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Dr. Mulazimoglu is Associate Professor of Infectious Diseases and Clinical Microbiology, Marmara University, and Dr. Yu is Professor of Medicine, VA Medical Center and University of Pittsburgh.
Correspondence to: Victor L. Yu, MD, Professor of Medicine, Infectious Disease Section (111E-U), VA Medical Center, University Dr C, Pittsburgh, PA 15240; e-mail: vly+{at}pitt.edu
Legionella is a relatively common cause of pneumonia. In patients with community-acquired pneumonia, the incidence ranges from 2 to 15%. Of pathogens that are of consequence in patients with community-acquired pneumonia, the mortality rate is highest for those with bacteremic pneumococcal pneumonia and Legionnaires disease. Of the atypical pneumonia pathogens, the mortality for Chlamydia pneumoniae and Mycoplasma pneumoniae is low. Consensus guidelines on empiric antibiotic therapy for patients with community-acquired pneumonia recommend that coverage be extended to Legionella in suspicious cases, although the criteria for "suspicious" is not explicitly delineated. Although numerous studies have shown that the clinical manifestations of Legionnaires disease are nonspecific, Burke Cunha1 from Winthrop University Hospital (WUH) has claimed that Legionnaires disease is a unique clinical syndrome as originally depicted in the early studies (Table 1 ). Cunha even devised a weighted point system, referred to as the WUH point scale for Legionnaires disease. If the WUH score was valid, then antibiotic selection might be simplified. We sought to assess the utility of the syndromic approach on the management of community-acquired pneumonia and Legionnaires disease.
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In the original outbreak of Legionnaires disease in 1976, the case fatality rates were highest for the ß-lactam antibiotics, aminoglycosides, and chloramphenicol. The case fatality rate was lowest for erythromycin and tetracycline.2 It was subsequently discovered that Legionella is an intracellular pathogen and that only those antibiotics that achieve high intracellular penetrations would be efficacious. In retrospect, only a minority of patients in the American Legion outbreak received therapy that would be considered efficacious today.
The clinical syndrome of Legionnaires disease was largely defined by
early outbreaks, especially the 1976 American Legion outbreak at a
hotel3
and an endemic situation at Wadsworth Veterans
Affairs Hospital in the late 1970s.4
5
The severity of the
clinical manifestations was impressive (Table 1)
, and subsequent case
descriptions from other early studies contributed to the image of
Legionnaires disease as being a distinct clinical syndrome of unusually
severe pneumonia with multisystem dysfunction. Legionnaires disease
occurred primarily in elderly male patients with underlying diseases
(eg, cardiac, pulmonary, or renal) who were cigarette
smokers.3
4
5
Underlying immunosuppressive illnesses,
especially in organ transplant recipients, were common. Symptoms that
were prominent included nonproductive cough, chest pain, diarrhea, and
confusion/delirium. Signs included temperature 
39°C, relative
bradycardia, and neurologic manifestations. Laboratory abnormalities
likewise were common (Table 1)
.
In 1982, we published a study6 in which all cases of pneumonia, both community-acquired and hospital-acquired, underwent specialized testing for Legionella (ie, serology, direct fluorescent antibody tests, and culture on selective media). To our surprise, we found that Legionella pneumophila was a relatively common cause of pneumonia. Furthermore, when compared to pneumonias of other bacterial etiologies, the clinical manifestations were similar and generally not distinctive. Since then, numerous large-scale studies of pneumonia have confirmed the nonspecificity of the clinical manifestations of Legionnaires disease.7 8 9 10 We now know that in severe cases of Legionnaires disease, blood cultures can be positive for L pneumophila11 and that bacteremic pneumonias of any etiology, be they pneumococcal, Staphylococcus aureus, or Gram-negative bacilli, can be expected to cause high mortality rates.
Chest radiographic features have been touted as characteristic for Legionnaires disease. These features have included pleural effusions, pleural-based infiltrates that mimicked pulmonary embolism, and circumscribed peripheral densities. The tendency for radiographic abnormalities to progress while the patient is receiving antibiotic therapy has been widely noted, and earlier studies12 13 14 15 have suggested that such progression is more frequent in patients with Legionnaires disease than in those with other types of pneumonia. In a study16 of hospital-acquired Legionnaires disease, 29% of patients showed progression of a unilateral infiltrate that spread to other lobes despite receiving erythromycin. Similarly, in a study17 of community-acquired Legionnaires disease, 65% of patients had a worsening of radiologic findings in the first week. Keep in mind that in earlier studies, specific antibiotic therapy against L pneumophila was likely to have been delayed more often than in cases of bacterial pneumonias of other etiologies.18 Pleural effusions are common but are of small volume. Tan et al17 found pleural effusions in 28% of patients with community-acquired Legionnaires disease on hospital admission, but the number of patients with pleural effusions increased to 63% during the hospital course. Nevertheless, when comparative studies5 13 17 19 20 21 22 23 have been performed, the chest radiographic findings also have been shown to be nonspecific.
