Section 3 Diagnosis

#### **Chapter 3**

## *Legionella* Pneumonia Due to Non-*Legionella pneumophila* Serogroup 1

*Akihiro Ito and Tadashi Ishida*

#### **Abstract**

*Legionella pneumophila* is one of the important pathogens in communityacquired (CAP) and hospital-acquired pneumonia that can cause severe pneumonia. Early diagnosis and treatment of *Legionella* pneumonia (LP) are essential because inappropriate therapy for *Legionella* pneumonia has been reported to worsen the prognosis. The most frequently identified causative pathogen of *Legionella* pneumonia is *Legionella pneumophila* serogroup 1. *Legionella* pneumonia due to non-*Legionella pneumophila* serogroup 1 is seen in 20% of cases. In diagnosing *Legionella* pneumonia caused by non-*Legionella pneumophila* serogroup 1, the urinary antigen test is usually negative; therefore, we need to suspect *Legionella* pneumonia by clinical information such as symptoms, vital signs, laboratory findings, and radiological findings. Based on our previous report, *Legionella* pneumonia due to non-*Legionella pneumophila* serogroup 1 was a mild to severe pneumonia. In addition, in about half of the patients, we could not suspect *Legionella* pneumonia using a six-point scoring system, which is one of the diagnostic scoring systems. Recently, a new urinary antigen test kit that could theoretically diagnose *Legionella* pneumonia due to non-*Legionella pneumophila* serogroup 1 was released in Japan. This can help in early diagnosis of *Legionella* pneumonia, including the one caused by non-*Legionella pneumophila* serogroup 1.

**Keywords:** diagnosis, *Legionella* pneumonia, *Legionella pneumophila* serogroup 1, non-*Legionella pneumophila* serogroup 1, urinary antigen

#### **1. Introduction**

*Legionella* pneumonia (LP) is caused by *Legionella* species that are important causative pathogens of community-acquired pneumonia (CAP) and hospitalacquired pneumonia. There are 58 species and three subspecies in the *Legionella* genus [1]. *Legionella* species are small to filamentous, Gram-negative rods [2].

The most frequently identified causative microorganism of *Legionella* pneumonia is *Legionella pneumophila* serogroup 1, accounting for about 80% of cases [3, 4]. In CAP, the rate of LP is reported to be 0.6–8% [5–8], although the rate differs in different areas and countries. However, in severe CAP that satisfies the Infectious Diseases Society of America/American Thoracic Society severe pneumonia criteria [9], LP is one of the most important etiologies, because the rate of LP was reported to be 13.5% in 133 patients [10] and 14.1% in 71 patients

<60 years old [11]. In addition, inappropriate initial therapy for LP was shown to be one of the independent factors predicting a worse prognosis [12]. Therefore, early and appropriate diagnosis of LP is very important to improve the prognosis of LP patients.

The gold standard in the diagnosis of LP is the identification of *Legionella* species in respiratory specimens such as sputum and bronchoalveolar lavage fluid. However, some LP patients have no sputum for culture, a dedicated culture medium, such as Wadowsky-Yee-Okuda-α or Buffered Charcoal Yeast Extract-α medium is needed, therefore identification of *Legionella* species is sometimes difficult, costly and time-consuming.

Currently, a urinary antigen test that detects soluble antigens is widely used for diagnosing LP in daily clinical practice worldwide. This diagnostic method is very useful because the examination procedure is simple and the results are known quickly. In a systematic review and meta-analysis, Shimada et al. reported that the specificity of the *Legionella* urinary antigen test was 99.1% and sensitivity was 74%; therefore, LP cannot be ruled out if this test is negative. Specifically, the sensitivity of the urinary antigen test for diagnosing LP due to non-*L. pneumophila* serogroup 1 is low [13]. Therefore, the *Legionella* urinary antigen test is not useful for diagnosing LP caused by non-*L. pneumophila* serogroup 1.

The diagnostic key for LP due to non-*L. pneumophila* serogroup 1 is to suspect *Legionella* pneumonia based on clinical information such as patients' symptoms, vital signs, laboratory findings, and radiological findings. Therefore, in this chapter, we describe the clinical characteristics of LP due to non-*L. pneumophila* serogroup 1 referred to in previous reports.

#### **2.** *Legionella* **pneumonia due to non-***Legionella pneumophila* **serogroup 1**

#### **2.1 Previous reports**

In earlier studies, LP due to non-*L. pneumophila* serogroup 1 could be a mild to moderate pneumonia [14, 15], not only a severe pneumonia admitted to intensive care unit [16–20]. Indeed, we reported a case of LP due to *L. pneumophila* serogroup 9 in which initial treatment with single-dose oral azithromycin appeared useful, although oral levofloxacin was administered subsequently [15].

There have been many case reports of LP caused by non-*L. pneumophila* serogroup 1, but there have been few case series. Therefore, we investigated the clinical characteristics of LP due to non-*L. pneumophila* serogroup 1 and compared with LP due to *L. pneumophila* serogroup 1 [21]. There were 11 patients with LP due to non-*L. pneumophila* serogroup 1 between March 2001 and June 2016 in our hospital. Their age range was 58–82 years, and eight patients (72.7%) were male. The most common comorbidities were diabetes mellitus, chronic liver disease, and malignant disease in each of the two patients. The most common symptom was fever (72.7%), followed by cough (54.5%), and sputum (54.5%). The distribution of bacterial strains was *L. pneumophila* serogroup 3 in six patients, *L. pneumophila* serogroup 9 in three patients, *L. pneumophila* serogroup 6 in one patient, and *L. longbeachae* in one patient. As to the severity of pneumonia, about half of the cases (5/11) were mild to moderate according to the pneumonia severity index (PSI) [22], whereas most cases (10/11) were mild to moderate based on CURB-65 [23]. Five patients whose PSI class was less than IV are all improved with oral azithromycin or oral levofloxacin. In contrast, four patients were admitted to the intensive care unit, and all four patients were administered appropriate empiric antimicrobial agents, but three patients died.

Legionella *Pneumonia Due to Non-*Legionella pneumophila *Serogroup 1 DOI: http://dx.doi.org/10.5772/intechopen.88187*

#### **2.2 Diagnostic scoring system**

We cannot rule out LP by a negative result of the urinary antigen test because the sensitivity of this test is not very good. To diagnose LP with a negative urinary antigen test, we need to suspect it based on the symptoms, vital signs, laboratory examinations, and radiological findings.

In 1998, Cunha advocated a diagnostic scoring system for LP called the "Winthrop-University Hospital (WUH) criteria" [24]. The WUH criteria comprised 15 clinical findings and seven laboratory findings, and it was therefore thought to be too complicated to use in the daily clinical practice.

In 2009, Fiumefreddo proposed a six-point scoring system for predicting LP [25], and this scoring system was validated by Haubitz [26]. This scoring system comprised one symptom, one vital sign, and four laboratory findings. The criteria for the six items are listed in **Table 1**. A score ≥5 had very high specificity (99.0%) and a high positive predictive value (17.4%), whereas a score <2 had high sensitivity (94.4%) and a high negative predictive value (99.6%). In our previous reports [21], using a cutoff value of ≥2 points, the sensitivity of this scoring system was 54.5% for non-*L. pneumophila* serogroup 1 patients and 95.7% for *L. pneumophila* serogroup 1 patients. Therefore, we could not rule out LP due to non-*L. pneumophila* serogroup 1 using this six-point scoring system. In **Figure 1**, the patient number


#### **Table 1.**

*Criteria for each item in the six-point scoring system.*

**Figure 1.**

*Total scores of the six-point scoring system in Legionella pneumonia due to non-L. pneumophila serogroup 1 and L. pneumophila serogroup 1.*

and total scores of the six-point scoring system in LP due to non-*L. pneumophila* serogroup 1 and *L. pneumophila* serogroup 1 are shown [21].

#### **3. Future perspective**

Patients with LP have a worse prognosis if they are not treated with appropriate antibiotic therapy as soon as possible. Some patients with LP due to *L. pneumophila* serogroup 1 have a negative urinary antigen test, and patients with LP due to non-*L. pneumophila* serogroup 1 are usually negative on this test. Therefore, it is important to suspect LP based on the clinical findings. However, as shown in our previous report, there are some LP patients in whom we cannot suspect LP based on the clinical findings specific to LP due to non-*L. pneumophila* serogroup 1. Thus, a simple method and a rapid test kit for diagnosing LP due to non-*L. pneumophila* serogroup 1 are needed.

In February 2019, Asahi Kasei Pharma Corporation released a urinary antigen test kit that could diagnose LP due to non-*L. pneumophila* serogroup 1, not only due to *L. pneumophila* serogroup 1. This kit uses an immunochromatographic method that has a monoclonal antibody recognizing a ribosomal protein L7/L12 unique region of *L. pneumophila* serogroups 1–15.

In the future, we expect that early diagnosis of LP including non-*L. pneumophila* serogroup 1 will be possible using this test kit.

#### **4. Conclusion**

LP due to non-*L. pneumophila* serogroup 1 can be a mild to severe pneumonia. To diagnose LP, there are some patients with LP caused by non-*L. pneumophila* serogroup 1 that could not be suspected to have LP based on their clinical findings, although diagnostic scoring systems have been reported to be useful for predicting LP. We need to investigate the usefulness of the new urinary antigen test kit that could theoretically diagnose these patients.

#### **Acknowledgements**

The authors would like to thank all of our colleagues who recruited and treated the patients. They would also like to thank Hiroyuki Fujii from the Department of Clinical Laboratory, Ohara Healthcare Foundation, Kurashiki Central Hospital, for performing sputum culture for *Legionella* species identification; Dr. Hiroshi Nakajima from the Department of Bacteriology, Okayama Prefectural Institute for Environmental Science and Public Health; and Dr. Junko Amemura-Maekawa from the Department of Bacteriology I, National Institute of Infectious Diseases, for performing *Legionella* species identification.

