Legionnaires' disease in Solid Organ Transplants

Authors: M. Luisa Pedro-Botet, M.D. and Victor L. Yu, M.D.

Monograph
Tables
What's New
Reviews
History

Legionnaires’ disease was first recognized as a hospital-acquired pneumonia in an outbreak of about 200 patients occurring at Wadsworth VAMC, Los Angeles in the 1980’s. Most of these patients were renal transplant recipients (39). The source of subsequent hospital-acquired outbreaks was subsequently found to be the drinking water (30, 67). In the early years following the recognition of hospital-acquired Legionnaires’ disease, transplant recipients seemed to be at markedly higher risk. For example, in the 1980s, 80% of hospital-acquired Legionnaires’ disease at Stanford University and University of Pittsburgh occurred in transplant recipients (9, 30).

This predilection for transplant patients may have occurred for a number of reasons: The obvious reason that immunosuppressed patients are prone to opportunistic pathogens. However, we suspect the primary reason is that physicians caring for such patients have a high index of suspicion for infections. Moreover, invasive diagnostic procedures including bronchoscopy, lung biopsy, and autopsy are performed more readily for transplant recipients compared to non-transplant patients such that Legionella would be more readily recovered from the patient.

We reviewed fifty articles reporting 287 cases of Legionnaires’ disease in solid organ transplant published from 1972 to 2011 so as to identify the risk factors for infection and define the best therapies and recommend preventive measures. For the 50 articles, about 3% of the transplants recipients in those institutions had contracted Legionnaires’ disease (Table 1).

BACTERIOLOGY

The bacterial family Legionellaceae consists of 50 species (4, 21). Legionella pneumophila is the most common species causing infection in at least 80 percent of human infections and was the most common species causing infection intransplant recipients (Table 2). L. micdadei was the most common non-pneumophila species involved although four other species were also identified: L. longbeachae, L. bozemanii, L. parisensis, L. cincinnatiens (Table 2). Within the species, serogroups 1, 4, and 6 were implicated in these transplant recipients; there are over 40 serogroups (24, 59).

PATHOGENESIS

Legionella species are part of the flora of aquatic ecosystems. Microbial parameters such as bacterial inocula and the virulence of the bacterium combined with immunity of the host are the factors predisposing to infection. After aspiration of contaminated water or inhalation of aerosols containing Legionella, the organism attaches to respiratory epithelial cells and alveolar macrophages via flagellae and pili (66). Legionella is then phagocytosed and is able to evade intracellular destruction by a number of mechanisms (31, 74). Cell immunity involving the pulmonary macrophages and IFN-gamma appears to be an important host defense (31, 34). Depression of cell-mediated immunity by glucocorticoids and anti-rejection drugs used in transplantation predisposes the host to Legionnaires' disease. Humoral immunity plays a secondary host defense role against Legionella infection. The precise role of polymorphonuclear leukocytes (PMNs) against Legionella is unclear. The organism does resist killing by PMNs even in the presence of specific antibody and complement.

EPIDEMIOLOGY

The incidence of Legionnaires' disease depends upon the degree of water reservoir contamination, the intensity of patient exposure to that water, and the susceptibility of the host. Successful diagnosis requires specialized laboratory tests, which are often not widely available. As mentioned, the strong link to transplant patients may result from diagnostic bias in that intensive diagnostic procedures including lung biopsy are more likely to be applied. For example, in one hospital, after confirmation by culture of 2 cases of hospital-acquired L. micdadei pneumonia in renal transplant recipients, L. micdadei serologic testing was performed retrospectively in transplant patients with pneumonia in whom microbial etiology was undetermined. Thirteen additional cases of pneumonia caused by L. micdadei in renal transplant and heart transplant recipients were uncovered (40). The most dramatic example of undiagnosed legionellosis in patients undergoing heart transplantation occurred at a major southwestern U.S. transplant center. Over a period of many years, sporadic cases of hospital-acquired legionellosis with deaths were diagnosed before it was discovered that the hospital water distribution system was the source.

Similarly, two outbreaks of L. micdadei occurred in a major eastern U.S. stem cell transplant center over a 15 year period before a copper-silver ionization unit was installed. At a university medical center in midwestern U.S., over 50 cases occurred over a 20 year period before effective water disinfection systems were installed. In the four outbreaks described above, transplantation surgery was placed on hold, media attention resulted, and millions of dollars were lost in the litigation that followed. At Wadsworth VA Medical Center, the largest renal transplant center in the VA system in the 1980s, was never re-opened following their outbreak of Legionnaires’ disease.

CLINICAL MANIFESTATIONS

The 50 articles on Legionella infection in solid organ transplant recipients that were reviewed (Table 1) included 262 hospital-acquired and 25 community-acquired cases. The highest absolute number of reported Legionellainfections occurred in kidney (n=174) and heart (n=92) transplant recipients. Two patients had undergone a kidney-pancreatic transplant (41, 75). The mean time from transplant to Legionella pneumonia was 1.7 years (4 d -10 years). 77.1% (81/105) (77.1%) occurred in the early post-transplant period (≤ 3 months). Legionella infection occurred following rejection in 52% (43/82) (Table 1). Most of the patients (83%, 24/29) developed Legionella infection after early rejection (≤ 3 months).

