Background
Legionella pneumophila, a gram-negative bacteria and the main causative agent of legionellosis, was first recognized in 1976 [
1]. Legionellosis has two distinct clinical presentations: (1) Pontiac fever, a self-limited, febrile, flulike illness; and (2) Legionnaires’ disease. Legionnaires’ disease is an atypical pneumonia that has clinical and radiographic findings similar to those of pneumococcal pneumonia [
2‐
6]. It has an incubation period of 2–14 days. Patients might present with fever, cough, myalgia, asthenia, anorexia, and relative bradycardia [
2]. Symptoms that are more suggestive of Legionnaires’ disease include gastrointestinal symptoms (diarrhea, nausea, vomiting, and abdominal pain) and neurologic symptoms (headache, obtundation, seizures, and focal neurologic findings) [
2,
7‐
10]. Legionnaires’ disease is also characterized by nonspecific laboratory findings such as hyponatremia; hypophosphatemia; leukocytosis with relative lymphopenia; elevated creatine kinase, erythrocyte sedimentation rate, C-reactive protein, and ferritin levels; myoglobulinuria; and microscopic hematuria [
2].
Legionnaires’ diseases accounts for 2–15 % of hospitalized community-acquired pneumonia (CAP) and up to 30 % of CAP requiring intensive care unit (ICU) admission [
11,
12]. The incidence of Legionnaires’ disease rose by 192 % in the United States between 2000 and 2009 to 11.5 cases per 1 million population [
13]. Sixty-two percent of the cases occur in the summer and autumn seasons. This is due to the increased use of air-conditioning systems and cooling towers as well as to increased rainfall [
14,
15]. Approximately 20 % of cases were travel-associated [
16]. Only 4 % of cases were associated with a known outbreak [
2]. The risk factors for Legionnaires’ disease include cardiopulmonary disease, cigarette smoking, age >50 years, diabetes, malignancy, and immunosuppressive state including glucocorticoid use [
11,
17].
Legionnaires’ disease causes significant morbidity and carries a mortality rate of 8–12 % [
18]. Among patients who survive, recovery is often slow, and they are left with fatigue, neurologic and neuromuscular symptoms, and post-traumatic stress disorder [
19]. Legionnaires’ disease is also very costly, with a healthcare-associated cost of more than $23,000 per case [
20].
The diagnosis of Legionnaires’ disease can be made using non-culture- and culture-based techniques [
2]. A urinary antigen test that detects a component of the cell wall lipopolysaccharide is the first-line diagnostic test for Legionnaires’ disease [
21,
22]. However, it detects only
L. pneumophila serogroup 1, which is the most virulent and most common cause of disease [
11,
22,
23]. In Europe, >90 % of Legionnaires’ disease cases were diagnosed by urinary antigen detection [
2]. It is a rapid test (results available within hours), with a sensitivity of 56–99 % [
22], and it is positive within 48–72 h of symptom onset and can remain positive for several weeks or months despite treatment [
21,
22]. In addition to urinary antigen detection, molecular tests such as a real-time polymerase chain reaction (PCR) assay that targets the 23S-5S ribosomal RNA (rRNA) intergenic spacer region can be used for rapid detection, and this test has the capability of differentiating
L. pneumophila from 50 non-
L. pneumophila species [
24].
The isolation of
Legionella bacteria by culture of the lower respiratory tract using buffered charcoal yeast extract (BCYE) medium is still the gold standard for detecting Legionnaires’ disease [
22] because it allows the diagnosis of all
Legionella species, outbreak investigation, further epidemiologic studies, and antimicrobial susceptibility testing [
2]. However, culture of
Legionella is very cumbersome and technically demanding, and the sensitivity is only around 20–80 % [
2,
22].
Legionella species are intracellular pathogens; therefore, antibiotics should accumulate and be bioactive within the cells [
2]. Azithromycin, doxycycline, or levofloxacin can be considered as first-line therapy [
2]. It is recommended that levofloxacin 750 mg daily for 5–10 days or azithromycin 500 mg daily for 3–5 days be used in patients with Legionnaires’ disease, except for patients with immunosuppression, severe disease, empyema, and extrapulmonary infection, as well as those undergoing inappropriate initial therapy, for whom an extended course is recommended [
25‐
28]. Early initiation of appropriate therapy is important in reducing mortality associated with Legionnaires’ disease [
2,
29,
30].
In the summer of 2013, there were 14 hospitalized cases of Legionnaires’ disease in the Niagara Region of the Province of Ontario, Canada. The primary aim of this study was to describe these14 cases of hospitalized community-acquired Legionnaires’ disease to increase awareness of this important and potentially lethal disease.
Discussion
Legionnaires’ disease is a life-threatening condition that requires prompt diagnosis and treatment. In this study, 64 % of the reported cases occurred from June to August 2013. This is typical in temperate climates in the northern hemisphere because the causative organism multiplies effectively in warm aquatic environments [
2]. The median age of our patient cohort was 58 years, which was less than what was published by Public Health Ontario in 2011. Indeed, most of our patients were <65 years of age (71 %), despite the fact that the incidence of Legionnaires’ disease is reported to increase with age [
34]. This suggests that age may not be a prominent characteristic for community-acquired Legionnaires’ disease that is not associated with a point source outbreak. Tobacco use is a well-documented risk factor for Legionnaires’ disease [
35], and our results showed that cigarette smoking was a common feature in our cohort of patients with Legionnaires’ disease. A less-established risk factor for Legionnaires’ disease is cannabis use. Results published by Nguyen
et al. provided support for an increased risk of Legionnaires’ disease in cannabis smokers and suggested that this risk may be cumulative with the risk incurred through tobacco use [
36]. Interestingly, in our cohort of patients with Legionnaires’ disease, we found that three patients were both cannabis and cigarette smokers.