#### **Conflict of interest**

The authors declare no conflict of interest.

Legionella *Pneumonia Due to Non-*Legionella pneumophila *Serogroup 1 DOI: http://dx.doi.org/10.5772/intechopen.88187*

#### **Author details**

Akihiro Ito\* and Tadashi Ishida Department of Respiratory Medicine, Ohara Healthcare Foundation, Kurashiki Central Hospital, Kurashiki, Okayama, Japan

\*Address all correspondence to: ai12306@kchnet.or.jp

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

#### **References**

[1] Cunha BA, Burillo A, Bouza E. Legionnaires' disease. The Lancet. 2016;**387**:376-385

[2] Edelstein PH. *Legionella*. In: Versalovic J, Carroll KC, Funke G, Jorgensen JH, Landry ML, Warnock DW, editors. Manual of Clinical Microbiology. 10th ed. Washington, DC: American Society of Microbiology Press; 2011. pp. 770-785

[3] Amemura-Maekawa J, Kura F, Helbig JH, Chang B, Kaneko A, Watanabe Y, et al. Working Group for Legionella in Japan. Characterization of *Legionella pneumophila* isolates from patients in Japan according to serogroups, monoclonal antibody subgroups and sequence types. Journal of Medical Microbiology. 2010;**59**:653-659

[4] Helbig JH, Bernander S, Castellani Pastoris M, Etienne J, Gaia V, Lauwers S, et al. Pan-European study on culture-proven legionnaires' disease: Distribution of *Legionella pneumophila* serogroups and monoclonal subgroups. European Journal of Clinical Microbiology & Infectious Diseases. 2002;**21**:710-716

[5] Ishida T, Hashimoto T, Arita M, Ito I, Osawa M. Etiology of communityacquired pneumonia in hospitalized patients: A 3-year prospective study in Japan. Chest. 1998;**114**:1588-1593

[6] Saito A, Kohno S, Matsushima T, Watanabe A, Oizumi K, Yamaguchi K, et al. Prospective multicenter study of the causative organisms of communityacquired pneumonia in adults in Japan. Journal of Infection and Chemotherapy. 2006;**12**:63-69

[7] von Baum H, Ewig S, Marre R, Suttorp N, Gonschior S, Welte T, 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. Clinical Infectious Diseases. 2008;**46**:1356-1364

[8] Cillóniz C, Ewig S, Polverino E, Marcos MA, Esquinas C, Gabarrús A, et al. Microbial aetiology of communityacquired pneumonia and its relation to severity. Thorax. 2011;**66**:340-346

[9] Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Campbell GD, Dean NC, et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clinical Infectious Diseases. 2007;**44**(Suppl 2):S27-S72

[10] Ishiguro T, Takayanagi N, Yamaguchi S, Yamakawa H, Nakamoto K, Takaku Y, et al. Etiology and factors contributing to the severity and mortality of community-acquired pneumonia. Internal Medicine. 2013;**52**:317-324

[11] Ishida T, Tachibana H, Ito A, Tanaka M, Tokioka F, Furuta K, et al. Clinical characteristics of severe community-acquired pneumonia among younger patients: An analysis of 18 years at a community hospital. Journal of Infection and Chemotherapy. 2014;**20**:471-476

[12] Viasus D, Di Yacovo S, Garcia-Vidal C, Verdaguer R, Manresa F, Dorca J, et al. Community-acquired *Legionella pneumophila* pneumonia: A singlecenter experience with 214 hospitalized sporadic cases over 15 years. Medicine (Baltimore). 2013;**92**:51-60

[13] Olsen CW, Elverdal P, Jørgensen CS, Uldum SA. Comparison of the sensitivity of the *Legionella* urinary

Legionella *Pneumonia Due to Non-*Legionella pneumophila *Serogroup 1 DOI: http://dx.doi.org/10.5772/intechopen.88187*

antigen EIA kits from Binax and Biotest with urine from patients with infections caused by less common serogroups and subgroups of *Legionella*. European Journal of Clinical Microbiology & Infectious Diseases. 2009;**28**:817-820

[14] Faris B, Faris C, Schousboe M, Heath CH. Legionellosis from *Legionella pneumophila* serogroup 13. Emerging Infectious Diseases. 2005;**11**:1405-1409

[15] Ito A, Ishida T, Tachibana H, Ito Y, Takaiwa T, Fujii H, et al. A case of community-acquired pneumonia due to *Legionella pneumophila* serogroup 9 in which initial treatment with single-dose oral azithromycin appeared useful. Japanese Journal of Infectious Diseases. 2017;**70**:660-662

[16] Chen CY, Chen KY, Hsueh PR, Yang PC. Severe communityacquired pneumonia due to *Legionella pneumophila* serogroup 6. Journal of the Formosan Medical Association. 2006;**105**:256-262

[17] Lück PC, Schneider T, Wagner J, Walther I, Reif U, Weber S, et al. Community-acquired legionnaires' disease caused by *Legionella pneumophila* serogroup 10 linked to the private home. Journal of Medical Microbiology. 2008;**57**:240-243

[18] Furugen M, Koide M, Baba M, Sato Y, Teruya H, Naha Y, et al. *Legionella* pneumonia caused by *Legionella pneumophila* serogroup 2: Second case report in Japan. Journal of Infection and Chemotherapy. 2008;**14**:161-165

[19] Kawanami T, Yatera K, Fukuda K, Yamasaki K, Kunimoto M, Nagata S, et al. Diagnosis of fulminant pneumonia caused by *Legionella pneumophila* serogroup 8 with the sequence analysis of the 16S rRNA gene. The Tohoku Journal of Experimental Medicine. 2011;**225**:65-69

[20] Grottola A, Forghieri F, Meacci M, Fabio A, Pozzi L, Marcheqiano P, et al. Severe pneumonia caused by *Legionella pneumophila* serogroup 11, Italy. Emerging Infectious Diseases. 2012;**18**:1911-1913

[21] Ito A, Ishida T, Washio Y, Yamazaki A, Tachibana H. *Legionella* pneumonia due to non-*Legionella pneumophila* serogroup 1: Usefulness of the sixpoint scoring system. BMC Pulmonary Medicine. 2017;**17**:211

[22] Fine MJ, Auble TE, Yealy DM, Hanusa BH, Weissfeld LA, Singer DE, et al. A prediction rule to identify lowrisk patients with community-acquired pneumonia. New England Journal of Medicine. 1997;**336**:243-250

[23] Lim WS, van der Eerden MM, Laing R, Boersma WG, Karalus N, Town GI, et al. Defining community acquired pneumonia severity on presentation to hospital: An international derivation and validation study. Thorax. 2003;**58**:377-382

[24] Cunha BA. Clinical features of legionnaires' disease. Seminars in Respiratory Infections. 1998;**13**:116-127

[25] Fiumefreddo R, Zaborsky R, Haeuptle J, Christ-Crain M, Trampuz A, Steffen I, et al. Clinical predictors for *Legionella* in patients presenting with community-acquired pneumonia to the emergency department. BMC Pulmonary Medicine. 2009;**9**(4). DOI: 10.1186/1471-2466-9-4

[26] Haubitz S, Hitz F, Graedel L, Batschwaroff M, Wiemken TL, Peyrani P, et al. Ruling out *Legionella* in community-acquired pneumonia. The American Journal of Medicine. 2014;**127**:1010.e11-1010.e19

Section 4

Treatment

### **Chapter 4**

## Legionnaires' Disease Treatment

*Jorge F. Velazco*

#### **Abstract**

Legionnaires' disease is an important cause of community-acquired pneumonia as well as hospital-acquired pneumonia. *Legionella pneumophila* is an important but uncommon respiratory pathogen with significant morbidity and mortality. Initially recognized as a fatal cause of pneumonia in the 1970s. Untreated Legionnaires' disease conveys high mortality, therefore a prompt treatment with appropriate antibiotics is of extreme importance. Currently, therapeutic options include macrolides and fluoroquinolones mainly, that have an effective therapeutic profile. Potential issues of bacterial resistance have risen, but overall, this is not a significant limitation of therapy. In addition, attempts to identify other cases related to the case will help find potential sources.

**Keywords:** *Legionella pneumonia*, *Legionella pneumophila*, Legionnaires' disease, Legionellosis, antimicrobial therapy

#### **1. Introduction**

*Legionella pneumophila* is responsible for 90% of Legionnaires' disease (LD) [1–3]. *Legionella pneumonia*, or LD has an increasing incidence, its mortality has progressively improved from 34% in 1980, to 12% in 1998, to 3.1% in 2010, however 20–25% of patients require mechanical ventilation with a mortality rate as high as 25% [4]. It is believed that the evolution of antibiotic therapy has improved outcomes [4]. *Legionella pneumonia* may have an atypical presentation that will contribute to its underdiagnosing and under-reporting [5], majority of reported cases are due to *Legionella pneumophila* serotype-1 (80%), that may reflect the relatively wide availability of commercial kits to test for this specific serotype [5]. Legionella is an ubiquitous environmental intracellular Gram-negative bacteria, therefore antibiotics capable of penetrating phagocytic cells should be selected, then macrolides and quinolones have become the recommended therapies [6–8]. Risk factors associated with higher mortality rates are older age, smoking, chronic cardiopulmonary disease, diabetes, alcohol abuse, cancer and immunosuppression [9]. Appropriate antibiotic selection will drop mortality significantly, from 60–70% to 10–20% [2, 7, 10, 11].

#### **2. Treatment**

For years, macrolides, specifically erythromycin, has been the mainstay of therapy until the 1990s [4, 12], however with the emergence of newer macrolides and quinolones, the therapeutic selection has shifted, and now Azithromycin or Levofloxacin are considered the mainstay of LD treatment [12]. Beta-lactam and

aminoglycoside antibiotics are ineffective in the treatment of LD, then empiric therapy based on either macrolides or quinolones for initial moderate to severe pneumonia will be a reasonable approach [12–14].