In this issue of CHEST, Gupta et al (see page 1064) evaluated the syndromic approach in patients with community-acquired pneumonia from the University of Indiana and found distinctive features for Legionnaires disease. Given their results, we re-evaluated the issue of whether Legionnaires disease could be characterized as a distinct clinical syndrome by reviewing comparative studies of Legionella vs other causes of pneumonia. Most studies have used serology as a criterion for the diagnosis of Legionnaires disease, but since the specificity of this test is uncertain at individual hospitals, we confined our analyses only to those studies that used a second confirmatory test, either urinary antigen, direct fluorescent antibody, or culture. We found 13 studies6 7 8 10 12 14 15 22 24 25 26 27 28 of community-acquired pneumonia that had sufficient clinical details for evaluation and that fulfilled our laboratory criteria for Legionnaires disease (Table 2 ). The study by Fang et al28 used all four diagnostic tests (ie, serology, direct fluorescent antibody, urinary antigen, and culture). Numerous clinical manifestations attained statistical significance (ie, headache, diarrhea, arthralgias or myalgias, neurologic symptoms including confusion, fever to 39°C, purulent sputum, hyponatremia, hepatic dysfunction, creatine phosphokinase [CPK] elevation, hypophosphatemia, proteinuria, and hematuria). In at least 2 of the 13 studies, the following parameters occurred significantly more often in patients with Legionnaires disease than in those with other etiologies of community-acquired pneumonia: receipt of prior antibiotics; diarrhea; neurologic signs, especially confusion; temperature > 39°C; hyponatremia; and hepatic dysfunction (ie, transaminase and bilirubin elevations) [Table 3 ] . Hematuria also was found to be significant in the Gupta study. Relative bradycardia was evaluated in two studies6 25 and was not found to be useful. The mortality rate ranged from 0% in three studies7 26 27 to 46%,6 with a median of 15%. Most studies showed a trend toward higher mortality for Legionnaires disease (Table 2) , but only one study12 showed a significantly greater mortality rate for Legionnaires disease compared to M pneumoniae.
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Critique of the Syndromic Approach
Gupta and colleagues evaluated the ability of the WUH criteria to identify Legionnaires disease in patients with community-acquired pneumonia who required hospital admission. Patients with bacteremic pneumococcal pneumonia were the negative control group. The ability of the WUH criteria to distinguish only two causative agents of community-acquired pneumonia might be justified on the grounds that the mortality rate is notable for these two microorganisms in patients with community-acquired pneumonia. In contrast, the mortality rate among patients with Haemophilus influenzae, M pneumoniae, and C pneumoniae was < 5%. Gupta et al found, somewhat to their surprise (and ours), that the sensitivity for the WUH score in diagnosing Legionnaires disease was 78 to 87%. The adjusted negative predictive value was 92%. On the other hand, the specificity was only 50 to 65%. An unpublished study by De Caroles et al also found the WUH score to be sensitive, but also nonspecific (De Caroles; personal communication, 1999). Other unpublished studies have utilized syndromic approaches for the diagnosis of Legionnaires disease. In the Community-Based Pneumonia Incidence Study,30 high fever, elevated lactate dehydrogenase, and hyponatremia were distinctive, and in a small study31 of 18 patients, high fever and nonproductive cough were distinctive. One potentially fatal flaw of the study by Gupta et al is that the authors conceded that a sizable number of patients had not undergone any testing for Legionella. If Legionella testing was skewed to patients who were severely ill or if tests were ordered primarily for those patients with the classic clinical manifestations listed in Table 2 , an overwhelming bias with circular reasoning would have confounded the study results.
