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Legionnaires’ DiseaseLegionnaires Disease in the ICU: Importance of High Index of Suspicion in Patients in the ICU With Community-Acquired Pneumonia FREE TO VIEW

Victor L. Yu, MD
Author and Funding Information

From the Department of Medicine, University of Pittsburgh; and the Special Pathogens Laboratory.

Correspondence to: Victor L. Yu, MD, Special Pathogens Laboratory, 1401 Forbes Ave, Ste 208, Pittsburgh, PA 15219; e-mail: vly@pitt.edu


Financial/nonfinancial disclosures: The author has reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2014;145(2):202-205. doi:10.1378/chest.13-2170
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From a layperson’s perception, Legionnaires’ disease seems to be increasing, as judged by newspaper headlines and TV reports. Whether this is because of increasing recognition with greater use of the Legionella urinary antigen or because of an actual absolute increase is not readily answered. This increasing incidence is supported by epidemiologic statistics from the US Centers for Disease Control and Prevention and Eurosurveillance.1,2 Speculation that proliferation of Legionella in natural aquatic bodies as a result of climate change, global warming, and flooding has contributed to this increase.

In this issue of CHEST (see page 290), Arancibia et al3 report a prospective multicenter observational study of 104 consecutive immunocompetent adult patients hospitalized in the ICU in four hospitals in Chile. Community-acquired pneumonia (CAP) in patients admitted to the ICU is oftentimes Legionnaires’ disease and second only to pneumococcal pneumonia in frequency,4,5 a finding that Arancibia et al3 have confirmed. Legionnaires’ disease (8.6%) was the second most common cause in this study, exceeded only by pneumococcal pneumonia (26%).

The clinical presentation of Legionnaires’ disease is nonspecific, so the diagnosis can be easily overlooked because standard bacteriologic testing and cultures will be nonrevealing. Earlier studies of Legionnaires’ disease listed a few clues that should raise the index of suspicion for this treatable pneumonia. High fever (> 39°C) and gastrointestinal symptoms (especially diarrhea) occur more commonly in Legionnaires’ disease than in other causes of CAP.6 The cough is often nonproductive, yet the Gram stain of sputum typically shows neutrophils; however, microorganisms are scanty or primarily nonspecific oral flora.

Detailed scoring systems based on clinical criteria have been proposed for distinguishing Legionnaires’ disease from other causes of CAP, including the Winthrop-University Hospital score7 and the Community-Based Pneumonia Incidence Study score.8 An inherent deficiency for these scores is that they were derived from surveys of hospitalized patients in an era when only those patients with severe CAP were evaluated by confirmatory microbiologic testing. Given subsequent studies, notably the Community-Acquired Pneumonia Network (CAPNETZ) studies from Germany, it is now clear that the spectrum of Legionnaires’ disease includes nonseverely ill patients who lack many of the classic diagnostic symptoms.9 Nevertheless, the ICU may be the ideal site where such scores may be useful. Patients in the ICU are akin to the patients with Legionnaires’ disease in the earlier era when the disease was unsuspected and appropriate therapy was not given early in the course. These scores tend to be moderately sensitive, but are not particularly specific (ie, a negative score does not predict absence of disease).10 In a study of consecutive patients admitted to the hospital from the ED, high fever (> 39°C), hyponatremia, and other abnormal laboratory test results (lactic dehydrogenase, thrombocytopenia, C-reactive protein) were more frequent in Legionnaires’ disease than in pneumonias of other causes.11 In the CAPNETZ study of ambulatory patients with community-acquired Legionnaires’ disease, the patients were younger, had fewer comorbidities, and experienced a milder clinical presentation, such that their scores would likely be lower.