Effective antibiotic therapy depends on the ability to concentrate in alveolar macrophages, and for these concentrations to be effective, it will need to range from 10 to 30 times greater than serum concentrations [15] Fluoroquinolones are antimicrobials with concentration-dependent bactericidal activity [16].

In cases of severe LD, combination therapy has been advocated without evidence of superiority [12]. The incidence of LD as cause of severe pneumonia requiring ICU admission has been reported as high as second most common behind Streptococcus pneumonia (17.8 versus 21.6%, respectively) [2, 13].

In a retrospective review of 3157 adult cases, from more than 400 U.S. hospitals between 2008 and 2013, it was noted that quinolones alone were used in 28.8%, whereas azithromycin alone was used in 34% of patients, only 1.8% of patients received combination therapy (see **Figure 1**). Hence, the majority of patients with LD in the US are treated with azithromycin and/or quinolone [4]. No prospective randomized trial has compared outcomes of levofloxacin versus azithromycin [14].

#### **2.1 Empiric therapy**

The choice of empiric antibiotic therapy is based on the premise of providing optimal therapy, the epidemiological features of the probable agents, and an inference of the most likely pathogen [17].

The empirical coverage for Legionnaires' disease is still a matter of debate, in view of low testing frequency that underscores poor emphasis on Legionella role in pneumonia [18]. The incidence of LD is higher in cases of severe pneumonia, hence patients admitted to an ICU setting should be tested and treated as potential Legionella pneumonia [17]. Historically empirical optimal monotherapy treatment has been based on doxycycline, a quinolone or azithromycin [19].

**Figure 1.** *In-hospital treatment strategies for patients with Legionnaires' disease. Adapted from Ref. [4].*

#### *Legionnaires' Disease Treatment DOI: http://dx.doi.org/10.5772/intechopen.88471*

Respiratory fluoroquinolones are an effective empiric treatment for bacterial community-acquired pneumonia, used as monotherapy in the outpatient setting, and hospitalized patients, as a first-line or alternative agents; in addition to be used as combination therapy in the ICU setting [20]. Azithromycin has a comparable antibiotic profile to fluoroquinolones, in addition has a favorable safety profile, higher intracellular concentrations and longer post antibiotic effect [21].

In a prospective observational study of 3934 hospitalized patients by Viasus et al., performed in Spain at a tertiary teaching hospital between 1995 and 2010, 214 (5.4%) patients were diagnosed with LD, and 24 patients (11.2% of the LD patients) received inappropriate empirical antibiotic therapy; among the other 190 patients, 111 received levofloxacin, 74 patients received macrolides, and three combination of quinolones and macrolides, 1 doxycycline and 1 clindamycin [22] (**Table 1**).

#### **2.2 Targeted therapy**

Early, targeted therapy that covers LD has shown to improve overall outcomes [19]. The most frequently identified of LD is *Legionella pneumophila* serogroup 1 in 80% of cases [23]. New diagnostic test had been added to the testing armamentarium (urinary antigen and polymerase chain reaction). Empirical therapy should be replaced by targeted therapy as soon as Legionella has been identified [17].

Garcia-Vidal et al. reported an observational cohort in Spain of all patients admitted with community acquired pneumonia from 2000 to 2014, 446 patients were diagnosed with LD; 335 patients (75.1%) received appropriate initial therapy with either quinolones, macrolides, combination with rifampin, or combination macrolide and quinolones. Primary outcome was overall 30-day in-hospital mortality. Thirty-six patients were excluded, 175 patients received levofloxacin, 177 patients received azithromycin and 58 patients received clarithromycin, without statistical significant difference for in-hospital 30-day mortality between the cohorts [24].

Once LD has been diagnosed, some experts suggest combined therapy instead of monotherapy for severe pneumonia, although there is no solid evidence support it [13]. In a retrospective observational multicenter Spanish series of 779 ICU patients admitted to the ICU with severe pneumonia, 25 patients (3.2%) were found to have LD, and prescription of monotherapy versus combination therapy was not


#### **Table 1.**

*Empiric therapy for Legionnaires' disease.*

protocolized, with ICU mortality as primary endpoint; it was found that there was no statistical significant difference of overall ICU mortality among both treatment groups; however if the severe pneumonia was associated to shock the difference became statistically significant [13].

#### **2.3 Antibiotic selection and duration**

There may be a role for a specific antibiotic choice based on severity of illness: need for intensive care unit (ICU) admission, need for invasive mechanical ventilation [4]. Dose and route of antibiotic delivery will be dictated by the severity, level of consciousness, and gastrointestinal function integrity [12]. Most of the antibiotics are available in oral presentations with excellent bioavailability (>90%), therefore transition among IV to oral regimens is seamless [19].

Despite absence of evidence, initial levofloxacin dose is recommended at 750 mg daily, and azithromycin 500 mg daily [14].

Levofloxacin use was associated with a shorter length of stay in the hospital, and shorter time to reach clinical stability [22]; moreover a small retrospective series showed no inferiority of ciprofloxacin to erythromycin in Japan [25]. In a retrospective single-center study at University of Michigan from 1999 to 2011, 41 patients with LD were analyzed after been treated with azithromycin versus fluoroquinolones, comparing clinical outcomes: all-cause mortality, length of stay in the hospital, time to clinical stability and development of complications, showing no significant differences among the two therapies [19, 21] (**Table 2**).

Duration of therapy is important to provide cure and prevent relapse [19]. The Infectious Diseases Society of America/American Thoracic Society (IDSA/ ATS) recommend that patients with LD to be treated for 5–14 days, shorter courses maybe appropriate if Azithromycin is the antibiotic of choice. Treatment should not be stopped until patients are afebrile for 48–72 hours [22].


**Table 2.** *Therapeutic options for severe Legionnaires' disease.*

#### *Legionnaires' Disease Treatment DOI: http://dx.doi.org/10.5772/intechopen.88471*

Immunocompromised patients have a higher incidence of LD; cavitation, empyema, extrapulmonary disease may occur; and urinary antigen is less sensitive. In this population an antibiotic combination, and longer course maybe indicated (21 days) [3], and despite this this population has a higher mortality rate than matched groups [26]. An extended course up to 21 days is recommended for immunocompromised patients, severe disease, extrapulmonary manifestations, and inappropriate initial therapy [14].

Combination therapy has included different regimens: rifampin-clarithromycin; clarithromycin-ciprofloxacin-rifampin, and clarithromycin-levofloxacin-rifampin [13].

Older macrolides will interact with drugs like tacrolimus and ciclosporin through the cytochrome P-450 enzyme system, then quinolones, doxycycline or azithromycin maybe used in transplanted hosts [14].

#### **2.4 Therapy outcome**

Early initiation of appropriate antibiotics, improves outcomes, therapy with quinolones within 8 hours of ICU admission reduces mortality [5, 19].

In the Viasus' Spanish series, 41 (19.1%) patients with LD developed severe disease (ICU admission or death), independent factors were identified in this group: current/former smoker, macrolide use, initial inappropriate antibiotic therapy and high risk pneumonia severity index (PSI) class. The overall cure rate is 95% at 10–14 days after therapy [22] (**Table 3**).

In a Portuguese observational series, it was noted that patient with severe LD complicated by refractory respiratory failure were able to be supported by extra corporeal membrane oxygenation (ECMO) with high survival rates (86%); those patients had a faster clinical deterioration with very early ECMO initiation [27]. In a retrospective case review from University of Michigan between 1994 and 2006, survival rates were also noted to be high (67%) [28].

Antibiotic resistance is always a concern, it was noted that acquired resistance to macrolides, fluoroquinolones or rifampin could be easily selected in vitro; however in clinical practice, antibiotic susceptibility testing is not commonly performed [29], due to the fact that *Legionella pneumophila* serogroup 1 strains did not show any in vitro resistance towards eight antibiotics tested by Vandewalle-Capo et al.


#### **Table 3.**

*Therapy and outcomes of patients with L. pneumophila and S. pneumoniae pneumonia.*

(ciprofloxacin, moxifloxacin, levofloxacin, azithromycin, erythromycin, clarithromycin, rifampin and doxycycline) [1].

In a systematic review and meta-analysis comparing quinolones versus macrolides effectiveness against LD, non-significant difference was found, however all studied outcomes favored quinolones, like mortality, clinical cure, time to fever resolution, length of stay in the hospital. Twelve studies were included in the analysis, and the absence of significance maybe related to lack of statistical power [30].

### **3. Conclusion**

Legionnaires' disease is a relative frequent cause of pneumonia syndromes, and it is associated to high morbidity and mortality [22], therefore a delay in starting appropriate therapy has been associated with increased mortality [17]. Consistent with current guidelines, antibiotic therapy should be based on either azithromycin or a quinolone to treat for Legionella pneumonia. Optimum therapy is not properly supported by clinical evidence, however in view of rare potential bacterial resistance to macrolides and quinolones, these antibiotic groups remain as mainstay of LD therapy.

### **Conflict of interest**

The author declares no conflict of interest related to this topic.