Pneumonia was confirmed radiographically in 90% (178/199) (Table 2). Cavitation was seen in 26% (20/78) (11,20, 23, 25, 35, 37, 46, 58, 77). The mortality of solid organ transplant patients with Legionella infection was 30%. The mortality for Legionella infection following transplant rejection was 35% (7/20). 16 patients experienced Pontiac fever, the nonpneumonic form of Legionellosis: 8 in heart transplant recipients and 8 in kidney transplant recipients (15, 30,36, 58). This diagnosis was based on antibody seroconversion following onset of a syndrome of fever.

Extrapulmonary Legionellosis

Extrapulmonary manifestations of Legionella infection have been described in 4 (1.3%) solid organ transplant patients (Table 4) (28, 38, 63, 71). Only one patient had concurrent pneumonia (71). The extrapulmonary sites were aorta (28), liver (71), pericardium (63) and soft tissue (38). All the cases were confirmed by tissue culture of the involved site (28, 71). Three out of 4 (75%) survived (28, 38, 63). Tokunaga described a two and a half month-old infant who underwent orthotopic liver transplantation (71). The infant died from fulminant hepatic failure and L. pneumophila was identified by direct immunofluorescence in both the grafted liver as well as the lung.

Mode of Transmission

The mode of transmission of Legionella in transplant recipients is usually aspiration although aerosolization has been widely publicized. We believe that many reports of aerosols emanating from hot tubs, springs and cooling towers were biased by the fact that the epidemiologic investigation failed to include drinking water sources. In this next millennium as more attention is focused on drinking water, a decrease in legionellosis attributed to aerosol transmission is likely to occur especially in hospital-acquired cases since water will be cultured; in community-acquired cases, drinking water is often overlooked. A decrease has already occurred for hospital-acquired legionellosis in which reports of cooling tower links have plummeted; virtually all of the identified water sources of hospital-acquired legionellosis are drinking water systems within the hospital. Cooling tower outbreaks continue to be reported, usually in the lay press, for community-acquired legionellosis and in these outbreaks drinking water sources are not cultured. In this review, for the 25 reports in which an environmental source was sought, 72% (18/25) of the patients were attributed to contamination of hospital tap water by Legionella (Table 2). In 10 patients, the molecular subtype of the patient isolate matched that of the environmental isolate (Table 2).

Since the first environmental isolation of L. pneumophila was taken from a shower head it was widely assumed shower aerosols might be the means of dissemination of the organism. However, an epidemiologic link between showering and acquisition of disease has never been shown in prospective studies and in at least two controlled studies, showering proved not to be a risk factor (6, 60). Humidifers and ultrasonic nebulizers have been linked as well as direct installation of contaminated water down respiratory tract tubing has been linked (2, 9, 49). Nasal gastric tube placement, a risk factor for aspiration, has been identified as a risk factor in hospitalized patients. Ice machines have been suspected as a source in an anecdotal reports.

LABORATORY DIAGNOSIS

Prompt diagnosis of Legionnaires' disease in solid organ transplant recipients is especially important since early initiation of appropriate therapy is directly linked to survival (28, 42). Because the clinical presentation of Legionnaires' disease is nonspecific, specialized diagnostic laboratory tests are the key feature for diagnosing Legionnaires' disease. Since most of Legionella cases in organ transplant patients are acquired in the hospital, Legionella diagnostic tests must be available in-hospital for hospitals performing transplants (8, 22). Among the species in the Legionellaceae family, L. pneumophila was responsible for 83% of Legionella infections in solid organ transplant (Table 1); however, serogroups or species other than L. pneumophila serogroup 1 were common (Table 2).

The urinary antigen test is the most commonly used laboratory method Legionella diagnosis for urinary antigen. Urinary antigen testing is rapid, sensitive, specific, and inexpensive but is only accurate for the diagnosis of L. pneumophila, serogroups 1. A metaanalysis of 30 studies by Shimada et al (61) showed a high specificity of 99% and a sensitivity of 74%. Thus, one-quarter of patients with confirmed legionellosis can have a negative test result. Duration of urine antigen positivity and excretion is longer in immunosuppressed patients (up to 3 weeks) and these patients also have prolonged duration of fever (65).

Culturing for Legionella spp. is the single most important laboratory test given the limitations of the urinary antigen for species other than Legionella pneumophila and serogroups other than serogroup 1. The availability of the patient isolate from culture can be used for subsequent epidemiologic investigations by comparing the patient isolate to the isolate from the drinking water (44). Given the frequency of Legionella as a pathogen in both community- and hospital-acquired pneumonia, culture on selective media should be routinely available in all clinical microbiology laboratories especially in those hospitals caring for transplant recipients. In fact, Legionella could be isolated by culture in 35 of the 50 studies. The combination of culture of respiratory specimens and urinary antigen testing are optimal as a diagnostic approach (76). The reported sensitivity of direct fluorescent antibody (DFA) stains has ranged from 25% to 75%. It is highly specific, and the monoclonal antibody test has eliminated the rare occurrence of cross-reactivity with other gram-negative bacilli. DFA may be performed if the direct culture of the specimen is overgrown by competing microflora. Its sensitivity and specificity depend on the experience of the observer. Serologic tests are generally far less useful for the diagnosis of Legionella infection in immunosuppressed patients and two paired serums over 3 months or more are frequently necessary to demonstrate seroconversion (12, 72).