Clinical recognition of Legionnaires’ disease is made difficult by the fact that patient presentation is often inconsistent with the clinical presentation documented in the literature [
2,
6]. Our data suggest that the diagnosis of Legionnaires’ disease on the basis of clinical presentation is unreliable.
Our results demonstrate that Legionnaires’ disease results in severe pneumonia, as reflected by the high PSI score and impacts on multiple organ systems rather than being confined solely to the pulmonary system. The multisystem nature of Legionnaires’ disease likely contributes in part to the acute presentation of patients with Legionnaire’s disease and the need for more intensive management. With almost three-fourths of the patients requiring admission to an ICU, almost two-thirds requiring mechanical ventilation for an average of 9 days, and over half requiring vasopressors, these results certainly corroborate the data suggesting that the clinical manifestations of Legionnaires’ disease are often more severe than those of pneumonias caused by other infectious agents [
37].
Chest x-rays are one of the first diagnostic tests performed on patients upon arrival in the emergency department. As with much of the presentation thus far, the chest x-ray of patients with Legionnaires’ disease does not possess any distinguishing features that would guide diagnosis. The initial chest x-ray of just over one-third of the patients demonstrated bilateral airspace disease; the remaining two-thirds had unilateral findings. However, six of the patients with unilateral findings on their initial x-ray progressed to bilateral findings on follow-up images. This progression of radiographic findings throughout hospital admission prior to noting improvements has been documented in the literature [
6]. There were not any identifiable patterns in terms of proclivity for specific lobes or features of lung involvement.
The most common method of Legionnaires’ disease diagnosis was urinary
Legionella antigen testing (92.9 %). In our case series, of the 13 patients tested for urinary
Legionella antigen, 12 had a positive result. One of the patients was infected by non-
L. pneumophila Legionella (diagnosed with BAL real-time PCR). As such, other forms of diagnostic tests, including real-time PCR and culture of sputum or BAL samples, are indicated if there is a suspicion of Legionnaires’ disease and the result of urinary
Legionella antigen testing is negative [
38]. It has been suggested that a combination of urinary
Legionella antigen testing and real-time PCR is the best initial approach to ensure detection of all
Legionella infections and obtain results within a time frame capable of influencing management [
39]. This is corroborated in our case series by the fact that one of the diagnoses would have been missed had a real-time PCR of a BAL sample not been done concurrently with urinary
Legionella antigen testing.
Delay in initiating appropriate antibiotic therapy is known to be a poor prognostic factor in patients infected by
Legionella [
39]. In our case series, four patients had delayed initiation of antibiotic therapy with a fluoroquinolone or azithromycin. Although none of these patients died as a result of this delay in diagnosis and treatment, two of these patients had hospital stays that exceeded 25 days, and both of them required mechanical ventilation and vasopressor support. One patient also required dialysis throughout the admission, and three patients required admission to the ICU. As such, it is evident that, while a delay in treatment did not result in a higher mortality rate, it has the potential to worsen disease severity and result in a need for more intensive management. Of note, the three patients who died were older (aged 66, 74, and 81 years, respectively). One patient was immunosuppressed on methotrexate and prednisone for rheumatoid arthritis; two patients had a significant cardiac history and diabetes; and two patients were cigarette smokers.
A study conducted in Switzerland demonstrated that patients infected with atypical pathogens, including
Legionella, had clinical instability refractory to treatment with a β-lactam and required the addition of a macrolide to the treatment regimen [
40]. The same study demonstrated that patients with more severe pneumonias benefited from a combination therapy as opposed to β-lactam monotherapy. As such, it is suggested that the initial treatment approach for patients presenting with severe CAP (those with a PSI category IV pneumonia) include a macrolide or fluoroquinolone with effectiveness in treating
Legionella rather than waiting for laboratory confirmation of infection [
40]. Our study suggests that patients presenting with severe multisystem disease during the summer or early autumn requiring admission to the ICU need atypical coverage with a macrolide or fluoroquinolone prior to laboratory confirmation. Atypical coverage should also be added to a treatment regimen when there is no improvement noted with β-lactam treatment.
Our study was limited by the fact that our data collection was dependent on the reporting and diagnostic tests ordered by other healthcare professionals. As a result, full patient histories and laboratory values could not be obtained for each patient. A prospective study would overcome this limitation. Last, we do not have a control group with non-Legionella CAP to assess risk factors for Legionnaires’ disease.
Acknowledgements
JLYT holds a McMaster University Department of Medicine Internal Career Research Award. We acknowledge Allison Brown and Dr. Matthew Greenway for their assistance in obtaining research ethics board approval. We also acknowledge Virginia Pullar, Kathleen Willis, and Phillip Guy for their efforts in obtaining the medical records of patients included in this study. Finally, we would like to thank the medical records staff of the Niagara Health System for locating the charts for review.