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Pulmonary Embolism in Patients with Unexplained Exacerbation of Chronic Obstructive Pulmonary Disease: Prevalence and Risk Factors

Isabelle Tillie-Leblond, MD, PhD; Charles-Hugo Marquette, MD, PhD; Thierry Perez, MD; Arnaud Scherpereel, MD, PhD; Christophe Zanetti, MD; André-Bernard Tonnel, MD, PhD; and Martine Remy-Jardin, MD, PhD
[+] Article and Author Information

From University Hospital A Calmette, Lille, France.


Acknowledgments: The authors thank Pierre Taupin for biostatistical help.

Grant Support: None.

Potential Financial Conflicts of Interest: None disclosed.

Requests for Single Reprints: Isabelle Tillie-Leblond, MD, PhD, Lung Department, University Hospital A Calmette, 1 rue Leclercq, CHRU, 59037 Lille Cedex, France.

Current Author Addresses: Drs. Tillie-Leblond, Marquette, Perez, Scherpereel, Zanetti, and Tonnel: Lung Department, University Hospital A Calmette, 1 rue Leclercq, CHRU, 59037 Lille Cedex, France.

Dr. Remy-Jardin: Department of Radiology, University Center Hospital Calmette, 1 rue Leclercq, CHRU, 59037 Lille Cedex, France.

Author Contributions: Conception and design: I. Tillie-Leblond.

Analysis and interpretation of the data: I. Tillie-Leblond, C.-H. Marquette, T. Perez, A.-B. Tonnel.

Drafting of the article: I. Tillie-Leblond, C.-H. Marquette, T. Perez, C. Zanetti, A.-B. Tonnel, M. Remy-Jardin.

Provision of study materials or patients: A. Scherpereel, C. Zanetti, A.-B. Tonnel.


Ann Intern Med. 2006;144(6):390-396. doi:10.7326/0003-4819-144-6-200603210-00005
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In this study, we showed that the frequency of PE was 25% in a series of 197 consecutive patients with COPD referred for severe exacerbation of unknown origin. This is similar to the value of 27% reported in the Geneva study (1). In contrast with the clinical scores recently developed for diagnosing PE in unselected patients, the Geneva score (1) and the score reported by Wells and colleagues (2), we found that only 3 factors predicted PE: history of thromboembolism, malignant disease, and a decrease in Paco2 of at least 5 mm Hg. Recent surgery, which was rare in the patients in our study group, was not identified as a risk factor for PE. Conversely, the clinical symptoms supporting the suspicion of PE, such as hemoptysis, chest pain, and edema of the lower limbs, did not definitively indicate PE in our study group. We did not identify age, long-term oxygen therapy, and severity of COPD as risk factors for PE. Similarly, right-heart failure identified in 26 patients at admission was not associated with PE. Only 1 study (14) has shown that a majority of patients (23 of 26) with emphysema and PE had clinical right-heart failure on admission. Of note, this study was conducted in patients with life-threatening PE and was based on autopsy data. The present study did not include patients who required invasive mechanical ventilation or fibrinolysis, and our conclusions are therefore not valid for such populations.

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Response to: PE in patients with unexplained exacerbations of COPD
Posted on March 23, 2006
Grégoire Le Gal
EA3878, Brest University Hospital; Division of Angiology and Hemostasis, Geneva University Hospital
Conflict of Interest: None Declared

Dear Sir, We read with great interest the article by Tillie-Leblond et al. on the prevalence of pulmonary embolism in patients with chronic obstructive pulmonary disease (COPD) hospitalized for severe exacerbation of unknown origin.(1) This paper deserves two comments. First, the authors report that a low clinical probability as assessed by the Geneva score (2) could not rule out pulmonary embolism. This is hardly a surprise, as that clinical prediction rule was never intended to be used alone to rule in or out pulmonary embolism. Rather, it allows a more rational interpretation of test results, the predictive value depending not only on test characteristics but also on pretest probability. The 9.2% prevalence of pulmonary embolism among patients classified as having a low clinical probability in that study is similar to that observed in previous studies using the Geneva rule and suggests that this rule has good performances in the particular setting of patients with COPD. Second, the authors proposed a "modified" Geneva score in which they replaced malignancy by recent surgery. That modification was arbitrary and should be validated in another patient population before it can be generalized. Indeed, the proportion of patients with malignancy was particularly high in the study by Tillie-Leblond et al. Finally, we would like to point out that this modified Geneva score has nothing to do and should not be confounded with the recently published revised Geneva score,(3) which was derived from a large multicenter database using recommended methodology for clinical prediction rules and externally validated.