### **Author details**

Jorge F. Velazco

Department of Medicine, Texas A&M Health Science Center—College of Medicine, Baylor Scott and White Health-Memorial Hospital, Temple, Texas, USA

\*Address all correspondence to: jorge.velazco@bswhealth.org

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

### **References**

[1] Vandewalle-Capo M, Massip C, Descours G, et al. Minimum inhibitory concentration (MIC) distribution among wild-type strains of *Legionella pneumophila* identifies a subpopulation with reduced susceptibility to macrolides owing to efflux pump genes. International Journal of Antimicrobial Agents. 2017;**50**:684-689. DOI: 10.1016/j. ijantimicag.2017.08.001

[2] Harris NJ, Harris AC, Spiro M. Management of Legionella in the intensive care setting. BMJ Case Reports. 2011;**2011**:1-7. DOI: 10.1136/ bcr.12.2010.3587

[3] Lanternier F, Ader F, Pilmis B, et al. Legionnaire's disease in compromised hosts. Infectious Disease Clinics of North America. 2017;**31**:123-135. DOI: 10.1016/j.idc.2016.10.014

[4] Gershengorn HB, Keene A, Dzierba AL, et al. The association of antibiotic treatment regimen and hospital mortality in patients hospitalized with *Legionella pneumonia*. Clinical Infectious Diseases. 2015;**60**:e66-e79. DOI: 10.1093/cid/ civ157

[5] Sharma L, Losier A, Tolbert T, et al. Pneumonia updates on *Legionella*, *Chlamydophila*, and *Mycoplasma pneumonia*. Clinics in Chest Medicine. 2017;**38**(1):45-58. DOI: 10.1016/j. ccm.2016.11.011

[6] Miyashita N, Higa F, Aoki Y, et al. Clinical presentation of *Legionella pneumonia*: Evaluation of clinical scoring systems and therapeutic efficacy. Journal of Infection and Chemotherapy. 2017;**23**:727-732. DOI: 10.1016/j.jiac.2017.09.001

[7] Beaute J. Legionnaires' disease in Europe, 2011 to 2015. Euro Surveillance. 2017;**22**(27):1-8. DOI: 10.2807/1560- 7917.ES.2017.22.27.30566

[8] Harrison CF, Kicka S, Trofimov V, et al. Exploring antibacterial compounds against intracellular *Legionella*. PLoS ONE. 2013;**8**(9):1-13. DOI: 10.1371/journal. pone.0074813

[9] Cecchini J, Tuffet S, Sonneville R, et al. Antimicrobial strategy for severe community-acquired legionnaires' disease: A multicenter retrospective observational study. The Journal of Antimicrobial Chemotherapy. 2017;**72**:1502-1509. DOI: 10.1093/jac/dkx007

[10] Kakeya H, Ehara N, Fukushima K, et al. Severe Legionnaires's disease successfully treated using a combination of fluoroquinolone, erythromycin, corticosteroid, and sivelestat. Internal Medicine. 2008;**47**:773-777. DOI: 10.2169/internalmedicine.47.0677

[11] Garcia-Vidal C, Carratala J. Current clinical management of Legionnaires' disease. Expert Review of Anti-Infective Therapy. 2006;**4**(6):995. DOI: 10.1586/14787210.4.6.995

[12] Phin N, Parry-Ford F, Harrison T, et al. Epidemiology and clinical management of Legionnaires' disease. The Lancet Infectious Diseases. 2014;**14**:1011-1021. DOI: 10.1016/ S1473-3099(14)70713-3

[13] Rello J, Gattarello S, Souto J, et al. Community-acquired *Legionella pneumonia* in the intensive care unit: Impact on survival of combined antibiotic therapy. Medicina Intensiva. 2012;**37**(5):320-326. DOI: 10.1016/j. medin.2012.05.010

[14] Cunha B, Burillo A, Bouza E. Legionnaires' disease. Lancet. 2016;**387**:376-385. DOI: 10.1016/ S0140-6736(15)60078-2

[15] Cunha CB, Cunha BA. Antimicrobial therapy for Legionnaires' disease: Antibiotic stewardship implications. Infectious Disease Clinics of North America. 2017;**31**:179-191. DOI: 10.1016/j.idc.2016.10.013

[16] Obrink-Hansen K, Hardlei TF, Brock B, et al. Moxifloxacin pharmacokinetic profile and efficacy evaluation in empiric treatment of community-acquired pneumonia. Antimicrobial Agents and Chemotherapy. 2015;**59**:2398-2404. DOI: 10.1128/AAC.04659-14

[17] Diederen BM. *Legionella* spp. and Legionnaires' disease. The Journal of Infection. 2008;**56**:1-12. DOI: 10.1016/j. jinf.2007.09.010

[18] Gramegna A, Sotgiu G, Di Pasquale M, et al. Atypical pathogens in hospitalized patients with community-acquired pneumonia: A worldwide perspective. BMC Infectious Diseases. 2018;**18**:677. DOI: 10.1186/ s12879-018-3565-z

[19] Chahin A, Opal SM. Severe pneumonia caused by *Legionella pneumophila*. Differential diagnosis and therapeutic considerations. Infectious Disease Clinics of North America. 2017;**31**:111-121. DOI: 10.1016/j. idc.2016.10.009

[20] Garau J, Fritsch A, Arvis P, et al. Clinical efficacy of moxifloxacin versus comparator therapies for community-acquired pneumonia caused by *Legionella* spp. Journal of Chemotherapy. 2010;**22**(4):264-266. DOI: 10.1179/joc.2010.22.4.264

[21] Nagel JL, Rarus RE,

Crowley AW, et al. Retrospective analysis of azithromycin versus fluoroquinolones for the treatment of *Legionella pneumonia*. P&T: A Peer-reviewed Journal for Formulary Management. 2014;**39**(3):203-205

[22] Viasus D, Di Yacovo S, Garcia-Vidal C, et al. Community-acquired *Legionella pneumophila* pneumonia. A singlecenter experience with 214 hospitalized sporadic cases over 15 years. Medicine. 2013;**92**:51-60. DOI: 10.1097/ MD.0b013e31827f6104

[23] Ito A, Ishida T, Tachibana H, et al. A case of community-acquired pneumonia due to *Legionella pneumophila* serogroup 9 wherein initial treatment with single-dose oral azithromycin appeared useful. Japanese Journal of Infectious Diseases. 2017;**70**:660-662. DOI: 10.7883/yoken.JJID.20176.548

[24] Garcia-Vidal C, Sanchez-Rodriguez I, Simonetti AF, et al. Clinical Microbiology and Infection. 2017;**23**:653-658. DOI: 10.1016/j. cmi.2017.02.030

[25] Haranga S, Tateyama M, Higa F, et al. Intravenous ciprofloxacin versus erythromycin in the treatment of *Legionella pneumonia*. Internal Medicine. 2006;**46**:353-357. DOI: 10.2169/internalmedicine.46.6006

[26] Pedro-Botet ML, Garci-Cruz A, Tural C, et al. Severe Legionnaires' disease successfully treated with levofloxacin and azithromycin. Journal of Chemotherapy. 2006;**18**(5):559-561. DOI: 10.1179/joc.2006.18.5.559

[27] Roncon-Albuquerque R Jr, Vilares-Morgado R, van der Heijden GT, et al. Outcome and management of refractory respiratory failure with timely extracorporeal membrane oxygenation: Singlecenter experience with *Legionella pneumonia*. Journal of Intensive Care Medicine. 2019;**34**(4):344-350. DOI: 10.1177./0885066617700121

[28] Bryner B, Miskulin J, Smith C, et al. Extracorporeal life support for the adult respiratory distress syndrome due to severe *Legionella pneumonia*. Perfusion. 2014;**29**(1):39-43. DOI: 10.1177/0267659113497229

*Legionnaires' Disease Treatment DOI: http://dx.doi.org/10.5772/intechopen.88471*

[29] Wilson RE, Hill RL, Chalker VJ, et al. Antibiotic susceptibility of *Legionella pneumophila* strains isolated in England and Wales 2007-12. The Journal of Antimicrobial Chemotherapy. 2018;**73**:2757-2761. DOI: 10.1093/jac/dky253

[30] Burdet C, Lepeule R, Duval X, et al. Quinolones versus macrolides in the treatment of legionellosis: A systematic review and meta-analysis. The Journal of Antimicrobial Chemotherapy. 2014;**69**:2354-2360. DOI: 10.1093/jac/ dku159

Section 5

## Advances in Treatment

#### **Chapter 5**

## Advances in Treatment and Outcomes of Patients with *Legionella* Infection

*Gilda Diaz-Fuentes, Ravish Singhal and Sindhaghatta Venkatram*

#### **Abstract**

Manifestations of *Legionella* infections range from benign, mild disease to a more severe form with increased morbidity and mortality, especially in untreated patients. Despite diagnostic advances, clinical diagnosis remains elusive. Macrolides and respiratory fluoroquinolones remain the antibiotics of choice for treatment of *Legionella*; however, several new antibiotics are currently under development or in clinical trials. The recommended duration of antibiotics is 5–7 days; although, some critically ill or immunosuppressed patients may require longer treatment. In vivo resistance to these antibiotics is rare, and there is no evidence that combination therapy is more beneficial than monotherapy. Early suspicion, diagnosis, and treatment are paramount for improving outcomes.

**Keywords:** *Legionella*, treatment, pneumonia, outcomes, antibiotics

#### **1. Introduction**

Initial recognition of Legionnaires' disease dates back to 1976 during an outbreak of respiratory illness in Philadelphia, PA at an American Legion convention [1]. The *Legionellaceae* family is extensive and contains more than 40 species, but less than half produce disease in humans, with *Legionella pneumophila* being the most common [2]. *Legionella* infections usually manifest in two forms. The most benign presentation is Pontiac fever, which typically presents as an acute, febrile, upper respiratory tract infection (non-pneumonic) that is often unrecognized and resolves spontaneously [3]. The most severe presentation is Legionnaires' disease, caused by *Legionella pneumophila*. It is an atypical pneumonia, generally affecting the lungs and gastrointestinal tract [4]. The disease affects people of all ages and causes significant morbidity and mortality, especially in patients with certain comorbid conditions. An estimated 10,000–18,000 people worldwide are infected with *Legionella* each year [5].

In a recent review, most *Legionella* pneumonia cases were reported in the Northern hemisphere. Common workplaces associated with this infection were industrial settings, office buildings, and healthcare facilities [6]. *Legionella* pneumonia was associated with mortality in 4.1% of all cases.

The clinical and radiological manifestations of *Legionella* are nonspecific. As a result, if suspected, empiric antibiotics treatment is recommended to improve morbidity and mortality associated with the disease [7, 8]. The goal of this review is to provide a concise discussion regarding indications for treatment of *Legionella*, update the information about antibiotic management, and discuss outcomes of the disease.