Specific laboratory testing for Legionella is necessary for diagnosis. Underdiagnosis results from lack of application of these confirmatory tests. The Legionella urinary antigen has revolutionized the diagnosis of Legionnaires’ disease because of the rapidity of the test (results available within 15 min of receipt of urine), simplicity in processing, and high specificity (> 90%); if the test is positive, the diagnosis is almost indisputable. It was the sole diagnostic test in the Arancibia et al3 study. So, it should be noted that their incidence is an underestimate. Note that the Legionella urinary antigen can also be applied to pleural fluid, as can the pneumococcal urinary antigen for pneumococcal empyema. However, if it is used as the sole test, about 20% of patients with Legionnaires’ disease will be missed. The urinary antigen test is unreliable in detecting the non-pneumophila species and non-serogroup 1 within the Legionellaceae family. As a result, we have recommended specialized Legionella culture for all cases of CAP admitted to the hospital and certainly those admitted to the ICU. Legionella culture of respiratory secretions using selective media with dyes and inhibitors is the gold standard.12 The sputum may not fulfill the Murray-Washington criteria (ie, presence of neutrophils and absence of squamous epithelial cells), yet Legionella still may be isolated.

Polymerase chain reaction has been much ballyhooed,13,14 but is not yet commercially available. Its disadvantage, unlike culture, is the inability to produce a microbe so epidemiologic links can be linked to a putative water source. The venerable Gram stain is surprisingly useful. In our hospital, physicians have found that Gram stain showing predominance of neutrophils but few, if any, microorganisms is a reliable clue for Legionnaires’ disease. This finding is sensitive if sputum is available. Such Gram stains are not specific; Mycoplasma, Chlamydia, and viruses may produce a similar Gram stain appearance.

Hyponatremia has been consistently observed to be an indicator in numerous studies since our initial observation in 198215 and even appears to be present in less severely ill patients, although to a lesser degree.9 In the Arancibia et al3 study, 67% of patients with Legionnaires’ disease experienced hyponatremia as compared with 15% of pneumonias of other cause. Hyponatremia was also an independent indicator for severity of Legionnaires’ disease. In the CAPNETZ study of ambulatory pneumonia, 19% of patients with Legionnaires’ disease experienced hyponatremia as compared with 9.5% of pneumonias of other cause; statistical significance was attained for both ICU and ambulatory patients. The mechanism is uncertain, but it is not due to inappropriate secretion of antidiuretic hormone (SIADH). We had garnered evidence that it was not due to SIADH, but confounding factors never allowed us to make a definitive conclusion. Schuetz et al16 found no concurrent increase in CT-ProVasopression levels, which mitigates against SIADH as the mechanism.

Higher procalcitonin levels correlated with severity of illness and poorer outcome. Persistently elevated procalcitonin levels over time was a harbinger of death.17,18 Chest radiographs are not useful for monitoring, and clearing of infiltrates may not occur until many weeks after recovery.

Hospitalized patients with Legionnaires’ disease are typically critically ill and often encounter respiratory failure complicated by renal and hepatic dysfunction. Noninvasive positive pressure ventilation has been successfully applied to such patients in anecdotal reports and is an alternative to mechanical ventilation.19 Extracorporeal life support for severe ARDS has also been reported as useful.20

The critical factor for survival is expeditious administration of an active antibiotic; delay of therapy leads to higher mortality in all studies. Mortality is similar for quinolones vs macrolide therapy; however, patients who receive quinolones seem to recover more quickly and are discharged earlier as compared with those receiving macrolides (although the macrolides compared were erythromycin and clarithromycin and not azithromycin).5,21 I recommend a short duration (3-5 days) of concomitant rifampin therapy for those critically ill or not responding to either a macrolide or a quinolone. The basis for this practice is the potent activity of rifampin in both in vitro studies and animal models. Drug interactions and reversible liver function abnormalities (especially bilirubin) are commonplace, but the effects should be minimal with short-duration therapy of rifampin. This recommendation is not based on controlled studies.22 Patients in the ICU may have sequelae of fatigue, lassitude, and neurologic symptoms that will persist for > 1 year.23

In summary, Legionnaires’ disease must be strongly considered for all patients with CAP admitted to the ICU. Both Legionella urinary antigen and culture on dye-containing selective media should be made available for all such patients, especially if Legionella is also found in the water supply of the hospital ICU.