Conflict of Interest:

None declared

References

1. Tillie-Leblond I, Marquette CH, Perez T, Scherpereel A, Zanetti C, Tonnel AB, Remy-Jardin M. Pulmonary embolism in patients with unexplained exacerbation of chronic obstructive pulmonary disease: prevalence and risk factors. Ann Intern Med 2006;144:390-6.

2. Wicki J, Perneger TV, Junod AF, Bounameaux H, Perrier A. Assessing clinical probability of pulmonary embolism in the emergency ward: a simple score. Arch Intern Med 2001;161(1):92-7.

3. Le Gal G, Righini M, Roy P-M, Sanchez O, Aujesky D, Bounameaux H, Perrier A. Prediction of Pulmonary Embolism in the Emergency Department: The Revised Geneva Score. Ann Intern Med 2006;144(3):165-171.

Emergency physicians commentaries
Posted on April 12, 2006
Caroline Boulouffe
Cliniques Universitaires UCL - Mont Godinne
Conflict of Interest: None Declared

Dear Sir,

Because the diagnosis of pulmonary embolism (PE) is a great challenge for emergency physicians, we read with interest the article « Pulmonary Embolism in Patients with Unexplained Exacerbation of Chronic Obstructive Pulmonary Disease: Prevalence and Risk Factors », I. Tillie-Lebond et al. (1). It suggests us two commentaries.

First, during COPD exacerbation, PE must be evoked in unexplained situations. This is a large prospective study but in- and outpatients are obviously different and constitute an heterogenous group. As emergency physicians, our challenge is to exclude clinically significant pulmonary embolism among outpatients in acute exacerbation. Because the conclusions are based on a mixed group, those are thus more difficult to apply in our current practice. In the general out-of-hospital population, the incidence of venous thromboembolism ranges from 1.87 "° per year to 1 % per year for people older than 75 years (2). Hospitalised patients with acute medical conditions are at significant risk of venous thromboembolism : approximately 10-30% of general medical patients may develop deep-vein thrombosis or pulmonary embolism (3,4). No comparison between in- and outpatients with COPD exacerbation of unknown origin was ever done until now. It would be of great interest to know the part of PE among these two different categories of patients, the time of hospitalisation before the diagnosis of PE, the characteristics of the patients in each group and eventual predictive factors for PE.

Second observation, Tillie-Lebond et al. (1) showed that the variation of Pa CO2 between the steady state and the crisis state (Δ Pa CO2) should be a good predictive factor of PE among COPD patients. Mispelaere et al. (5) didn't found the fall of Pa CO2 as a significant criterion. In the Emergency Department of our teaching hospital, we reviewed the COPD patients admitted for acute increase of dyspnea. The first analysis of the results doesn't found the fall of Pa CO2 as a discriminating criterion of pulmonary embolism among COPD patients. Forthcoming large prospective studies should investigate this factor as PE predictive (or not) among COPD patients in exacerbation.

(1) Tillie-Leblond I et al. Pulmonary Embolism in Patients with Unexplained Exacerbation of Chronic Obstructive Pulmonary Disease: Prevalence and Risk Factors. Ann Intern Med. 2006;144:390-396.

(2) Oger E. Incidence of venous thromboembolism: a community-based study in Western France. EPI-GETBP Study Group.Thromb Haemost. 2000 May;83(5):657-60.

(3) Cohen AT et al. Assessment of venous thromboembolism risk and the benefits of thromboprophylaxis in medical patients. Thromb Haemost. 2005 Oct;94(4):750-9.

(4) Leizorovicz A and Mismetti P. Preventing Venous Thromboembolism in Medical Patients. Circulation. 2004;110[suppl IV]:IV-13"“IV-19.

(5) Mispelaere D, Glerant JC, Audebert M, Remond A, Sevestre-Pietri MA, Jounieaux V. Embolie pulmonaire et formes sibilantes des décompensations de bronchopneumopathie chronique obstructive. Rev Mal Respir 2002 ; 19 : 415-423.

Conflict of Interest:

None declared

Geneva score in patients with Pulmonary Embolism and Chronic Obstructive Pulmonary Disease.
Posted on May 15, 2006
Juan Francisco Sánchez Muñoz-Torrero
H.San Pedro de Alcantara (Cáceres) Spain
Conflict of Interest: None Declared

Dear Sir,

We read the article by Tillie-Leblond et al, in which the authors suggest that in patients with chronic obstructive pulmonary disease (COPD) the modified Geneva score substituting cancer for recent surgery may improve its performance in excluding pulmonary embolism (PE) 1. In their series only 4% of the PE patients had recent surgery, while 43% had cancer. This change lead the modified score to improve its performance in excluding PE from 9.2% to 3.2%.