Polymerase chain reaction (PCR)-based detection of Legionella DNA in sputum, urine and blood has been described. When testing clinical samples from the lower respiratory tract, PCR has been shown to have sensitivity equal to or greater than culture (10). Moreover, PCR can detect species and serogroups other than L. pneumophila serogroups 1 (62, 73). False positive results have been reported using both in-house and commercial assays (13). Legionella DNA can also be detected from other samples, but with reduced sensitivity (48).

ANTIBIOTIC THERAPY

Legionella is an intracellular pathogen which has relevance to the efficacy of the antibiotic (32). Antibiotics capable of achieving high intracellular concentrations are more effective clinically than antibiotics with poor intracellular penetration. Tetracyclines, macrolides, rifampin and quinolones have intracellular penetration superior to that of beta-lactam agents.

Therapeutic data were available in 36% (103/287) of Legionella infection cases in this review (Table 5). Erythromycin was the most common antibiotic administered (Table 5), but this is likely a reporting bias from an earlier era. Only 11 patients 11% (11/103) did not receive any specific anti-Legionella antibiotic therapy and their mortality was a shocking 91% (10/11). Although macrolides were effective, patients receiving quinolones had the lowest mortality 7.6% (1/13) (Table 5). Note that azithromycin was not used in any of these studies.

Quinolones are more active than any of the macrolides in both in vitro and in vivo methods and in intracellular models (3,16,18,19,25,68,70). The results of five observational clinical studies totalling 598 patients suggest that quinolones are more effective than macrolides (erythromycin and clarithromycin) based on time to defervescence and length of hospital stay (52), although the mortality was similar for both classes of antibiotics.

Combinations of antibiotics have been used in patients unresponsive to monotherapy, the most frequent being macrolides-rifampin, macrolides-quinolones or quinolones-rifampin. The addition of rifampin failed to show any advantage in 3 retrospective clinical studies totaling 122 patients (14, 26, 33). Rifampin commonly causes hyperbilirubin levels which is reversible upon discontinuation of the rifampin. In vitro and in vivo studies do not show a consistent synergistic effect against Legionella. In contrast, the combination of macrolides and quinolones has shown promising results in in vitro and in vivo models and in anecdotal cases (53).

Drug interactions are of concern in transplant recipients. Rifampin interacts with numerous drugs affected by hepatic metabolism. Erythromycin and clarithromycin interacts with tacrolimus by interfering with their hepatic metabolism through the CYP3A subclass (1). Azithromycin appears to have fewest drug interactions because of minimal CYP34A inhibition (51). In fact, there is only one published case of interaction between azithromycin and cyclosporine (50). Quinolones do not affect hepatic P450 enzyme, CYP3A4 and they may be the preferred antibiotic for transplant recipients. The occasional case reports of apparent interactions of quinolones with other drugs interacting with this enzyme are difficult to assess (56).

PROPHYLAXIS

The use of antibiotics prophylaxis for Legionella infection in transplant recipients is questionable. The unusually low incidence of Legionella infection observed in some immunosuppressed patients such as HIV-infected patients or renal transplant recipients has been attributed to the use of trimethoprim-sulfamethoxazole (TMP-SMZ) as prophylaxis for other opportunistic infections (54). Relapse of Legionella infection has been described in severely immunosuppressed patients especially in the erythromycin era (55). Molecular subtyping has documented that someLegionella infections are relapses (47). Clinical failures due to resistance of the organism to the antimicrobial agent have not been documented. In vitro susceptibility of clinical isolates of Legionella to macrolides and quinolones has been consistent. Therefore the likely cause for persistence of the organism and the need for prolonged therapy in immunocompromised patient is the failure of the host’s immune system to assist fully in clearing the infection (64).

The routine administration of prophylactic trimethoprim-sulfamethoxazole (TMP-SMZ) (160-800 mg given orally once daily) while in-hospital after transplantation appeared to prevent nosocomial Legionella pneumonia in renal transplant recipients (43). On the other hand, an outbreak of hospital-acquired Legionnaires’ disease occurred in a Pittsburgh liver transplant service despite receipt of TMP-SMZ for Pneumocystis prophylaxis.

INFECTION CONTROL MEASURES

Most of the cases are hospital-acquired Legionnaires’ disease resulting from contamination of tap water (Table 2). U.S. Centers for Disease Control and Prevention (CDC) have recommended that hospitals with solid organ and hematopoietic stem cell transplant programs perform periodic culturing for Legionella in the potable water supply of the transplant unit as a method for prevention (8, 21). In the event of an outbreak, drinking of tap water should be proscribed until disinfection of the water supply is complete. Banning showering is commonplace but unnecessary; ironically, lack of showering has been linked to contracting Legionnaires’ disease (6, 60). Bottled water should be used for feeding purposes and sterile water for humidifiers.