References

Hicks LA, Garrison LE, Nelson GE, Hampton LM. Legionellosis—United States, 2000-2009. Am J Transplant. 2012;12(1):250-253. [CrossRef] [PubMed]
 
Beauté J, Zucs P, de Jong B; European Legionnaires’ Disease Surveillance Network. Legionnaires’ disease in Europe, 2009-2010. Euro Surveill. 2013;18(10):20417. [PubMed]
 
Arancibia F, Cortes CP, Valdés M, et al. Importance ofLegionella pneumophilain the etiology of severe community-acquired pneumonia in Santiago, Chile. Chest. 2014;145(2):290-296.
 
Vergis EN, Akbas E, Yu VL. Legionellaas a cause of severe pneumonia. Semin Respir Crit Care Med. 2000;21(4):295-304. [CrossRef] [PubMed]
 
Viasus D, Di Yacovo S, Garcia-Vidal C, et al. Community-acquiredLegionella pneumophilapneumonia: a single-center experience with 214 hospitalized sporadic cases over 15 years. Medicine (Baltimore). 2013;92(1):51-60. [CrossRef] [PubMed]
 
Mulazimoglu L, Yu VL. Can Legionnaires disease be diagnosed by clinical criteria? A critical review. Chest. 2001;120(4):1049-1053. [CrossRef] [PubMed]
 
Cunha BA. Severe Legionella pneumonia: rapid presumptive clinical diagnosis with Winthrop-University Hospital’s weighted point score system (modified). Heart Lung. 2008;37(4):311-320. [CrossRef] [PubMed]
 
Fernández-Sabé N, Rosón B, Carratalà J, Dorca J, Manresa F, Gudiol F. Clinical diagnosis of Legionella pneumonia revisited: evaluation of the Community-Based Pneumonia Incidence Study Group scoring system. Clin Infect Dis. 2003;37(4):483-489. [CrossRef] [PubMed]
 
von Baum H, Ewig S, Marre R, et al; Competence Network for Community Acquired Pneumonia Study Group. Community-acquired Legionella pneumonia: new insights from the German competence network for community acquired pneumonia. Clin Infect Dis. 2008;46(9):1356-1364. [CrossRef] [PubMed]
 
Gupta SK, Imperiale TF, Sarosi GA. Evaluation of the Winthrop-University Hospital criteria to identify Legionella pneumonia. Chest. 2001;120(4):1064-1071. [CrossRef] [PubMed]
 
Fiumefreddo R, Zaborsky R, Haeuptle J, et al. Clinical predictors forLegionellain patients presenting with community-acquired pneumonia to the emergency department. BMC Pulm Med. 2009;9:4. [CrossRef] [PubMed]
 
Stout JE, Rihs JD, Yu VL. Legionella.. In:Murray PR, Baron EJ, Jorgensen JH, Pfaller MA, Yolken RH., eds. Manual of Clinical Microbiology. Washington, DC: ASM Press; 2003.
 
Shachor-Meyouhas Y, Kassis I, Bamberger E, et al. Fatal hospital-acquired Legionella pneumonia in a neonate. Pediatr Infect Dis J. 2010;29(3):280-281. [CrossRef] [PubMed]
 
Murdoch DR, Podmore RG, Anderson TP, et al. Impact of routine systematic polymerase chain reaction testing on case finding for Legionnaires’ disease: a pre-post comparison study. Clin Infect Dis. 2013;57(9):1275-1281. [CrossRef] [PubMed]
 
Yu VL, Kroboth FJ, Shonnard J, Brown A, McDearman S, Magnussen M. Legionnaires’ disease: new clinical perspective from a prospective pneumonia study. Am J Med. 1982;73(3):357-361. [CrossRef] [PubMed]
 