#### **2. Pathogenesis**

*Legionella* are aerobic, Gram-negative, facultative, intracellular bacilli found widely in the environment; they have been isolated from many water sources and often colonize manufactured water systems. Humans are infected by exposure to water contaminated with *Legionella*. Person-to-person transmission has been demonstrated in only one case thus far and is not considered to be a primary means of transmission. Thus, the human body may be considered a "dead-end" for *Legionella*. *Legionella* can cause sporadic and potentially life-threatening infections in immunocompromised individuals, especially the young and elderly.

Infection begins when humans inhale *Legionella*, which travels to the lower respiratory tract where the organism binds to alveolar macrophages and engulfed into the phagosomal vacuoles (also known as phagosomes). *Legionella* then blocks fusion of the phagosome with lysosomes, preventing the release of lysosomal enzymes that destroy bacterial cells. Consequently, the bacteria can freely divide in the phagosome. Eventually, the cell ruptures, releasing bacteria that can infect other cells, resulting in inflammation and sepsis. Given the lifecycle of *Legionella*, an effective antibiotic requires both anti-*Legionella* activity and a high intracellular minimum inhibitory concentration in alveolar macrophages [9]. Antibiotics that have demonstrated clinical effectiveness in Legionnaires' disease include macrolides, fluoroquinolones, tetracyclines, trimethoprimsulfamethoxazole (TMP-SMX), and rifampin [9]. We describe the details of each of these antibiotics below.

#### **3. Treatment**

#### **3.1 Macrolides**

Bacterial ribosomes have two subunits (30S and 50S) that function in protein synthesis. In contrast, the ribosomes in animal cells have 40S and 60S subunits, and this difference ensures that different classes of antibiotics are active against bacteria and not human cells. Macrolides are bacteriostatic agents that bind reversibly to the 50S ribosomal subunit and inhibit protein synthesis [10]. They are active against a wide range of bacteria, including intracellular pathogens such as *Legionella*. Macrolides, especially azithromycin, reach peak concentration in 2–3 hours and are rapidly absorbed and distributed throughout body tissues and with good cell distribution [10]. In the past, macrolides, especially erythromycin, have been the drug of choice for treatment of Legionnaires' disease. A newer derivative, azithromycin, recently surpassed erythromycin, because azithromycin has fewer side effects and fewer interactions with other drugs than erythromycin or its counterpart, clarithromycin.

Despite macrolides' effectiveness, bacteria have developed multiple resistance mechanisms to these drugs. One mechanism is an active efflux pump to pump the drug out of the cell. Another resistance mechanism involves changing the ribosomal subunit, either by inducing genes to produce a methylase enzyme (*ermA*,

*Advances in Treatment and Outcomes of Patients with* Legionella *Infection DOI: http://dx.doi.org/10.5772/intechopen.88481*

*ermB*, and *ermC*) that modifies the ribosome target or by causing chromosomal mutation of the 50S ribosomal subunit. Changes in the ribosomal subunit structure decrease drug binding to the ribosome and result in decreased efficacy of the drug [10].

Common side effects of macrolides include gastrointestinal disturbances like dyspepsia, anorexia, flatulence, and arthralgias, and disturbance in taste and smell. Rarely, hepatitis, hepatic failure, thrombocytopenia, interstitial nephritis, photosensitivity, and renal failure are observed [10]. A prolonged QTc is more common with older macrolides, such as erythromycin and clarithromycin. Azithromycin, even is taken with antacids, appears to be free of drug interactions." Caution is advised, nevertheless, when using azithromycin in conjunction with drugs known to interact with erythromycin [10].

#### **3.2 Fluoroquinolones**

Along with macrolides, fluoroquinolones (levofloxacin, moxifloxacin, and ciprofloxacin) have increasingly become a drug of choice against *Legionella*. These drugs have broad-spectrum activity against Gram-positive and Gram-negative organisms, such as *Legionella* [11]. Fluoroquinolones inhibit DNA gyrase subunit A, a bacterial enzyme that relieves the tension produced when DNA unwinds during replication. Binding to DNA gyrase inhibits the transcription of bacterial DNA, resulting in bacterial cell death. Levofloxacin has an advantage in treating pneumonia, as this drug has two to five times higher concentrations in lung tissue than in serum. Bioavailability for levofloxacin is 99% for oral and intravenous (IV) medications [11]. Fluoroquinolones exhibit concentration-dependent antimicrobial activity [12].

Bacterial resistance to quinolones mostly occurs by chromosomal mutations to the DNA gyrase gene, resulting in reduced affinity of the drug to the enzyme. Also, similar to macrolides, alterations in drug efflux or cell membrane porin channels can occur, decreasing the intracellular concentration of drug [11].

Side effects of fluoroquinolones include benign rash, headaches, nausea, vomiting, diarrhea, prolonged QTc, and arrhythmia. Tendonitis and tendon rupture have been reported in young and elderly patients. Fluoroquinolones can also cause liver dysfunction. Many over-the-counter (e.g., iron, calcium, zinc, and non-steroidal anti-inflammatory drugs) and prescription medications (e.g., warfarin) can interact with levofloxacin [13].

#### **3.3 Tetracyclines**

Tetracyclines are a class of antibiotics that include doxycycline, minocycline, tetracycline, and tigecycline. These drugs are reversible competitive inhibitors and inhibit protein synthesis at the level of the ribosome via inhibition of the codonanticodon interaction between tRNA and mRNA. These antibiotics block binding of tRNA to the 30S ribosomal subunit, thus preventing the addition of new amino acids for protein building. Because this process is reversible, these drugs are bacteriostatic [14].

Resistance to tetracyclines is acquired via bacterial conjugation, where plasmids or transposons containing resistance genes are transferred to the previously sensitive bacteria. The resistance genes produce modified bacterial porins, preventing uptake of the tetracyclines into the bacterial cell. Other mechanisms of resistance include increased drug efflux, decreased ribosomal binding, and enzymatic inactivation [14].

Tetracyclines can cause many adverse effects, including several that are lifethreatening. Tetracyclines concentrate in growing teeth and bones and thus should be avoided by children and pregnant patients [14]. Additionally, tetracyclines can cause nephrotoxicity and hepatotoxicity due to fatty degeneration. Pregnant women are at increased risk of hepatotoxicity, and tetracyclines can potentiate the nephrotoxic effects of aminoglycosides and other nephrotoxic drugs. Furthermore, tetracyclines can induce photosensitivity in persons exposed to the sun during treatment [14].

#### **3.4 Trimethoprim-sulfamethoxazole**

TMP-SMX is one of the most widely used antibiotics in the world. Sulfonamides such as SMX are competitive inhibitors of para-aminobenzoic acid, and TMP inhibits dihydrofolate reductase to block the formation of tetrahydrofolate, a key cofactor in the construction of purine, thymidine, DNA, and amino acids [15]. Bacterial dihydrofolate reductase is inhibited 50–60,000 times more than mammalian enzymes; thus, this antibiotic has minimal effect on human cells [15]. Both sulfonamides and TMP act synergistically and have maximal activity when the concentration of SMX is 20 times greater than that of TMP.

Although well tolerated, TMP-SMX can cause many gastrointestinal side effects, including nausea, vomiting, and anorexia as well as rash. Sulfonamides can cause skin rashes, including hypersensitivity reactions that can progress from a mild reaction to erythema multiforme as Stevens-Johnson syndrome. Rarely, TMP-SMX can cause aplastic anemia, agranulocytosis, and fulminant hepatic necrosis [15]. Sulfonamides can cause hemolytic anemia in patients with glucose-6-phosphate dehydrogenase deficiency.

#### **3.5 Rifampin**

Rifampin is also effective against *Legionella*, as this drug inhibits bacterial and mycobacterial RNA synthesis by binding to the beta subunit of DNA-dependent RNA polymerase to prevent RNA transcription [16]. Rifampin is absorbed readily and has good penetration into the lungs and pleural fluid. Depending on concentrations reached in the infected cell and the susceptibility of the organism, rifampin can exert either bactericidal or bacteriostatic effects [16]. Most bacteria develop resistance to rifampin as the result of a gene mutation in the beta subunit of DNA-dependent RNA polymerase. Rifampin therapy is recommended only for patients with severe disease or significant comorbid conditions (e.g., poorly controlled diabetes, tobacco use, or obstructive lung disease) including immunocompromised hosts and those refractory to conventional monotherapy regimens. Significant adverse drug events and drugdrug interactions should be considered with the use of rifampin.

Rifampin should not be used as monotherapy but rather can provide a significant synergistic effect when used in combination with other antibiotics such as macrolides or quinolones [17].

Oral and IV dosing is equivalent. Rifampin induces many hepatic CYP450 isoenzymes and can enhance the metabolism of endogenous substrates, including adrenal hormones, thyroid hormones, and vitamin D. Other side effects include maculopapular rash, fever, nausea, and vomiting. Furthermore, this antibiotic can cause *Clostridium difficile* colitis, hepatitis, and liver toxicity and can result in yellow, red, or orange discoloration of bodily fluids. Soft contact lenses may be permanently stained. Rifampin can also cause postnatal hemorrhages in the mother and infant [16] (**Table 1**).

#### **3.6 Drug dosing and duration**

A summary of the most common antibiotics used with doses and duration can be seen below in **Table 1**.


#### **Table 1.**

*Recommended drug dosing and duration for antibiotics effective against Legionella.*

#### **3.7 Macrolides compared with fluoroquinolones**

Previous studies have shown that patients treated with older macrolides have a higher recurrence of disease after antibiotics are withdrawn. Levofloxacin and azithromycin appear to be the ideal drugs against *Legionella* because re-growth is not observed. In fact, numerous societies, including Infectious Diseases Society of America, British Thoracic Society, and the Dutch Association of Chest Physicians, recommend fluoroquinolones or azithromycin as the preferred antimicrobial therapy for *Legionella* [18]. Comparison of levofloxacin with azithromycin in the treatment of *Legionella* has shown no difference between the two antibiotics regarding time to defervescence, time to achieve clinical stability, length of IV therapy, or length of hospital stay [12].