Numerous disinfection methods have been tried over many years. Two methods have proven to be cost-effective: superheating and flushing and copper–silver ionization (45, 69). Chlorine dioxide is widely used and continuing evaluation is indicated; some installations have failed. Copper and silver and chlorine dioxide concentrations should be monitored regularly. Routine environmental cultures performed simultaneously with disinfection concentrations should be performed at regular intervals for the lifespan of the system. Monochloramine is under evaluation and appears to be promising.

Thermal eradication, often termed “superheat and flush” consists in increasing the hot water tank temperature to 70ºC and flushing all distal sites (faucets and showerheads) with hot water for 30 minutes. The advantage is that this rapid method is effective in an outbreak situation and inexpensive to implement. It is logistically tedious to flush the faucets and measure the temperature at distal points. Unfortunately, several days are needed to flush all the hospital faucets since a high temperature must be maintained making it necessary to repeat this process at regular intervals (57).

Given the proliferation of numerous commercial firms offering disinfection systems, failures have become commonplace with patients contracting Legionnaires’ disease and distal tap water sites yielding Legionella despite installation of these expensive systems. Failure to monitor Legionella levels and disinfectant concentrations were reasons for the failure. One consistent finding was noted in the failures: the purchase of the disinfection system was made by healthcare facility managers with minimal or no input from infection control practitioners. Thus, we recommend that infection control practitioners select the disinfection method and vendor using evidence-based medicine and experience of the vendor as criteria for selection. Healthcare facilities managers should only play a consultative role.

References

1. Amsden GW. Macrolides versus adalides. A drug interaction update. Ann Pharmacother 1995;29:906-17. [PubMed]

2. Arnow PM, Chou T, Weil D, Shapiro EN, Kretzschmar C. Nosocomial Legionnaires' disease caused by aerosolized tap water from respiratory devices. J Infect Dis 1982;146:460-7. [PubMed]

3. Baltch AL, Bopp LH, Smith RP, et al. Antibacterial activities of gemifloxacin, levofloxacin, gatifloxacin, moxifloxacin and erythromycin against intracellular Legionella pneumophila and Legionella micdadei in human monocytes. J Antimicrob Chemother 2005;56:104-9. [PubMed]

4. Benson RF, Fields BS. Classification of the genus Legionella. Semin Respir Infect 1998; 13:90-99. [PubMed]

5. Best M, Yu VL, Stout J, Goetz A, Muder RR, Taylor F. Legionellaceae in the hospital water-supply. Epidemiological link with disease and evaluation of a method for control of nosocomial legionnaires' disease and Pittsburgh pneumonia. Lancet 1983;2:307-10. [PubMed]

6. Blatt SP, Parkinson MD, Pace E, Hoffman P, Dolan D, Lauderdale P, Zajac RA, Melcher GP. Nosocomial Legionnaires’ disease: aspiration as a primary mode of disease acquisition. Am J Med 1993;95:16-22. [PubMed]

7. Centers for Disease Control and Prevention. Guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients. Morbid Mortal Wkly Rep 2000:49:1-128. [PubMed]

8. CDC and Healthcare Infection Control Practice Advisory Committee. Guidelines for preventing health care–associated pneumonia. 2003. MMWR 3/26/2004. 53(RR03), 1-36. [PubMed]

9. Chow JW, Yu VL. Legionella: a major opportunistic pathogen in transplant recipients. Semin Respir Infect. 1998;13:132-9. [PubMed]

10. Cloud JL, Carroll KC, Pixton P, ERali M, Hillyard DR. Detection of Legionella species in respiratory specimens using PCR with sequencing confirmation. J Clin Microbiol 2000;38:1709-12. [PubMed]

11. Copeland J, Wieden M, Feinberg W, et al. Legionnaires’ disease following cardiac transplantation. Chest 1981;79:669-71. [PubMed]

12. De Boer JW, Yzerman EPF. Diagnosis of Legionella infection in Legionnaires’ disease. Eur J Clin Microbiol Infect Dis 2004;23:871-8. [PubMed]

13. Diederen BM. Legionella spp. and Legionnaires’ disease. J Infect 2008;56:1-12. [PubMed]

14. Dournon E, Mayaud C, Wolff M, et al. Comparison of the activity of three antibiotic regimens in severe Legionnaires’ disease. J Antimicrob Chemother 1990;26 Suppl B:129. [PubMed]

15. Dowling JN, Pasculle AW, Frola FN, et al. Infections caused by Legionella micdadei and Legionella pneumophila among renal transplant recipients. J Infect Dis 1984;149:703-13. [PubMed]

16. Edelstein PH, Edelstein MA, Lehr KH, Ren J. In-vitro activity of levofloxacin against clinical isolates of Legionella spp., its pharmacokinetics in guinea pigs, and use in experimental Legionella pneumophila pneumonia. J Antimicrob Chemother 1996;37:117-26. [PubMed]