Schuetz P, Haubitz S, Christ-Crain MJ, Albrich W, Zimmerli W, Muller B. Hyponatremia and anti-diuretic hormone in Legionnaires’ disease [abstract]. Paper presented at: 95th Annual Meeting of the Endocrine Society; June 15-18, 2013; San Francisco, CA.
 
de Jager CP, de Wit NC, Weers-Pothoff G, van der Poll T, Wever PC. Procalcitonin kinetics inLegionella pneumophilapneumonia. Clin Microbiol Infect. 2009;15(11):1020-1025. [CrossRef] [PubMed]
 
Haeuptle J, Zaborsky R, Fiumefreddo R, et al. Prognostic value of procalcitonin in Legionella pneumonia. Eur J Clin Microbiol Infect Dis. 2009;28(1):55-60. [CrossRef] [PubMed]
 
Eryüksel E, Karakurt S, Balci M, Celikel T. Non-invasive positive pressure ventilation for a severe Legionella pneumonia case. Tuberk Toraks. 2009;57(3):348-351. [PubMed]
 
Bryner B, Miskulin J, Smith C, et al. Extracorporeal life support for acute respiratory distress syndrome due to severe Legionella pneumonia [published online ahead of print July 17, 2013]. Perfusion. doi:10.1177/0267659113497229.
 
Pedro-Botet L, Yu VL. Legionella: macrolides or quinolones? Clin Microbiol Infect. 2006;12(suppl 3):25-30. [CrossRef] [PubMed]
 
Varner TR, Bookstaver PB, Rudisill CN, Albrecht H. Role of rifampin-based combination therapy for severe community-acquiredLegionella pneumophilapneumonia. Ann Pharmacother. 2011;45(7-8):967-976. [CrossRef] [PubMed]
 
Lettinga KD, Verbon A, Nieuwkerk PT, et al. Health-related quality of life and posttraumatic stress disorder among survivors of an outbreak of Legionnaires disease. Clin Infect Dis. 2002;35(1):11-17. [CrossRef] [PubMed]
 

Figures

Tables

References

Hicks LA, Garrison LE, Nelson GE, Hampton LM. Legionellosis—United States, 2000-2009. Am J Transplant. 2012;12(1):250-253. [CrossRef] [PubMed]
 
Beauté J, Zucs P, de Jong B; European Legionnaires’ Disease Surveillance Network. Legionnaires’ disease in Europe, 2009-2010. Euro Surveill. 2013;18(10):20417. [PubMed]
 
Arancibia F, Cortes CP, Valdés M, et al. Importance ofLegionella pneumophilain the etiology of severe community-acquired pneumonia in Santiago, Chile. Chest. 2014;145(2):290-296.
 
Vergis EN, Akbas E, Yu VL. Legionellaas a cause of severe pneumonia. Semin Respir Crit Care Med. 2000;21(4):295-304. [CrossRef] [PubMed]
 
Viasus D, Di Yacovo S, Garcia-Vidal C, et al. Community-acquiredLegionella pneumophilapneumonia: a single-center experience with 214 hospitalized sporadic cases over 15 years. Medicine (Baltimore). 2013;92(1):51-60. [CrossRef] [PubMed]
 
Mulazimoglu L, Yu VL. Can Legionnaires disease be diagnosed by clinical criteria? A critical review. Chest. 2001;120(4):1049-1053. [CrossRef] [PubMed]
 
Cunha BA. Severe Legionella pneumonia: rapid presumptive clinical diagnosis with Winthrop-University Hospital’s weighted point score system (modified). Heart Lung. 2008;37(4):311-320. [CrossRef] [PubMed]
 