Other antibiotics potentially effective for *Legionella* include tigecycline. A small study in eight patients with *Legionella* suggest tigecycline as potential second-line agent for treatment of patients with severe Legionnaire's responding poorly to conventional first line agents such as levofloxacin and azithromycin [19].

#### **4. Outcomes**

A majority of patients with *Legionella* pneumonia have favorable outcomes. Mortality ranges from 1.8 to 10%. Mortality is higher in patients with sporadic infections compared to outbreak-related cases [20, 21]. Mortality is also higher in patients with hospital-acquired legionellosis, transplant recipients with unusual presentations, and missed diagnosis with negative urinary antigen [22, 23]. ICU admissions vary based on severity and underlying conditions, especially immunocompromised status.

Clinical features of *Legionella* infection in immunocompromised patients include infection (most commonly presenting as pneumonia), cavity, and empyema. Extrapulmonary disease can be present, and the urine antigen test is less

sensitive [24]. There are no differences in mortality rates, length of hospital stay, development of *C. difficile* infection, or hospital costs based on chosen therapy (fluoroquinolones versus azithromycin) [25].

#### **4.1** *Legionella* **pneumonia and extracorporeal membrane oxygenation (ECMO)**

Patients with *Legionella* pneumonia with severe acute respiratory distress syndrome can be treated with ECMO. Several case reports describe the outcomes of patients with *Legionella* pneumonia requiring ECMO [26–28]. With respect to outcomes for refractory respiratory failure in patients with *Legionella* pneumonia, Roncon et al. reported that 14 of 112 patients treated with ECMO had *Legionella* pneumonia [29]. *Legionella* pneumonia was associated with earlier ECMO initiation, higher static compliance and a non significant trend towards hospital survival.

#### **4.2 HIV infection and** *Legionella* **pneumonia**

*Legionella* pneumonia in HIV-infected patients is uncommon; however, some studies suggest that it occurs 40 times more frequently in patients with AIDS than in the general population [30–32]. There are also conflicting reports on the severity and outcomes of HIV infection and *Legionella* pneumonia [33]. A recent review reported that the incidence of *Legionella* pneumonia occurs in 6% of bacterial pneumonias in HIV infected patients [34]. Some reasons for a lower incidence in AIDS patients include a possible protective role of *Pneumocystis jirovecii* pneumonia (PJP) prophylaxis with TMP-SMX or the failure to isolate or diagnose *Legionella* as a coinfection. A recent study revealed that *Legionella* could be found in the bronchoalveolar fluid in AIDS patients presenting with tuberculosis and PJP [35]. This study also revealed that species-specific coinfection could occur, associating *L. pneumophila* with *M. tuberculosis* and other *Legionella* species with *P. jirovecii*.

Although most of the data on *Legionella* pneumonia in HIV patients are from case reports, a recent case-matched, case-control study reported that HIV patients presenting with community-acquired *Legionella* pneumonia have similar outcomes compared to non-HIV patients. HIV infection is not associated with higher ICU admission or increased length of hospital stay in these patients [36], and the duration of therapy is similar to non-HIV patients.

#### **4.3 Pregnancy and** *Legionella* **pneumonia**

The estimated prevalence of antepartum pneumonia is similar to that for the non-pregnant population at 0.78–2.7 per 1000 [37]. Although *Streptococcus pneumoniae* is the most common responsible pathogen, *Legionella* has also been reported [38, 39]. *Legionella* was implicated as a causative agent in 1.2% of pneumonias in pregnancy [40]. Treatment is similar to that of non-pregnant women. Worse outcomes have not been described, and fetal demise rarely occurs [38, 39, 41]. Factors associated with favorable outcomes include a high index of suspicion, the institution of appropriate early therapy, and presentation in the late third trimester [38].

#### **5. Conclusions**

Appropriate and timely administration of antibiotics in patients suspected with *Legionella* infection is highly recommended. Macrolides and fluoroquinolones are considered the drugs of choice for treatment. In critically ill patients or those patients not responding appropriately, combination therapy should be considered

*Advances in Treatment and Outcomes of Patients with* Legionella *Infection DOI: http://dx.doi.org/10.5772/intechopen.88481*

with careful evaluation of side effects and drug interactions. As for other infections, outcomes are not only related to the choice of antibiotics but also specific host factors and aggressive supportive measures. Furthermore, it is important to review antibiotic resistance patterns not only in clinical patients but also in environmental strains that are a potential source of the clinical infections [18].

### **Conflict of interest**

The authors have no conflict of interest to declare.

#### **Author details**

Gilda Diaz-Fuentes1,2\*, Ravish Singhal1,2 and Sindhaghatta Venkatram1,2

1 Department of Medicine, Division of Pulmonary and Critical Care, BronxCare Health System, Bronx, NY, USA

2 Icahn School of Medicine at Mount Sinai, NY, USA

\*Address all correspondence to: gfuentes@bronxcare.org

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

### **References**

[1] Fraser DW et al. Legionnaires' disease: Description of an epidemic of pneumonia. The New England Journal of Medicine. 1977;**297**(22):1189-1197

[2] Dedicoat M, Venkatesan P. The treatment of Legionnaires' disease. The Journal of Antimicrobial Chemotherapy. 1999;**43**(6):747-752

[3] Kaufmann AF et al. Pontiac fever: Isolation of the etiologic agent (*Legionella pneumophilia*) and demonstration of its mode of transmission. American Journal of Epidemiology. 1981;**114**(3):337-347

[4] Cunha BA, Burillo A, Bouza E. Legionnaires' disease. Lancet. 2016;**387**(10016):376-385

[5] Herwaldt LA, Marra AR. Legionella: A reemerging pathogen. Current Opinion in Infectious Diseases. 2018;**31**(4):325-333

[6] Principe L, Tomao P, Visca P. Legionellosis in the occupational setting. Environmental Research. 2017;**152**:485-495

[7] Sharma L et al. Atypical pneumonia: Updates on *Legionella*, *Chlamydophila*, and *Mycoplasma* pneumonia. Clinics in Chest Medicine. 2017;**38**(1):45-58

[8] Carratala J, Garcia-Vidal C. An update on legionella. Current Opinion in Infectious Diseases. 2010;**23**(2):152-157

[9] Cunha CB, Cunha BA. Antimicrobial therapy for Legionnaire's disease: Antibiotic stewardship implications. Infectious Disease Clinics of North America. 2017;**31**(1):179-191

[10] Bakheit AH, Al-Hadiya BM, Abd-Elgalil AA. Profiles Drug Substances Excipients and Related Methodology. Vol. 39. 2014. pp. 1-40 [11] Wimer SM, Schoonover L, Garrison MW. Levofloxacin: A therapeutic review. Clinical Therapeutics. 1998;**20**(6):1049-1070

[12] Garcia-Vidal C et al. Levofloxacin versus azithromycin for treating legionella pneumonia: A propensity score analysis. Clinical Microbiology and Infection. 2017;**23**(9):653-658

[13] Ewig S, Tuschy P, Fatkenheuer G. Diagnosis and treatment of legionella pneumonia. Pneumologie. 2002;**56**(11):695-703

[14] Chopra I, Hawkey PM, Hinton M. Tetracyclines, molecular and clinical aspects. The Journal of Antimicrobial Chemotherapy. 1992;**29**(3):245-277

[15] Smilack JD. Trimethoprimsulfamethoxazole. Mayo Clinic Proceedings. 1999;**74**(7):730-734

[16] Glatman-Freedman A. Rifampin. Pediatrics in Review. 1996;**17**(8):294-295

[17] Varner TR et al. Role of rifampinbased combination therapy for severe community-acquired *Legionella pneumophila* pneumonia. The Annals of Pharmacotherapy. 2011;**45**(7-8):967-976

[18] Sharaby Y et al. Antimicrobial agent susceptibilities of *Legionella pneumophila* MLVA-8 genotypes. Scientific Reports. 2019;**9**(1):6138

[19] Slawek D et al. Tigecycline as a second-line agent for Legionnaires' disease in severely ill patients. Open Forum Infectious Diseases. 2017;**4**(4):ofx184

[20] Dominguez A et al. Factors influencing the case-fatality rate of Legionnaires' disease. The International Journal of Tuberculosis and Lung Disease. 2009;**13**(3):407-412

*Advances in Treatment and Outcomes of Patients with* Legionella *Infection DOI: http://dx.doi.org/10.5772/intechopen.88481*

[21] Sopena N et al. Sporadic and epidemic community legionellosis: Two faces of the same illness. The European Respiratory Journal. 2007;**29**(1):138-142

[22] Sivagnanam S et al. Legionnaires' disease in transplant recipients: A 15-year retrospective study in a tertiary referral center. Transplant Infectious Disease. 2017;**19**(5)

[23] Jespersen S et al. Clinical features and predictors of mortality in admitted patients with community- and hospitalacquired legionellosis: A Danish historical cohort study. BMC Infectious Diseases. 2010;**10**:124

[24] Lanternier F et al. Legionnaire's disease in compromised hosts. Infectious Disease Clinics of North America. 2017;**31**(1):123-135

[25] Gershengorn HB et al. The association of antibiotic treatment regimen and hospital mortality in patients hospitalized with *Legionella* pneumonia. Clinical Infectious Diseases. 2015;**60**(11):e66-e79

[26] Harris DJ, Duke GJ, McMillan J. Extracorporeal membrane oxygenation for legionnaires disease: A case report. Critical Care and Resuscitation. 2002;**4**(1):28-30

[27] Jones NC. Outbreak of legionnaires' disease in the United Kingdom. Extracorporeal membrane oxygenation should be considered in severe cases. BMJ. 2 Nov 2002;**325**(7371):1033

