New Diagnostic Tests for Pulmonary Embolism
Kline JA, et al Ann Emerg Med 2000;35:168
This paper was written in 1999, and because it seems like thousands of papers have subsequently been written on this topic, I will attempt to review this paper as well as some of the more recent data.
Pulmonary embolism is a common and deadly illness with a reported annual incidence of about one case per 1,000 population. It is thought to account for up to 200,000 deaths per year in the U.S. Unfortunately, as many of us know, diagnosing PE is difficult because the clinical signs and physical exam are unreliable, as are many of the tests. Treating PE is also dangerous, and physicians would like to be as certain as possible before diagnosing and beginning treatment.
In 1977, one study pointed out that PE was being overdiagnosed in previously healthy patients because of the inappropriate use of diagnostic studies. (Ann Intern Med 1977;87:775.) Researchers have been driven to come up with quick, easy, and accurate tests to screen for and diagnose PEs so that the diagnosis is not missed, that unnecessary, dangerous tests are not performed searching for the diagnosis, and that dangerous and sometimes lifelong therapy is not begun unnecessarily.
Pulmonary angiography has long been considered the gold standard for the diagnosis of PE. Unfortunately, this test has many limitations. It takes a significant length of time to perform, requires an expertise in performance and interpretation, is invasive, and has several serious associated risks. Because of these limitations, pulmonary angiography is now reserved for the small subgroup of patients in whom the diagnosis of PE cannot be made by less invasive means even though the pretest probability of having the illness is high.
The multi-center Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED), published in 1990, compared the diagnostic value of the radioisotopic ventilation-perfusion lung scan (V/Q scan) with pulmonary angiography for diagnosing PE. This landmark study and a later comprehensive analysis of the results demonstrated that the sensitivity of a normal or near-normal V/Q scan reading was 99% and the specificity of a high-probability reading was 98%. So why then is the V/Q scan not the ideal test?
Unfortunately, only a minority of the patients ultimately diagnosed with PE (via pulmonary angiogram) had a high-probability scan. Seventy-eight percent of the V/Q scans in the PIOPED study were read as intermediate or low probability, and, of those, 33 percent in the intermediate-probability and 12 percent in the low-probability were diagnosed with PE. The PIOPED study tells us that V/Q scans are extremely helpful about 22 percent of the time but not so valuable about 78 percent of the time.
D-dimers are fibrin cross-links that are cleaved and released into the circulation by the action of plasmin during fibrinolysis. This normally occurs within one hour after thrombus formation. The continued fibrinolysis of a PE usually increases the D-dimer concentration for at least one week and then decreases. Some experts hold that some false-negative D-dimer tests that clinicians encounter are because the patient's symptoms lasted longer than seven days.
The utility of the D-dimer test is advertised as a screening tool. It's a rather noninvasive test, has no immediate risk, and is fast and rather inexpensive. Kline et al spend a lot of time in this paper describing the different D-dimer tests; the major types are the enzyme-linked immunsorbent assay (standard ELISA) and the latex agglutination tests. To date, there are varieties of each with very high sensitivities (94%-99%). It is important for each clinician to find out which type is used at his institution and what the sensitivities and specificities are. Unfortunately the specificity of the higher sensitivity tests is quite low (about 45%), and therefore lead to a lot of unnecessary subsequent invasive, expensive, and risky testing. In fact, a recent study demonstrated that a highly sensitive rapid ELISA D-dimer test led to a significant increase in the number of tests performed, but had no change in the number of patients diagnosed with PE. (Acad Emerg Med 2006;13:519.)
Many studies in recent years have demonstrated that the D-dimer test can reliably rule out PE when used in low-risk patients. This is still quite controversial because the “low-risk” patients in many of these studies have a pre-test probability of three percent to five percent to begin with. (Ann Intern Med 2006;144:812; Chest 2006;129:1417.) Any screening test looks good when the pre-test probability is so low. Another limiting feature of many of these studies is that they use CT angiogram (CTA) and V/Q scans as the gold standard. Needless to say, neither of them is close to being 100% sensitive, so D-dimers may miss more than we think.
In most institutions, the CTA has become the diagnostic tool of choice for diagnosing or ruling out PE. The long awaited PIOPED II study (New Engl J Med 2006;354:22) was a prospective, multicenter investigation of the accuracy of multidetector CTA alone and combined with venous-phase imaging (CTA-CTV) for the diagnosis of acute PE. The addition of CTV looks for pelvic and lower extremity deep venous thromboses. The results were less than stellar, to say the least. The sensitivity of CTA was 83%, with a specificity of 96%. The CTA-CTV performed better with a sensitivity and specificity of 90 and 95% respectively. The take-home message from this study is that CTA alone misses 17 percent of PEs. Adding CTV (or lower extremity duplex ultrasounds) decreases the miss rate some, but we still miss 10 percent of PEs if the results of this study are correct. Equally worrisome in this study is that among patients with a low clinical probability of PE (those we order D-dimers on), 42 percent of the CTA readings were false positive. We may unnecessarily be diagnosing a large number of patients with PE, burdening and possibly harming them with needless long-term anticoagulation.