17. Edelstein PH, Edelstein MA, Ren J, et al. Activity of trovafloxacin CP-99, 219. against Legionella isolates: In vitro activity, intracellular accumulation and killing in macrophages, and pharmacokinetics and treatment of guinea pigs with L. pneumophila pneumonia. Antimicrob Agents Chemother 1996;40:314-331. [PubMed]

18. Edelstein PH, Edelstein MA, Weindenfeld J, Dorr MB. In vitro activity of sparfloxacin CI-978;AT-4140. for clinical Legionella isolates, pharmacokinetics in guinea pigs, and use to treat guinea pigs with L. pneumophila pneumonia. Antimicrob Agents Chemother 1990;34:2122-27. [PubMed]

19. Edelstein PH, Shinzato T, Doyle E, Edelstein MAC. In vitro activity of gemifloxacin (SB-265805, LB20304a) against Legionella pneumophila and its pharmacokinetics in guinea pigs with L. pneumophila pneumonia. Antimicrob Agents Chemother 2001;45:2204-9. [PubMed]

20. Ernst A, Gordon FD, Hayek J, Silvestri RC, Koziel H. Lung abscess complicating Legionella micdadei pneumonia in an adult liver transplant recipient: case report and review. Transplantation 1998;35:130-4. [PubMed]

21. Euzèby, JP. List of prokaryotic names with standing in nomenclature. http//www.bacterio.citr.fr. (Accessed June 11, 2008). [PubMed]

22. Fiore, AE, Butler, JC, Emori, TG, Gaynes, RP. A survey of methods used to detect nosocomial legionellosis among participants in the National Nosocomial Infections Surveillance System. Infect Control Hosp Epidemiol 1999; 20:412.[PubMed]

23. Fraser TG, Zembower TR, Lynch P, Fryer J, Salvalaggio PRO, Yeldandi AV, Stosor V. Cavitary Legionella pneumonia in a liver transplant recipient. Trans Infect Dis 2004;6:77-80. [PubMed]

24. Ginevra, C, Duclos, A, Vanhems, P, et al. Host-related risk factors and clinical features of community-acquired legionnaires disease due to the Paris and Lorraine endemic strains, 1998-2007, France. Clin Infect Dis 2009; 49:184.[PubMed]

25. Gombert M, Josephson A, Goldstein EJC, et al. Cavitary Legionella pneumonitis:nosocomial infection in renal transplant recipients. Am J Surg 1984;147:402-5. [PubMed]

26. Grau S, Mateu-de Antonio J, Ribes E, et al. Impact of rifampin addition to clarithromycin in Legionella pneumophila pneumonia. Int J Antimicrob Agents 2006;28:249-252. [PubMed]

27. Griffin GK, Pope TL, Armstrong P. Pittsburgh pneumonia agent in a cadaveric renal transplant recipient. Clin Nephrol 1983;20:263-6. [PubMed]

28. Guyot S, Goy JJ, Gersbach P, Jaton K, Blanc DS, Zanetti G. Legionella pneumophila aortitis in a heart transplant recipient. Trans Infect Dis 2007;9:58-9. [PubMed]

29. Heath CH, Grove DI, Looke DFM. Delay in appropriate therapy of Legionella pneumonia associated with increased mortality. Eur J Clin Microbiol Infect Dis 1996; 15:286. [PubMed]

30. Horbach I, Fehrenbach FJ. Legionellosis in heart transplant recipients. Infection 1990;18:361-3. [PubMed]

31. Horwitz, MA. Toward an understanding of host and bacterial molecules mediating L. pneumophila pathogenesis. In: Legionella-Current Status and Emerging Perspectives, Barbaree, JM, Breiman, RF, Dufour, AP (Eds), American Society of Microbiology, Washington, DC, 1993, p. 55. [PubMed]

32. Horwitz MA, Silvertein SC. Intracellular multiplication of Legionnaires’ disease bacteria (Legionella pneumophila) in human monocytes is reversibly inhibited by erythromycin and rifampin. J Clin Invest 1983;71:15-26.[PubMed]

33. Hubbard RB, Mathur RM, Mac Farlane JT. Severe community-acquired Legionella pneumonia: treatment, complications and outcome. Q J Med 1993;86:327-32. [PubMed]

34. Hubber A, Roy CR. Modulation of host cell function by Legionella pneumophila type IV effectors. Annu Rev Cell Dev Biol 2010;26:261-83. [PubMed]

35. Humphreys H, Marshall RJ, MacKay I, et al. Pneumonia due to Legionella bozemanii and Chlamydia pneumoniae TWAR following renal transplantation. J Infect 1992;5:67-71. [PubMed]

36. Jacobs F, liesnard C, Goldstein J, et al. AsymptomaticLegionella pneumophila infections in heart transplant recipients. Transplantation 1990;50:174-5. [PubMed]