[28] Madurka I et al. Successful extracorporeal membrane oxygenation (ECMO) treatment in *Legionella* pneumonia. Orvosi Hetilap. 2019;**160**(6):235-240

[29] Roncon-Albuquerque R Jr et al. Outcome and management of refractory respiratory failure with timely extracorporeal membrane oxygenation: Single-center experience with *Legionella*

pneumonia. Journal of Intensive Care Medicine. 2019;**34**(4):344-350

[30] Pedro-Botet ML et al. Legionnaires' disease and HIV infection: An opportunistic infection? Medicina Clínica (Barcelona). 2004;**123**(15):582-584

[31] Pedro-Botet ML et al. Legionnaires disease and HIV infection. Chest. 2003;**124**(2):543-547

[32] Stroup JS, Hendrickson SE, Neil M. Legionella pneumonia and HIV infection: A case report. The AIDS Reader. 2004;**14**(5):267-270

[33] Sandkovsky U et al. *Legionella* pneumonia and HIV: Case reports and review of the literature. AIDS Patient Care and STDs. 2008;**22**(6):473-481

[34] Benito N et al. Pulmonary infections in HIV-infected patients: An update in the 21st century. The European Respiratory Journal. 2012;**39**(3):730-745

[35] Head BM et al. Legionella co-infection in HIV-associated pneumonia. Diagnostic Microbiology Infectious Disease. 14 Mar 2019. pii: S0732-8893(18)30315-8

[36] Cilloniz C et al. Communityacquired *Legionella* pneumonia in human immunodeficiency virusinfected adult patients: A matched case-control study. Clinical Infectious Diseases. 2018;**67**(6):958-961

[37] Kaunitz AM et al. Causes of maternal mortality in the United States. Obstetrics and Gynecology. 1985;**65**(5):605-612

[38] Eisenberg VH et al. Legionnaire's disease during pregnancy: A case presentation and review of the literature. European Journal of Obstetrics, Gynecology, and Reproductive Biology. 1997;**72**(1):15-18 [39] Vimercati A et al. Legionnaire's disease complicating pregnancy: A case report with intrauterine fetal demise. Journal of Perinatal Medicine. 2000;**28**(2):147-150

[40] Lim WS, Macfarlane JT, Colthorpe CL. Pneumonia and pregnancy. Thorax. 2001;**56**(5):398-405

[41] Gaillac N et al. *Legionella pneumophila* pneumonia during pregnancy: A case report. The Journal of Infection. 2006;**52**(6):e163-e164

### Section 6

## Legionnaires' Disease in Immunocompromised Host

#### **Chapter 6**

### Legionnaires Disease in Immunocompromised Host

*Venkat Rajasurya and Salim Surani*

#### **Abstract**

Legionella bacteria are aerobic, pleomorphic, gram negative bacilli found in fresh water environments and are usually transmitted through inhalation aerosols from contaminated water or soil. Legionnaire's disease is a severe form of pneumonia caused by legionella species and can be community acquired or hospital acquired. The reported incidence of Legionnaires' disease is approximately 1.4–1.8 cases per 100,000 persons and immunocompromised state is a very important risk factor. Some of the other important risk factors include old age, impaired cellular immunity, hematologic malignancies, solid organ transplantation, splenectomy, tumor necrosis factor-alpha inhibitors, chronic respiratory disease, diabetes and end stage renal disease. *Legionella pneumophila* serotype 1 is the most commonly reported cause of human Legionella infections. The pathogenesis of legionnaire's disease involves invasion of alveolar macrophages and cell mediated immunity is the primary means of immune control. The prevalence of Legionnaires disease has risen possibly from increased awareness and reporting. The symptoms of the disease are nonspecific requiring a high index of suspicion in vulnerable hosts, as effective treatment could be life-saving. Sensitivity of urinary antigen testing is lower in immunocompromised patients because of higher likelihood of infections caused non L. pneumophila species. Extrapulmonary manifestations and higher mortality are particularly more common in immunocompromised patients than in immunocompetent hosts.

**Keywords:** transplant, legionnaires' disease, immunocompromised patients, immunocompromised hosts

#### **1. Introduction**

Legionnaire's disease is a severe form of atypical pneumonia caused by gramnegative bacteria Legionella [1]. Although Legionnaire's disease is commonly reported in immunocompetent patients, immunocompromised state, particularly impaired cellular immunity is an independent risk factor for legionella infection. Diabetes, hematologic malignancies, chronic corticosteroid use, solid organ transplantation, TNF-alpha inhibitors are all risk factors for development of legionella infection [2]. *Legionella micdadei*, *Legionella longbeachae*, *Legionella bozemanae*, *Legionella dumoffii* and *Legionella feeleii* are some of the non-pneumophila species that predominantly cause infections in individuals with impaired immunity [3]. In immunosuppressed patients legionella can disseminate outside the lungs causing extrapulmonary manifestations like skin abscess, cellulitis, septic arthritis, myocarditis, endocarditis, peritonitis etc. [4]. Secondary to the increased incidence Legionella testing should be routinely done in immunosuppressed patients presenting with symptoms suggestive of Community acquired pneumonia.

#### **2. Anti-Legionella immunity**

*Legionella pneumophila* is an intracellular pathogen that replicates within alveolar macrophages. There are more than 60 species of legionella and out of which, serogroup 1 causes majority of legionella disease. Humans become infected after inhaling contaminated aerosols. *L. pneumophila* then enters and replicates within the lung alveolar macrophages. Bacteria are initially engulfed by phagocytes from a vacuole that blocks phagolysosome fusion by delivering bacterial proteins into host cell cytosol [5]. These proteins subsequently modulate endoplasmic reticulum and prevent lysosomal mediated killing of the bacteria. Another defense mediator of the body involves toll like receptors (TLR) on host cells, which senses various signaling proteins produced by *L. pneumophila*. This is in turn induces transcription factor, nuclear factor kappa B and produces inflammatory cytokines that sets up a potent immune response against *L. pneumophila*. A common genetic variation of the stop codon in the ligand binding domain of TLR increases the risk of acquiring legionella infection [6].

Tumor necrosis factor alpha is vital in protecting the body from *L. pneumophila* infection and the incidence of Legionnaires disease is reported to be higher in patients receiving TNF-alpha antagonists when compared to controls [7]. Defective monocytic-macrophagic system seen in hematological conditions can lead to the development of Legionnaire's disease. T lymphocytes are essential for effective anti-legionella control but the exact role of B lymphocytes is unclear. Though some studies have highlighted the role of immunoglobulins during legionella infection an increased incidence of Legionnaire's disease has not been found in patients with humoral immune deficiency [8].

#### **3. Splenectomized patients**

Legionella infection has not been frequently reported in splenectomized patients as these patients primarily have impairment in humoral immune response and B-lymphocyte function. A case report in 2004 reported two cases of Legionnaire's disease in splenectomized patient. The first patient developed multiorgan failure and laboratory testing was positive for *Legionella hackeliae* and *Legionella longbeachae*. The second patient was positive for *Legionella micdadei* [9]. Another patient with hairy cell leukemia and splenectomy died from multiorgan failure from *L. longbeachae* infection [10]. In 2012, *Legionella pneumophila* pneumonia was been reported in a patient with Myelodysplastic syndrome and splenectomy [11].

#### **4. Primary immunodeficiencies**

Primary immunodeficiency disorder is the result of defective immune system development and the absence of functional immune system leads to severe infections. There has been only one case of legionella pneumonia reported in a patient with primary immunodeficiency disorder. It was a 35-year-old male with hyper IgE disease who presented with hemoptysis and was later diagnosed to have cavitary pneumonia due to legionella which was isolated from the BAL cultures and the patient also had a positive urinary legionella antigen [12].

#### **5. Organ transplant patients**

Although there are many species of Legionella, *L. pneumophila* is the most common one to cause pneumonia in recipients of organ transplant. Among the non-pneumophila species, *L. micdadei*, followed by *L. longbeachae*, *L. bozemanii*, *L. parisiensis* and *L. cincinnatiensis* commonly caused pneumonia in transplant recipients [3].

A Spanish group of physicians retrospectively reviewed 287 cases of Legionnaires' disease in solid organ transplant patients. They reported that 3% of the transplant recipients had contracted Legionnaires' disease. Incidence of legionnaire's disease was variable but higher in kidney, lung and heart transplant patients [13].

Extrapulmonary manifestations of *Legionella* infection were described in four solid organ transplant patients. The extrapulmonary sites were aorta, pericardium, liver and soft tissue.

A group in Seattle, Washington reviewed 15 year longitudinal data in a hospital that cares for transplant patients and reported 32 cases of Legionnaires disease over a period of 15 years and 10 of them were in solid organ transplant patients [14].

#### **6. Biologic agents**

Biologic drugs are very commonly used for treatment of number of diseases and are associated with an increased risk of serious infections by lowering the immunity. A study done in France in 2006 over a period of 1 year revealed a case series of 10 patients treated with anti-TNF alpha therapy who were diagnosed with *Legionella pneumophila* infection [15]. Another French study that looked into risk factors for legionella infection from 2004 to 2007 concluded that anti TNF alpha therapy was associated with 13-fold increased risk of developing legionella infection. There was a 15-fold higher risk associated with infliximab, 38-fold higher risk associated with adalimumab and 3-fold increase with etanercept. Patients had different degrees of presentation. 28% presented with bilateral pneumonia, 24% had ARDS, 33% were hospitalized in ICU and 1 patient died [7]. A recent review from 2004 to 2011 reported 105 cases of Legionnaire's disease in patients treated with biologic treatment [16].

#### **7. Malignancies**

Patients with hematological and solid tumors are at higher risk for developing legionnaire's disease. A study found that Legionella caused 29% of pneumonia in patients with head and neck malignancies [17]. A retrospective study over 4 years conducted in a oncology center in 1986 found 36 cases of Legionnaire's disease. 42% had hematological malignancy and 22% had lung cancer. Neutropenic patients and patients on chronic steroids had higher risk of getting legionnaire's disease [18].