We have recently compared the clinical characteristics, laboratory findings and clinical outcomes of all enrolled patients with acute PE, with or without underlying cardiopulmonary diseases in the RIETE Registry 2. In addition, the performance of 2 clinical models (the Geneva and the Pisa scores) for the diagnosis of PE was retrospectively evaluated. Of a total of 4,444 patients with symptomatic PE enrolled in RIETE, 632 patients (14%) had COPD. Of them, 109 patients (17%) had cancer and 70 (11%) had recent surgery. Substituting cancer for recent surgery in our series did not improve its performance: the initial 23% of PE patients with COPD who fell into the low pretest probability category converted to 22% using the modified score.

The strength of the RIETE Registry is the prospective collection of data from actual practice, from a very large number of consecutive patients with objectively confirmed PE, and by strictly applying objective criteria for diagnosis of PE. Data captured and reported in the registry will therefore reflect "real-world" approaches and outcomes in the treatment of PE. In our experience the percentage of COPD patients with PE developing shortly after surgery was higher than in the Tillie-Leblond series. Thus, we failed to confirm that the modified Geneva score might improve its performance in excluding PE in patients with COPD.

References:

1.- Tillie-Leblond I, Marquette CH, Perez T, Scherpereel A, Zanetti C, Tonnel AB, Remy-Jardin M. Pulmonary embolism in patients with unexplained exacerbation of chronic obstructive pulmonary disease : Prevalence and risk factors. Ann Intern Med 2006; 144:390-396.

2.- Monreal M, Sánchez Muñoz-Torrero JF, Naraine V, Jiménez D, Soler S, Rabuñal R, Gallego P, and the RIETE Investigators. Pulmonary Embolism in Patients with Chronic Obstructive Pulmonary Disease or Congestive Heart Failure. Findings from the RIETE Registry. Am J Med 2006 (in press).

Conflict of Interest:

None declared

In Response
Posted on May 22, 2006
Isabelle Tillie-Leblond
Hopital Calmette, University hospital, Lille, France
Conflict of Interest: None Declared

The aim of the study (1) was to evaluate the prevalence of PE in a selected population of COPD patients admitted for severe exacerbations of « unknown origin ». Statistical analysis to select predictive variables for PE identified three criteria: cancer, previous thromboembolic disease and a decrease in PaCO2 from baseline. Defining a specific score in COPD patients with a severe exacerbation of unknown origin based on a multivariate logistic regression model as in the Geneva study (2) was not possible. We agree that the Geneva score should not be considered alone to rule in or out PE. It should primarily be associated with a clinical probability assessment (2). In the population selected in our work (1), alternative diagnosis such as infection, pneumothorax, iatrogenic event were ruled out (1). In the COPD patients selected according to the clinical criteria « severe exacerbation of unknown origin », we calculated the Geneva score to evaluate its diagnostic value. The prevalence observed in COPD was 9.2% (95%CI, 4.7-15.9) of PE in a low probability group assessed by the Geneva score (1), similar to that observed in the Geneva study (10%, 95%CI, 8-13) (2). A key question is to consider if 9 or 10% of PE in a low probabiliy group has a sufficient negative predictive value. We agree that the clinical suspicion of PE is particularly difficult in COPD. However, missing one out of ten diagnosis of PE in the low probability group could be deleterious in a population with a poor baseline respiratory condition. The second comment concerns the « modified score ». We agree that this score was not prospectively evaluated and needs further validation (1). In our clinical practice, only 3 % of COPD patients admitted for severe exacerbation have had a recent surgical procedure. Surgery is included in the Geneva score (3 points) (2). In the COPD population, cancer occurs in a much higher prevalence and was a risk factor for PE in our study (1,3). For this reason, we modified the Geneva score with a more relevant risk factor for COPD patients (1). This score has currently no clinical value since it is not yet validated in a prospective study.

1- Tillie-Leblond I, Marquette CH, Perez T, Scherpereel A, Zanetti C,Tonnel AB, Remy-Jardin M. Pulmonary embolism in patients with unexplained exacerbation of chronic obstructive pulmonary disease: prevalence and risk factors. Ann Intern Med. 2006;144:390-6.

2-Wicki J, Perneger TV, Junod AF, Bounameaux H, Perrier A. Assessing clinical probability of pulmonary embolism in the emergency ward: a simple score. Arch Intern Med. 2001;161:92-7.

3-Tockman MS, Comstock GW. Respiratory risk factors and mortality:longitudinal studies in Washington County, Maryland. Am Rev Respir Dis. 1989;140:S56-63.

Conflict of Interest:

None declared

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