37. Jernigan DB, Sanders LI, Waites KB, Brookings ES, Benson RF, Pappas PG. Pulmonary infection due to Legionella cincinnatiensis in renal transplant recipients: two cases and implications for laboratory diagnosis. Clin Infect Dis 1994;18:385-9. [PubMed]

38. Kilborn JA, Manz LA, O’Brien M, Douglass MC, Horst HM, Kupin W, Fisher EJ. Ncrotizing cellulitis caused by Leginella micdadei. Am J Med 1992;92:104-6. [PubMed]

39. Kirby BD, Snyder KM, Meyer RD, Finegold SM. Legionnaires' disease: Report of 65 nosocomially acquired cases and a review of the literature. Medicine (Baltimore) 1980; 59:188. [PubMed]

40. Knirsch CA, Jacob K, Schoonmaker D, Kiehlbauch JA, Wong SJ, Della-Latta Ph, Whittier S, Layton M, Scully B. An outbreak of Legionella micdadei pneumonia in transplant patients: evaluation, molecular epidemiology, and control. Am J Med 2000;108:290-5. [PubMed]

41. Kumar Ajay, Will EJ. Necrotizing fasciitis and Legionnaires’ disease after combined renal and pancreatic transplantation: a penalty of overseas travel. Nephrol Dial Transplant 1999;14:1781-3. [PubMed]

42. Lepine LA, Jernigan DB, Butler JC, et al. A recurrent outbreak of nosocomial legionnaires' disease detected by urinary antigen testing: evidence for long-term colonization of a hospital plumbing system. Infect Control Hosp Epidemiol 1998; 19:905. [PubMed]

43. LeSaux NM, Sekla L, McLeod J, Parker S, Rush D, Jeffery JR, Brunhaum RC. Epidemic of nosocomial Legionnaires’ disease in renal transplant recipients: a case-control and environmental study. CMAJ 1989;140:1047-53. [PubMed]

44. Marrie TJ. Diagnosis of legionellaceae as a cause of community-acquired pneumonia- "... continue to treat first and not bother to ask questions later"--not a good idea. Am J Med 2001; 110:73. [PubMed]

45. Mòdol J, Sabrià M, Reynaga E, Pedro-Botet ML, Sopena N, Tudela P, Casas I, Rey-Joly C. Hospital-acquired Legionnaires’ disease in a university hospital: impact of the copper-silver ionization system. Clin Infect Dis 2007;44:263-265. [PubMed]

46. Moore EH, Webb WR, Gamsu G, et al. Legionnaires’ disease in the renal transplant patient:clinical presentation and radiographic progression. Radiology 1984;153:583-93. [PubMed]

47. Morley JN, Smith LC, Baltch AL, Smith RP. Recurrent infection due to Legionella pneumophila in a patient with AIDS. Clin Infect Dis 1994;19:1130-2. [PubMed]

48. Murdoch DR. Diagnosis of Legionella Infection. Clin Infect Dis 2003;36:64-9. [PubMed]

49. Phillips SJ, Zeff RH, Gervich D. Legionnaires' disease. Ann Thorac Surg 1987;44:564. [PubMed]

50. Page RL End, Ruscin JM, Fish D, Lapointe M. Possible interaction between intravenous azithromycin and oral cyclosporine. Pharmacotherapy 2001;21:1436-43. [PubMed]

51. Periti P, Mazzei T, Mini E, et al. Pharmacokinetic drug interactions of macrolides. Clin Pharmacokinet 1992;23:106-31.[PubMed]

52. Pedro-Botet ML, Yu VL. Treatment strategies on Legionella infection. Expert Opin Pharmacother 2009;10 :1109-21. [PubMed]

53. Pedro-Botet ML, Yu VL. Legionella: macrolides or quinolones? Clin Microbiol Infect 2006;12(Suppl 3):25-30.[PubMed]

54. Pedro-Botet ML, Sabrià M, Sopena N, García-Núñez M, Domínguez MJ, Reynaga E, Rey-Joly C. Legionnaires’ disease and HIV infection. Chest 2003;124:543-47. [PubMed]

55. Pedro-Botet ML, Sabriá Leal M, Sopena N, Manterola JM, Morera J, Blavia R, Padilla E, Matas L, Gimeno JM. Role of immunosuppression in the evolution of Legionnaires’ disease. Clin Infect Dis 1998;26:14-19. [PubMed]

56. Qaqish R, Polk RE. Drug-drug interactions. In: Hooper DC, Wolfson JS. Eds. Quinolones Antimicobial Agents. Washington, D.C.; ASM Press: 2003:133-46. [PubMed]

57. Ragull S, ML. Pedro-Botet M. García-Núñez M. Esteve N. Sopena C. Rey-Joly, Sabrià M. El choque térmico como medida de control de un brote de legionelosis hospitalaria. Med Clin (Barc) 2006;127:211-3. [PubMed]

58. Renoult E, Kessler M, Jonon B, et al. Significance of seroconversion against Legionella after renal transplantation:report of five cases. Clin Nephrol1990;33:209. [PubMed]