Two retrospective studies were done at MD Anderson cancer hospital in Texas. First study reported 49 cases of Legionnaire's disease in cancer patients over a period of 13 years from 1991 to 2003. The majority of patients had an underlying hematologic malignancy. 37% were bone marrow transplant recipients. Lymphopenia, use of corticosteroids and chemotherapy were the most common risk factors in these patients [19]. Second retrospective study reviewed 33 consecutive cases of Legionnaire's disease between 2002 and 2014. Out of this 27 had hematologic malignancies, 23 had neutropenia, 6 had allogeneic hematopoietic stem cell transplant and all patients except 1 had lung infection [20].

Clinical presentation of LD in immunocompromised patients:

Legionnaires disease in immunocompromised patients presents with fever, cough, chills, shortness of breath. GI symptoms can also occur. The incubation period for Legionnaires' disease is usually around 2–10 days from the time of exposure to symptom onset. In immunocompromised patients in addition to consolidation legionnaire's disease can present with cavitations, diffuse bilateral infiltrates and pleural effusions. In transplant patients nodular opacities that eventually cavitate have been reported [21]. Pleural effusions have been reported in 15–50% of cases.

Pneumonia with cavitation has been reported in L pneumophila serotypes 1, 3, 4, 5, 6, and 8 as well as other Legionella species including *L. micdadei*, *L. bozemanae*, *L. dumoffii*, and *L. longbeachae* [22]. Legionella species can also cause lung abscesses and the most important risk factor for it is prolonged use of glucocorticoid therapy. Abscesses generally arise after 4 weeks of starting high dose glucocorticoid therapy. Complicated pleural effusions, empyema and lung abscesses caused by legionella are more commonly seen in patients with solid organ transplant [23].

Extrapulmonary manifestations are usually seen in immunocompromised hosts [4]. The incidence of Neurologic manifestations including meningoencephalitis, meningitis and transverse myelitis are similar to as in immunocompetent hosts. Cutaneous legionella has been reported in patients on chronic corticosteroids, solid organ transplants, stem cell transplants and hematological malignancies. They present with erythema, nodules, induration, ulcer or abscess. Most of them have concomitant lung infection [24].

Legionella can also affect the heart. *L. pneumophila* causing aortitis has been reported in heart transplant patients. Twelve cases of pericarditis were reported and most of them were in immunocompromised patients including transplant recipients, dialysis patients and cancer patients [25].

#### **8. Conclusion**

In conclusion while Legionella infection can occur in both immunocompetent and immunocompromised patients, certain risk factors in the immunocompromised are associated with an increased incidence. T cell and cell mediated immunity play a key role in body's defense against the bacteria. TNF Alpha inhibitors are associated with an increased risk of Legionnaire's disease. Extrapulmonary manifestations involving the skin, pericardium and aorta were seen more in immunocompromised, predominantly in patients on chronic corticosteroids, solid organ and stem cell transplant patients. The incidence of neurological manifestations remained the same. The signs and symptoms of Legionnaire's disease are non-specific and patients with the above high risk features, especially on TNF alpha inhibitors should be screened for Legionella infection.

*Legionnaires Disease in Immunocompromised Host DOI: http://dx.doi.org/10.5772/intechopen.89550*

### **Author details**

Venkat Rajasurya1 and Salim Surani<sup>2</sup> \*

1 Novant Health, Winston-Salem, North Carolina, USA

2 Texas A&M University, Health Science Center, College of Medicine, Texas, USA

\*Address all correspondence to: srsurani@hotmail.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

### **References**

[1] Fraser DW, Tsai TR, Orenstein W, Parkin WE, Beecham HJ, Sharrar RG, et al. Legionnaires' disease: Description of an epidemic of pneumonia. The New England Journal of Medicine. 1977;**297**(22):1189-1197

[2] Marston BJ, Lipman HB, Breiman RF. Surveillance for Legionnaires' disease. Risk factors for morbidity and mortality. Archives of Internal Medicine. 1994;**154**(21):2417-2422

[3] Chow JW, Legionella YVL. A major opportunistic pathogen in transplant recipients. Seminars in Respiratory Infections. 1998;**13**(2):132-139

[4] Sivagnanam S, Pergam SA. Legionellosis in transplantation. Current Infectious Disease Reports. 2016;**18**(3):9

[5] Roy CR, Tilney LG. The road less traveled: Transport of Legionella to the endoplasmic reticulum. The Journal of Cell Biology. 2002;**158**(3):415-419

[6] Kawai T, Akira S. The role of pattern-recognition receptors in innate immunity: Update on tolllike receptors. Nature Immunology. 2010;**11**(5):373-384

[7] Lanternier F, Tubach F, Ravaud P, Salmon D, Dellamonica P, Bretagne S, et al. Incidence and risk factors of *Legionella pneumophila* pneumonia during anti-tumor necrosis factor therapy: A prospective French study. Chest. 2013;**144**(3):990-998

[8] Schlossberg D, Bonoan J. Legionella and immunosuppression. Seminars in Respiratory Infections. 1998;**13**(2):128-131

[9] Gorelik O, Lazarovich Z, Boldur I, Almoznino-Sarafian D, Alon I, Modai D, et al. Legionella in two splenectomized

patients. Coincidence or causal relationship? Infection. 2004;**32**(3):179-181

[10] Lang R, Wiler Z, Manor J, Kazak R, Boldur I. *Legionella longbeachae* pneumonia in a patient splenectomized for hairy-cell leukemia. Infection. 1990;**18**(1):31-32

[11] Cunha BA, Hage JE. *Legionella pneumophila* communityacquired pneumonia (CAP) in a post-splenectomy patient with myelodysplastic syndrome (MDS). Heart & Lung. 2012;**41**(5):525-527

[12] Di Stefano F, Verna N, Di Gioacchino M. Cavitary Legionella pneumonia in a patient with immunodeficiency due to hyper-IgE syndrome. The Journal of Infection. 2007;**54**(3):e121-e123

[13] Gudiol C, Garcia-Vidal C, Fernandez-Sabe N, Verdaguer R, Llado L, Roca J, et al. Clinical features and outcomes of Legionnaires' disease in solid organ transplant recipients. Transplant Infectious Disease. 2009;**11**(1):78-82

[14] Sivagnanam S, Podczervinski S, Butler-Wu SM, Hawkins V, Stednick Z, Helbert LA, et al. Legionnaires' disease in transplant recipients: A 15-year retrospective study in a tertiary referral center. Transplant Infectious Disease. 2017;**19**(5). DOI: 10.1111/tid.12745

[15] Tubach F, Ravaud P,

Salmon-Ceron D, Petitpain N, Brocq O, Grados F, et al. Emergence of *Legionella pneumophila* pneumonia in patients receiving tumor necrosis factor-alpha antagonists. Clinical Infectious Diseases. 2006;**43**(10):e95-e100

[16] Viasus D, Di Yacovo S, Garcia-Vidal C, Verdaguer R, Manresa F, Dorca J, et al.

*Legionnaires Disease in Immunocompromised Host DOI: http://dx.doi.org/10.5772/intechopen.89550*

Community-acquired *Legionella pneumophila* pneumonia: A single-center experience with 214 hospitalized sporadic cases over 15 years. Medicine (Baltimore). 2013;**92**(1):51-60

[17] Johnson JT, Yu VL, Wagner RL, Best MG. Nosocomial *Legionella pneumonia* in a population of head and neck cancer patients. The Laryngoscope. 1985;**95**(12):1468-1471

[18] Nunnink JC, Gallagher JG, Yates JW. Legionnaires' disease in patients with cancer. Medical and Pediatric Oncology. 1986;**14**(2):81-85

[19] Jacobson KL, Miceli MH, Tarrand JJ, Kontoyiannis DP. Legionella pneumonia in cancer patients. Medicine (Baltimore). 2008;**87**(3):152-159

[20] Han XY, Ihegword A, Evans SE, Zhang J, Li L, Cao H, et al. Microbiological and clinical studies of Legionellosis in 33 patients with cancer. Journal of Clinical Microbiology. 2015;**53**(7):2180-2187

[21] Ernst A, Gordon FD, Hayek J, Silvestri RC, Koziel H. Lung abcess complicating *Legionella micdadei* pneumonia in an adult liver transplant recipient: Case report and review. Transplantation. 1998;**65**(1):130-134

[22] Ampel NM, Wing EJ. Legionella infection in transplant patients. Seminars in Respiratory Infections. 1990;**5**(1):30-37

[23] Guy SD, Worth LJ, Thursky KA, Francis PA, Slavin MA. *Legionella pneumophila* lung abscess associated with immune suppression. Internal Medicine Journal. 2011;**41**(10):715-721

[24] Padrnos LJ, Blair JE, Kusne S, DiCaudo DJ, Mikhael JR. Cutaneous legionellosis: Case report and review of the medical literature. Transplant Infectious Disease. 2014;**16**(2):307-314 [25] Scerpella EG, Whimbey EE, Champlin RE, Bodey GP. Pericarditis associated with Legionnaires' disease in a bone marrow transplant recipient. Clinical Infectious Diseases. 1994;**19**(6):1168-1170

### *Edited by Salim Surani and Joseph Varon*

More than 10,000 patients are hospitalized every year with Legionnaires' disease in the United States alone. Legionnaires' disease is also an important public health topic as it involves environmental and public issues, as far as its spread and prevention are concerned. With an aging population, increasing number of transplants, increasing use of immunosuppressive medications, and compromised immunity due to multiorgan system disease, Legionnaires' disease is emerging as an important disease.

Published in London, UK © 2020 IntechOpen © royaltystockphoto / iStock

Hospital Acquired Infection and Legionnaires' Disease

Hospital Acquired Infection

and Legionnaires' Disease

*Edited by Salim Surani and Joseph Varon*