What else is out there? The alveolar-arterial oxygen gradient is completely useless for screening and diagnostic purposes (yet we still hear our medicine colleagues torturing our patients with these archaic tests daily). The MRI is impractical and insensitive, as are the transthoracic and transesophageal echocardiograms.
Pretest probability is truly of utmost importance in determining which study must be done next in assisting the diagnosis of PE. The most commonly used clinical decision rule is the Wells score. (Thromb Haemost 2000;83:416.) This rule is a point system that categorizes people at low, moderate, or high likelihood of a PE, or as likely and unlikely, depending on which study you read. A recent study evaluated the accuracy of determining pretest probability of PE, comparing clinical gestalt and clinical prediction rules. (JAMA 2003;290:2849.) Surprisingly (or perhaps not so), the clinical gestalt of experienced clinicians was as accurate as clinical prediction rules. For some reason, the authors still recommended using the clinical prediction rules.
Management of Tuberculosis in the United States
Small PM, Fujiwara PI N Engl J Med 2001;345(3):189
Mycobacterium tuberculosis infects approximately one-third of the world's population; eight million new cases and two million deaths are reported each year. In the United States, there was a resurgence of tuberculosis in the mid-1980s and early 1990s likely due to a combination of forces at work: the HIV epidemic, deteriorating public health infrastructure, urban crowding, and increasing immigration. Since its peak in 1992, the case rate for tuberculosis in the U.S. has decreased steadily from 10.5 per 100,000 to 5.8 cases per 100,000 in 2000.
Virtually all M. tuberculosis is transmitted by airborne particles. Transmission is greatly influenced by the characteristics of the source case (number of bacteria excreted) and the nature of the encounter (duration and closeness of exposure). Infection results when as few as one to five bacteria are deposited in the terminal alveolus. Primary tuberculosis is generally a self-limited, mild pneumonic illness that generally goes undiagnosed. During this illness, bacillemia and seeding of other organs may occur, setting the stage for subsequent reactivation in extrapulmonary sites.
The symptoms of tuberculosis include constitutional symptoms such as fever, night sweats, anorexia, weight loss, and weakness. Additionally organ-specific symptoms of pulmonary tuberculosis include cough, pleuritic pain, and hemoptysis. In patients with primary tuberculosis, chest x-rays often show infiltrates in the middle or lower lung zones, with ipsilateral hilar adenopathy. This x-ray pattern differs from reactivation tuberculosis, which classically shows upper-lobe infiltrates, frequently with cavitation.
The treatment of tuberculosis requires a complex interaction between clinical care and public health. All states require that cases of tuberculosis be reported to public health authorities. There are five first-line antimicrobial agents that form the basis of currently recommended anti-tuberculosis therapy. Whenever possible, isoniazid should be used (in conjunction with other drugs) for the duration of therapy. If rifampin is not used, 18 months is the minimal duration of therapy associated with acceptable cure rates. In the absence of drug resistance, isoniazid plus rifampin for nine months is curative. The addition of pyrazinamide for the first two months allows the regimen to be shortened to six months, and is associated with improved compliance and cure rates. The most commonly used regimen consists of isoniazid, rifampin, and pyrazinamide administered daily for eight weeks, followed by isoniazid and rifampin given daily, twice a week, or three times a week for 16 weeks. Ethambutol and/or streptomycin also may be used if there is known isoniazid resistance in the community.
When tuberculosis infection rates were rising rapidly in the late 1980s, it became clear that a substantial number of patients were not completing treatment. To address this problem, the American Thoracic Society and the CDC recommended that direct observation therapy by trained health care workers be considered for all patients, regardless of level of education, race, income, or other demographic and social factors.
Treatment of latent tuberculosis infection is a basic component of preventive health care for individual patients and an extremely important public health intervention. Latent tuberculosis is diagnosed via tuberculin skin testing. Because of a limited specificity, widespread application to low-risk populations will likely generate false positive results in most cases so only high-risk groups should be tested. These include HIV-infected patients, immigrants from countries with high rates of tuberculosis, homeless persons, health care professionals, and persons living or working in long-term care facilities. Tests are considered positive based on the diameter of induration as a result of the tuberculin skin test, read 48 to 72 hours after application. Depending on how immunosuppressed a patient is and what type of risk he has of having a latent infection, a positive test is either 5, 10, or 15 mm of induration. Isoniazid is the mainstay of therapy for latent tuberculosis infection, although other medications may be used depending on the situation.
About the LLSA
As part of its continuous certification program, the American Board of Emergency Medicine has developed the Lifelong Learning and Self-Assessment (LLSA) program to promote continuous education of diplomates. Each year, beginning in 2004, 16 to 20 articles are chosen based on the Emergency Medicine Model. A list of these articles can be found on the ABEM web site, www.abem.org.
ABEM is not authorized to confer CME credit for the successful completion of the LLSA test, but it has no objection to physicians participating in such activities. EMN's CME activity, Learning to Live with the LLSA, is not affiliated with ABEM's LLSA program, and reading this article and completing the quiz does not count toward ABEM certification. Rather, participants may earn 1 CME credit from the Lippincott Continuing Medical Education Institute, Inc., for each completed EMN quiz.