59. Ricketts KD, Joseph CA. Legionnaires disease in Europe: 2005-2006. Euro Surveill 2007; 12:E7. [PubMed]

60. Sabria, M, Yu, VL. Hospital-acquired legionellosis: solutions for a preventable infection. Lancet Infect Dis 2002; 2:368.[PubMed]

61. Shimada T, Noguchi Y, Jackson JL, et al. Systematic review and metaanalysis: urinary antigen tests for legionellosis. Chest 2009;136:1576-85. [PubMed]

62. Siegel MO, Fedorko DP, Drake SK, Calhoun LB, Holland SM. Legionella feeleii serotype 2 pneumonia in a man with chronic lymphocytic leukemia: a challenging diagnosis. J Clin Microbiol 2010;48:2294-7. [PubMed]

63. Singh N, Muder RR, Yu VL, Gayowski T. Legionella infection in liver transplant recipients: implications for management. Transplantation 1993;56:1549-51. [PubMed]

64. Singh N, Stout JE, Yu VL. Prevention of Legionnaires’ disease in transplant recipients: recommendations for a standardized approach. Transplant Infectious Diseases 2004;6:58-62. [PubMed]

65. Sopena N, Sabrià M, Pedro-Botet ML, Reynaga E, García-Núñez M, Domínguez J, Matas L. Factors related to persistence of Legionella urinary antigen excretion in patients with Legionnaires’ disease. Eur J Clin Microbiol Infect Dis 2002; 21: 845-848. [PubMed]

66. Stone BJ, Abu KY. Expression of multiple pili by Legionella pneumophila: Identification and characterization of a type IV pilin gene and its role in adherence to mammalian and protozoan cells. Infect Immun 1998; 66:1768.[PubMed]

67. Stout J, Yu VL, Vickers RM, Zuravleff J, Best M, Brown A, Yee RB, Wadowsky R. Ubiquitousness of Legionella pneumophila in the water supply of a hospital with endemic Legionnaires' disease. N Engl J Med 1982;306:466-8.[PubMed]

68. Stout JE, Sens K, Mietzner S, et al. Comparative activity of quinolones, macrolides and ketolides against Legionella species using in vitro broth dilution and intracellular susceptibility testing. Int J Antimicrob Agents 2005;25:302-7.[PubMed]

69. Stout JE, Yu VL. Experiences of the first 16 hospitals using copper-silver ionization for Legionella control: implications for the evaluation of other disinfection modalities. Infect Control Hosp Epidemiol 2003;24:563. [PubMed]

70. Tano E, Cars O, Löwdin E. Pharmacodynamic studies of moxifloxacin and erythromycin against intracellular Legionella pneumophila in an in vitro kinetic model. J Antimicrob Chemother 2005;56:240-2. [PubMed]

71. Tokunaga Y, Concepcion W, Berquist WE, Cox KL, Wiviott LD, Garcia-Kennedy R, Itasaka H, Nakazato P, Esquivel CO. Graft involvement by Legionella in a liver transplant recipient. Arch Surg 1992;127:475-7. [PubMed]

72. Vickers RM, Fang G, Kohler, RB, Gottron S, Rihs JD, Yu VL. Prospective assessment of monoclonal direct fluorescent antibody, urinary antigen and acid pretreatment culture techniques in the diagnosis of Legionnaires’ disease Intersci Conf Antimicrob g Chemother #181, New York, 1987. [PubMed]

73. von Baum H, Ewig S, Marre R, Suttorp N, Gonschior S, Welte T, Lück C. Community-acquired Legionella pneumonia: new insights from the German competence network for community acquired pneumonia. Clin Infect Dis 2008;46:1356-64.[PubMed]

74. Vogel JP, Andrews HL, Wong SK, Isberg RR. Conjugative transfer by the virulence system of Legionella pneumophila. Science 1998; 279:873. [PubMed]

75. Wilczek H, Kallings I, Nystrom B, et al: Nosocomial Legionnaires’ disease following renal transplantation. Transplantation 1987;43:846-51. [PubMed]

76. Yu VL Stout JE. Rapid diagnostic testing for community-acquired pneumonia. Can innovative technology for clinical microbiology be exploited? Chest2009;136:1618-21. [PubMed]

77. Zamarron Sanz C, Novoa García D, Fernandez Vazquez E, Sanchez Guisande D, Perez del Molino M. Absceso pulmonary y empiema pleural por Legionella pneumophila en un paciente transplantado renal. An Med Intern 1993;10:547-8. [PubMed]

Table 1. Epidemiology of Legionnaires’ disease in Solid Organ Transplants

			Acquired (# patients)
Organ, # refs	Age (mean, range)	Gender(M/F)	Community	Hospital	Rejection	% Transplant
Kidney, 27	44 years (9-66)	55/15	163	11	63% (34/54)	3% (124/4,524)
Heart, 12	52 years (41-61)	13/14	84	8	20% (2/10)	4% (81/2,204)
Liver, 9	38 years (2.5 mos. -67)	8/8	13	6	44% (7/16)	1.5% (12/806)
Lung, 2	50 years (47-52)	2/0	2	0	0	7% (1/14)
Total – 50	46 years (2.5 mos-67	78/37	262	25	52% (43/82)	3% (218/7,548)

Footnotes: Denominator is not 287 for all parameters because of missing data
# refs = number of references cited in this review
M/F=males/females
Time to infection = number of days from transplantation date to onset of Legionnaires’ disease
Rejection=Legionnaires’ disease occurred during rejection phase
% Transplant = number of transplant recipients with Legionnaires’ disease/total number of transplants during that study period.