Fernández-Sabé N, Rosón B, Carratalà J, Dorca J, Manresa F, Gudiol F. Clinical diagnosis of Legionella pneumonia revisited: evaluation of the Community-Based Pneumonia Incidence Study Group scoring system. Clin Infect Dis. 2003;37(4):483-489. [CrossRef] [PubMed]
 
von Baum H, Ewig S, Marre R, et al; Competence Network for Community Acquired Pneumonia Study Group. Community-acquired Legionella pneumonia: new insights from the German competence network for community acquired pneumonia. Clin Infect Dis. 2008;46(9):1356-1364. [CrossRef] [PubMed]
 
Gupta SK, Imperiale TF, Sarosi GA. Evaluation of the Winthrop-University Hospital criteria to identify Legionella pneumonia. Chest. 2001;120(4):1064-1071. [CrossRef] [PubMed]
 
Fiumefreddo R, Zaborsky R, Haeuptle J, et al. Clinical predictors forLegionellain patients presenting with community-acquired pneumonia to the emergency department. BMC Pulm Med. 2009;9:4. [CrossRef] [PubMed]
 
Stout JE, Rihs JD, Yu VL. Legionella.. In:Murray PR, Baron EJ, Jorgensen JH, Pfaller MA, Yolken RH., eds. Manual of Clinical Microbiology. Washington, DC: ASM Press; 2003.
 
Shachor-Meyouhas Y, Kassis I, Bamberger E, et al. Fatal hospital-acquired Legionella pneumonia in a neonate. Pediatr Infect Dis J. 2010;29(3):280-281. [CrossRef] [PubMed]
 
Murdoch DR, Podmore RG, Anderson TP, et al. Impact of routine systematic polymerase chain reaction testing on case finding for Legionnaires’ disease: a pre-post comparison study. Clin Infect Dis. 2013;57(9):1275-1281. [CrossRef] [PubMed]
 
Yu VL, Kroboth FJ, Shonnard J, Brown A, McDearman S, Magnussen M. Legionnaires’ disease: new clinical perspective from a prospective pneumonia study. Am J Med. 1982;73(3):357-361. [CrossRef] [PubMed]
 
Schuetz P, Haubitz S, Christ-Crain MJ, Albrich W, Zimmerli W, Muller B. Hyponatremia and anti-diuretic hormone in Legionnaires’ disease [abstract]. Paper presented at: 95th Annual Meeting of the Endocrine Society; June 15-18, 2013; San Francisco, CA.
 
de Jager CP, de Wit NC, Weers-Pothoff G, van der Poll T, Wever PC. Procalcitonin kinetics inLegionella pneumophilapneumonia. Clin Microbiol Infect. 2009;15(11):1020-1025. [CrossRef] [PubMed]
 
Haeuptle J, Zaborsky R, Fiumefreddo R, et al. Prognostic value of procalcitonin in Legionella pneumonia. Eur J Clin Microbiol Infect Dis. 2009;28(1):55-60. [CrossRef] [PubMed]
 
Eryüksel E, Karakurt S, Balci M, Celikel T. Non-invasive positive pressure ventilation for a severe Legionella pneumonia case. Tuberk Toraks. 2009;57(3):348-351. [PubMed]
 
Bryner B, Miskulin J, Smith C, et al. Extracorporeal life support for acute respiratory distress syndrome due to severe Legionella pneumonia [published online ahead of print July 17, 2013]. Perfusion. doi:10.1177/0267659113497229.
 
Pedro-Botet L, Yu VL. Legionella: macrolides or quinolones? Clin Microbiol Infect. 2006;12(suppl 3):25-30. [CrossRef] [PubMed]
 
Varner TR, Bookstaver PB, Rudisill CN, Albrecht H. Role of rifampin-based combination therapy for severe community-acquiredLegionella pneumophilapneumonia. Ann Pharmacother. 2011;45(7-8):967-976. [CrossRef] [PubMed]
 
Lettinga KD, Verbon A, Nieuwkerk PT, et al. Health-related quality of life and posttraumatic stress disorder among survivors of an outbreak of Legionnaires disease. Clin Infect Dis. 2002;35(1):11-17. [CrossRef] [PubMed]
 
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