Given the results of this review, can the use of clinical criteria be useful in the management of this disease? Although sensitivity was relatively high, 13 to 22% of patients with Legionnaires disease were missed by the WUH score in the Gupta study. Given the high mortality rate, the authors correctly point out that the WUH score cannot be used to focus antibiotic therapy (eg, using a ß-lactam agent only on those patients who do not fulfill the criteria). Since the specificity was low (50 to 65%), the application of the WUH score also could lead to unnecessarily broad coverage.
Despite the knowledge that Legionella can be widespread in the community, most hospitals currently do not have diagnostic laboratory tests available for Legionella testing. The rationale is that the disease is relatively rare and that the application of an expensive test would be of low yield. This leads to a "catch-22" situation, in that the diagnosis cannot be made unless tests are available. And while we believe that the urinary antigen test for Legionella (Binax; S Portland, ME) should be performed for all community-acquired pneumonia patients requiring hospital admission, this has not been recommended by the consensus guidelines for community-acquired pneumonia of either the American Thoracic Society or the Infectious Diseases Society of America, with expense cited as one reason.32 33 The latter organization’s guidelines recommend that Legionella testing be performed if "clinical features are supportive of the disease."33 The WUH score might be used to screen patients for specialized Legionella testing. If the WUH score were fulfilled, the patient could receive anti-Legionella antibiotics as empiric therapy without Legionella laboratory testing. But, if the criteria were not fulfilled, Legionella testing could be performed on these patients to cover the 13 to 22% of patients who do not have the classical syndrome.
If Legionella testing (especially culture or selective media and urinary antigen testing) becomes routinely available for patients with pneumonia, we suspect that the syndromic approach for clinical suspicion of Legionnaires disease will be less useful, because Legionnaires disease will be diagnosed earlier and the manifestations of severe pneumonia will be muted. On the other hand, in patients who present for medical care late in the course of the disease or in patients in whom the diagnosis of Legionnaires disease is overlooked by the physician, the application of the syndromic approach may suggest the correct diagnosis. Also, the WUH score may allow the targeting of patients for longer duration of therapy and the administration of more active therapy (such as quinolones and rifampin). In future comparative studies of community-acquired pneumonia etiology,34 Legionella laboratory testing should be performed on all patients; testing for Legionella with serology as the sole test is inadequate. Until then, the current approach of using empiric anti-Legionella therapy (ie, macrolides or quinolones) for all patients with community-acquired pneumonia requiring hospitalization should prevail.32 33 35 A pathogen-directed approach using the syndromic approach is not recommended. Further studies focusing on the application of the WUH score to assess its utility, if any, are necessary.
Acknowledgements
We thank Jordi Roig, Lionel A. Mandell, Michael Niederman, Antoni Torres, and Miguel Sabria for their critical comments.
References
This article has been cited by other articles:
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  S. J. Gluckman Acute Respiratory Infections in a Recently Arrived Traveler to Your Part of the World Chest, July 1, 2008; 134(1): 163 - 171. [Abstract] [Full Text] [PDF]
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V. L. Yu, R. N. Greenberg, N. Zadeikis, J. E. Stout, M. M. Khashab, W. H. Olson, and A. M. Tennenberg Levofloxacin Efficacy in the Treatment of Community-Acquired Legionellosis Chest, June 1, 2004; 125(6): 2135 - 2139. [Abstract] [Full Text] [PDF]
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T. M. File Jr, J. Garau, F. Blasi, C. Chidiac, K. Klugman, H. Lode, J. R. Lonks, L. Mandell, J. Ramirez, and V. Yu Guidelines for Empiric Antimicrobial Prescribing in Community-Acquired Pneumonia Chest, May 1, 2004; 125(5): 1888 - 1901. [Abstract] [Full Text] [PDF]
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 B. Roson, J. Carratala, N. Fernandez-Sabe, F. Tubau, F. Manresa, and F. Gudiol Causes and Factors Associated With Early Failure in Hospitalized Patients With Community-Acquired Pneumonia Arch Intern Med, March 8, 2004; 164(5): 502 - 508. [Abstract] [Full Text] [PDF]
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 K. E. Templeton, S. A. Scheltinga, P. Sillekens, J. W. Crielaard, A. P. van Dam, H. Goossens, and E. C. J. Claas Development and Clinical Evaluation of an Internally Controlled, Single-Tube Multiplex Real-Time PCR Assay for Detection of Legionella pneumophila and Other Legionella Species J. Clin. Microbiol., September 1, 2003; 41(9): 4016 - 4021. [Abstract] [Full Text] [PDF]
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