Table 2: Microbiology, environmental source, and clinical manifestation of Legionnaires’ disease in transplant patients

Organ	Legionella spp	Environmental link. Molecular confirmation	Pneumonia
Kidney	pneumophila 1,3,6,11 micdadei, longbeachae, cincinnatiensis, bozemanii	85% (11/13) 5 Mol	92% (126/137)
Heart	pneumophila 1,4,6 longbeachae, micdadei,	44% (4/9) 4 Mol	80% (35/44)
Liver	pneumophila 1,6 bozemanii, parisiensis, micdadei,	100% (2/2)	94% (15/16)
Lung	pneumophila 1,4	100% (1/1) 1 Mol	100% (2/2)
Total	pneumophila plus 5 other species	72% (18/25) 10 Mol	90% (178/199)

Footnotes: Denominator is not 287 for all parameters because of missing data.
Environmental link = Link made to hospital water by isolation of Legionella spp. of the same serogroup from both patient and water.
Mol=Molecular confirmation of matching patient isolate to environmental water isolate

Table 3: Time to Legionella Infection for community-acquired and for hospital-acquired cases

	Origin		Time to Legionella Infection
	Community	Hospital	Community	Hospital
Kidney	11	163	2,122 d (163d - 3,650)	176 (4d - 2,190d)
Heart	8	84	38.5 d (21d - 56d)	131 (10d - 480d)
Liver	6	13	2,737d (2,555d - 2,920d)	26 (3d - 90d)
Lung	0	2	-----	45d (14 - 81d)
Total	25	262	1,632.5d (21d - 3,650d)	95 d (3d - 2,190d)

d=days
Time to Legionella infection after transplant surgery

Table 4: Extrapulmonary Legionnaires’ disease in transplant recipients

Ref.	Type of transplant	Cases n	Extrapulmonary sites	Pneumonia	Species	Treatment Clari	Outcome
Guyot S, 2007, Switzerland(29)	Heart	1	Aortitis	No	pneumophilaserogroup 6	Clair/ Rifampin	Survived
Tokunaga Y, 1992, USA(30)	Liver	1	Liver	Yes	pneumophilaserogroup 1	Erythromycin	Death
Singh N, 1993, USA(31)	Liver	1	Pericarditis	No	pneumophilaserogroup 6	Erythromycin	Survived
Kilborn JA, 1992, USA (32)	Kidney	1	Cellulitis	No	micdadei	TMP/SMX + Doxycycline + Rifampin	Survived

Clari=Clarithromycin
TMP/SMX=Trimethoprim/sulfamethoxazole

Table 5: Antibiotic therapy and outcome of Legionnaires’ disease in transplant recipients

Organ/ No. Patients	Macrolide	Quinolone	Combination	None	Mortality
Kidney, 27	59% (44/75)	5% (4/75)	21% (16/75)	13% (16/75)	28.3%(34/120)
Heart, 12	10% (1/10)	30% (3/10)	60% (6/10)	0 (0/10)	5.5%(1/18)
Liver, 9	50% (8/16)	38% (6/16)	13% (2/16)	0% (0/16)	18.7% (3/16)
Lung, 2	0% (0/12)	0% (0/2)	50% (1/2)	50% (1/2)	50% (1/2)
Total, 50	51% (53/103)	13% (13/103)	24% (25/103)	11% (11/103)	25%(39/156

Macrolide=Erythromycin, clarithromycin as monotherapy
Quinolone =Ciprofloxacin, levofloxacin as monotherapy
Combination = Combination of antibiotics including quinolones, macrolides, rifampin, doxycycline, TMP-SMZ

Stout JE, Muder RR. Role of Environmental Surveillance in Determining the Risk of Hospital-Acquired Legionellosis: A National Surveillance Study with Clinical Correlations. Infect Control Hosp Epidemiol 2007;28:818-824.

Gudiol C, Verdaguer R, et al. Outbreak of Legionnaires' Disease in Immunosuppressed Patients at a Cancer Centre: Usefulness of Universal Urine Antigen Testing and Early Levofloxacin Therapy. Clin Microbiol Infect. 2007 Nov;13:1125-8.

Stout JE. Preventing Legionellosis. ASHRAE Journal. 2007:58-62.

Yu VL, Greenberg RN, et al. Levofloxacin Efficacy in the Treatment of Community-Acquired Legionellosis. Chest 2004;125 (6):2135-2139.

Stout JE, Yu VL. Experience of the First 16 Hospitals Using Copper-Silver Ionization for Legionellosis Control: Implications for the Evaluation of Other Disinfection Modalities. Infect Control Hosp Epidemiol 2003;24 (8):563-568.