More than 70% of pulmonary arteriovenous malformations are associated with the genetic condition, hereditary hemorrhagic telangiectasia, also known as the Osler-Weber-Rendu syndrome (1). Hereditary hemorrhagic telangiectasia is a disorder of vascular development resulting from mutations in components of the transforming growth factor-[beta] receptor complex, either activin receptor-like kinase 1 or endoglin (2). This autosomal dominant condition is characterized by mucocutaneous and gastrointestinal telangiectasia presenting with recurrent epistaxes and gastrointestinal blood loss. Larger ateriovenous malformations can also affect the cerebral, hepatic, and pulmonary circulations. Cerebral arteriovenous malformations may bleed causing seizures and paresis, whereas shunting of blood through large hepatic arteriovenous malformations may cause high-output cardiac failure (3). Pulmonary arteriovenous malformations occur in more than 30% of patients with hereditary hemorrhagic telangiectasia, vary in size from microscopic to greater than 50 mm in diameter, are usually multiple, and occur most commonly in the lung bases. The larger malformations are associated with arterial hypoxemia, transient ischemic attacks, and stroke (incidence 25%) secondary to paradoxical embolism and cerebral abscess (incidence of 10-15%) (4). Transcatheter coil embolization has replaced surgical resection as the treatment of choice. Therapeutic embolization improves hypoxemia and exercise capacity. The identification of pulmonary arteriovenous malformations also necessitates the use of prophylactic antibiotics before dental and surgical procedures to reduce the risk of embolic abscesses. Thus it is critical that physicians looking after patients with hereditary hemorrhagic telangiectasia screen for pulmonary arteriovenous malformations. Unfortunately, the absence of dyspnea or normal resting oxygen saturation does not exclude clinically significant pulmonary arteriovenous malformations and all patients should therefore undergo some form of screening. The article by Cottin and colleagues (5) in this issue of the Journal (pp. 994-1000) addresses the important question of which is the most accurate test to diagnose clinically significant or treatable pulmonary arteriovenous malformations, while avoiding computed tomography or angiography in most patients.
In a group of 105 patients with hereditary hemorrhagic telangiectasia, Cottin and colleagues (5) compared the accuracy of a panel of noninvasive screening tests for pulmonary arteriovenous malformations against spiral volumetric thoracic computed tomography (CT) scan or digital subtraction pulmonary angiography (as gold standards) (6). Patients underwent an assessment of dyspnea, chest radiograph, measurement of alveolar-arterial oxygen gradient (breathing 100% oxygen), contrast echocardiography, and radionuclide perfusion lung scanning. The strength of this study was that nearly all patients underwent all tests. Contrast echocardiography possessed the best attributes for a single screening test: sensitivity of 92% and predictive value for a negative test of 97%. Specificity, however, against CT or angiographically confirmed pulmonary arteriovenous malformations was only 62%. The high sensitivity of contrast echocardiography has been shown previously (7). The relatively low specificity probably reflects the presence of microscopic pulmonary arteriovenous malformations beyond the detection limit of the CT and angiography. A clinical history of dyspnea, and each of the other noninvasive tests, were less efficient for screening, with sensitivities of less than 75% and negative predictive value of less than 80%.
The authors acknowledge that this was a retrospective study in a specialized center and their series had an unusually high frequency of pulmonary arteriovenous malformations (48%), which naturally increased the pretest probability of disease. To attempt to correct for this problem, the authors used Bayesian theory to vary the pretest probability of disease. For low and high estimates of pretest probability, the combination of chest X-ray and contrast echocardiography excluded the diagnosis of pulmonary arteriovenous malformation with a probability of 100%. The authors recommend that both these tests be performed when screening patients with hereditary hemorrhagic telangiectasia and, if either is positive, a chest CT should be performed. If pulmonary arteriovenous malformations are confirmed on a CT scan, pulmonary angiography should be undertaken to assess whether the malformations are suitable for coil embolization. If the CT scan is negative in the face of a positive contrast echo study, this indicates microscopic malformations that would not be suitable for embolization. Consideration should still be given to antibiotic prophylaxis in such patients. This study by Cottin and colleagues has helped clarify the approach to screening patients with hereditary hemorrhagic telangiectasia for pulmonary arteriovenous malformations. The high specificity but low sensitivity of the chest radiograph has been previously documented (7). Cottin and colleagues also confirm that the simple anteroposterior chest radiograph had a specificity of 98% and a positive predictive value of 97%, and pulmonary arteriovenous malformations large enough to be visible on the radiograph usually warranted embolization. Based on this, a reasonable approach would be to screen patients initially by chest radiography. If this is positive, a confirmatory CT scan should be performed followed by angiography if embolization is contemplated. If the chest X-ray is negative, a significant pulmonary arteriovenous malformation cannot be excluded, and contrast echocardiography would be the next test of choice. Sequential, rather than simultaneous, application of these tests would seem to be the most efficient method of screening.
Although local practices continue to influence which tests are used, the study by Cottin and colleagues (5) has provided the best comparison of tests to date. Indeed, the accuracy of these tests when screening for pulmonary arteriovenous malformation is to be envied. Moreover, coil embolization provides an effective treatment for the malformations (8, 9). The real question now becomes: what is the outcome of screening and intervention in patients with hereditary hemorrhagic telangiectasia? Coil embolization is certainly effective for reducing right-to-left shunt, improving arterial hypoxemia, and increasing exercise capacity in patients with large or numerous pulmonary arteriovenous malformations (9). The effect of screening, however, will be to reveal patients with fewer malformations who are clinically asymptomatic. The rationale for embolization in this group is to reduce the frequency of cerebral events. Convincing data on this aspect, however, are lacking. Many specialist centers now adopt an aggressive approach to pulmonary arteriovenous malformations and attempts are made to embolize all treatable malformations. Cerebral events continue to occur in patients who have undergone extensive embolization, many of whom can be shown to have a persisting shunt on contrast echocardiography, presumably reflecting shunting through microscopic malformations (10, 11). The best technique for quantification of shunt that persists after embolization is uncertain (12). Although it seems to make sound clinical sense that therapeutic embolization should reduce the risk of cerebral events, the procedure is not trivial, and significant complications may occur in 6% of procedures (8). With the rise of specialist centers treating patients with hereditary hemorrhagic telangiectasia it should be possible to obtain a clearer picture of the risk-benefit ratio of embolization therapy in patients with pulmonary arteriovenous malformations, and particularly in patients without hypoxemia.
References
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DOI: 10.1164/rccm.2402026
Conflict of Interest Statement: N.W.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
NICHOLAS W. MORRELL, M.D.
University of Cambridge School of Clinical Medicine
Cambridge, United Kingdom
Copyright American Thoracic Society May 1, 2004
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