defined by the same criteria as ALI, but with more severe hypoxemia (PaO2:FiO2 , F200). No radiographic distinction was made between ALI and ARDS. The study showed high inter-observer variability despite the use of these definitions by volunteers recruited from participants at the Toronto Mechanical Ventilation Workshop, November 1997 and from the National Institute of Health (NIH) ARDS Network w36x. Investigators without formal consensus training could achieve moderate levels of agreement. Consensus training is necessary to achieve the substantial or almost perfect levels of agreement optimal for the conduct of clinical trials. To minimize bias, chest radiograph films were shuffled and the patient identifications were covered and replaced with a film number to minimize bias that might occur if investigators reviewed serial films from a single patient sequence. Repeated reviews of the training film sets with one another, discussing the reason for disagreements, agreement on how to deal with difficult judgement, and refining the standards, were accepted methods of maximizing agreement in a wide variety of clinical ratings. The process was referred to as a ‘standardized review’ w22x. 6.3. Interyintra observer reproducibility A study on HRCT in smoking-induced disease w38x showed that reproducibility of lung attenuation in HRCT is affected by variation in scanning techniques, contrast media enhancement, slice thickness, tube voltage, positioning of the patient in the scanner, object size, reconstruction algorithm and type of scanner. All the factors mentioned above affect the image attenuation (Hounsfield numbers) and thus, the reproducibility of CT densitometric measurements. With modern equipment, these factors are considered to have minimal influence w38x. A patient related factor that could lead to reproducibility error is the respiratory status of the patient (i.e. level of inspiration). Spirometric-gated CT-scanning, which could possibly counteract this problem, is not widely used. 7. Future perspectives We have revised CT scoring systems for ARDS (which is analogous to PGD), CF and IPF. It is well established that CT images are more detailed compared with X-ray images. Despite this detail in CT, it is still possible to achieve high levels of reproducibility amongst observers. Sixty-four-MSCT imaging technique provides immense detail such as three-dimensional images of lung tissue, pulmonal angiography, right ventricle angiography and images that are comparable to gross pathological specimens. With the help of this technique, it could be possible to distinguish between BOOP and other forms of PGD, if indeed PGD is shown to be a heterogenous syndrome. Other studies on scoring systems of IPF have also been able to show that HRCT correlated to a similar degree with impairment of lung function w39, 40x.

Further studies could be made on the descriptive evaluation of 64-MSCT findings in relation to histology, lung biopsies and physiological examinations like blood gas analysis and lung function tests after lung transplantation. Further efforts could be made to standardize scoring methods for lung tissue with regards to PGD and to test for differences in scoring and grading of lung tissue at a segmental level, as compared to scoring at a lobal level. This may be relevant for future designs of score methods for lung tissue, with regards to PGD. 8. Proposal We propose to evaluate the diagnostic value of 64 detectors MSCT imaging, after lung transplantation, in characterizing PGD. Over a period of 24 months, all patients expected to undergo lung transplantation will receive an offer to participate in the project. We expect to examine 70 consecutive patients that are recommended for lung transplantation at Rigshospsitalets Lungetransplantations Klinik, Copenhagen, Denmark, where there are about 35 lung transplantations a year. Patients will be scanned four times over a period of a year. See Table 5 for MSCT scan plan. CT images will be reviewed in random by three observers (one Radiologist, one Lung Specialist and one MD). The scoring system for PGD will be based on; assessing each transplanted lung at a lobal level, both centrally and peripherally. The lung lobes will be evaluated for several parameters, clearly defined in Table 6. Each lobe will be given a score according to the degree of affection, and these scores will be summarized to give an overall score, and an objective picture of the degree, to which the transplanted lung is affected. See Table 7 for an example of a scoring sheet. 9. Conclusion There are many suggestions and methods on how lung tissue images, derived by HRCT, can be scored and graded. However, there does not seem to be a golden standard to evaluate these images, which makes comparison between methods difficult. There were a few studies on scoring systems in patients with ARDS, which is analogous to PGD, and no studies in which 64-MSCT was used to describe PGD in lung tissue. Most of the studies on scoring systems were designed for, and tested on patients with CF. These scoring systems evaluated the presence, severity, and extent of parenchymal change in the lung. HRCT is considered relevant and superior in evaluating disease severity, disease progression, and in evaluating the effects of therapy regimes in the lung. It is, however, not clear what these scoring methods mean for grading PGD. References w1x Carter YM, Davis RD. Primary graft dysfunction in lung transplantation. Semin Respir Crit Care Med 2006;27:501–507. w2x Burton CM, Iversen M, Milman N, Zemtsovski M, Carlsen J, Steinbruchel D, Mortensen J, Andersen CB. Outcome of lung transplanted patients

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