Legionella

OVERVIEW: What every practitioner needs to know

Are you sure your patient has legionella infection? What should you expect to find?

Symptoms: Fever, cough which is often non-productive, dyspnea, chest pain, nausea, vomiting, diarrhea, lethargy, myalgias, headache, confusion/delirium
Signs: patients may present with temperature greater than or equal to 39°C, hypotension, and findings of consolidation on chest and lung exam

How did the patient develop legionella infection? What was the primary source from which the infection spread?

Infection is thought to be acquired by aspiration of contaminated water or through inhalation of aerosolized fresh water sources or soil within the community and hospital. Patients commonly present with signs and symptoms of pneumonia but can also develop extra-pulmonary infection in rare circumstances, predominantly through bacteremia. Examples of extra-pulmonary infection include sinusitis, pyelonephritis, cellulitis, pancreatitis, pericarditis, endocarditis, and myocarditis.

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Legionella presents as one of two clinical syndromes:

Legionnaires’ Disease: multiorgan system infection; predominately pneumonia. Delayed onset of symptoms within 2-14 days of exposure. Appropriate antibiotic treatment is imperative.

Pontiac Fever: self-limited, influenza-like illness but not pneumonia. abrupt onset of symptoms within 24-48 hours of exposure. Treatment is supportive care; Antimicrobial therapy is not routinely recommended.

Which individuals are of greater risk of developing disease legionella infection?

Tobacco smoking, chronic lung disease, older age (>50), male gender, immunosuppression, especially related to solid organ transplantation (lung and heart) and hematopoietic stem cell transplantation when these patients experience rejection or acute/chronic graft versus host disease, respectively, diabetes, end-stage renal disease, and hematologic malignancy

Beware: there are other diseases that can mimic disease Legionella:

Other pathogens implicated in community acquired pneumonia such as Mycoplasma pneumoniae and Streptococcus pneumoniae. Among immunosuppressed populations polymicrobial pneumonia is not uncommon (Concurrent infection, including with opportunistic pathogens, may be encountered: cytomegalovirus, respiratory viruses, fungi, atypical mycobacteria, Pneumocystis jirovecii. )

What laboratory studies should you order and what should you expect to find?

Results consistent with the diagnosis

Peripheral white blood cells (WBC) with differential (leukocytosis or leukopenia with left shift, thrombocytosis, or thrombocytopenia associated with disseminated intravascular coagulation), basic metabolic panel (hyponatremia, acute kidney injury).
Urinalysis (proteinuria, hematuria), hyponatremia, elevated transaminases, elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), elevated serum ferritin, elevated procalcitonin.

Results that confirm the diagnosis

Legionella is a fastidious, catalase positive, aerobic Gram-negative rod. Approximately 40 species of Legionella are identified but only half have been implicated in causing infection.
Gram stain may show weakly staining gram negative coccobacilli or no microbes in the setting of multiple polymorphonuclear neutrophils. Direct fluorescent antibody (DFA) has relatively low sensitivity.
Respiratory cultures (including sputum, pleural fluid, or bronchoalveolar lavage) on buffered charcoal yeast (BCYE) extract agar are most specific and gold standard for diagnosis. Sensitivity of culture ranges anywhere from 20-80%. However, Legionella is difficult to isolate from sputum as infected patients tend to produce minimal sputum which is often nonpurulent. In addition, legionella has poor survival in secretions and must be cultured as soon as possible upon collection of specimen. Invasive diagnostic tests (bronchoscopy, bronchoalveolar lavage) may be required, especially in immunocompromised patients. Non-pneumophila Legionella spp which may be encountered more frequently in immune-depressed patients, may be more fastidious and require longer incubation time for growth.
Legionella urine antigen test has sensitivity 53-56% and specificity of approximately 99% for detecting infection due to Legionella pneumophila, serotype 1. Rapid detection within 24 hours. Notably, this test will not detect infection due to non-serogroup 1 Legionella pneumophila and non-pneumophila Legionella spp and therefore may miss 10% of these infections.

What imaging studies will be helpful in making or excluding the diagnosis of legionella?

Chest X-ray: although no diagnostic pattern, tends to show patchy, alveolar infiltrate ($60-125). Can see nodular infiltrates, similar to those associated with fungal infection, in solid organ and hematopoietic stem cell transplant recipients, especially with infection caused by non-pneumophila Legionella spp.

What consult service or services would be helpful for making the diagnosis and assisting with treatment?

Infectious diseases for proper antimicrobial selection, pulmonary for assistance in diagnosis with bronchoscopy or thoracentesis, if required. Documented cases of legionella infection are reportable to the local health department.

If you decide the patient has Legionella infection, what therapies should you initiate immediately?

Initiate antimicrobial coverage for atypical bacterial pathogens within 48 hours of symptom onset.

1. Anti-infective agents

If I am not sure what pathogen is causing the infection what anti-infective should I order?

Empiric therapy with antibiotics possessing high intracellular concentrations such as fluoroquinolones (Levofloxacin, Moxifloxacin) and macrolides (Azithromycin proven most efficacious) are preferred. Preferred agent is Levofloxacin or Azithromycin as these anti-microbials have proven most efficacious in treatment in the literature. Alternative regimens include rifampin, bactrim or doxycycline. For hospitalized patients, parenteral therapy is given until there is a clinical response. Recommended treatment course for immunocompetent hosts is 10-14 days; 21 days for immunosuppressed hosts, more severe disease or extrapulmonary disease.

Table I. Treatment of Legionella Infection.

Table I.

Antibiotic	Dose	Alternative
Levofloxacin	250-750mg PO/IV q24h (dosing dependent on renal function, 750mg preferred)	Moxifloxacin 400mg PO/IV q24h, Gemifloxacin 320mg PO q24h
Azithromycin	500mg PO/IV q24h	Clarithromycin 500mg PO/IV q12h, Erythromycin 1g IV q6h or 500mg PO q6h
TMP-SMX	1-2 DS tabs PO q12-24h -OR- 8-20mg/kg/day IV q6-12h
Doxycycline	100mg PO/IV q12h	Minocycline 100mg PO/IV q12h, Tetracycline 500mg PO/IV q6h

2. Next list other key therapeutic modalities.

Use of rifampin in addition to a respiratory fluoroquinolone or macrolide remains controversial. Rifampin has good oral bioavailability and lung penetration and has been hypothesized to provide synergistic effect in treatment of life-threatening infection.
Current antimicrobials under investigation for treatment of Legionella include newer generation fluoroquinolones (Garenoxacin, Olamufloxacin) and ketolides (Telithromycin, Cethromycin)

What complications could arise as a consequence of legionella?

Septic shock, multi-organ failure, empyema, pulmonary cavitary lesions, bullous emphysema, neurologic disorders

What should you tell the family about the patient's prognosis?

With appropriate and timely treatment, one should expect defervescence and symptom improvement within 3-5 days.
Poorer outcomes occur in patients with older age, comorbidities such as underlying lung disease, delayed antibiotic treatment or initiation of incorrect antibiotic treatment (e.g., Beta-lactams and aminoglycosides do not treat legionella), and acute respiratory failure.
Morbidity includes permanent disruption to lung architecture, multi-organ failure sequelae, or septic shock.
Mortality from legionnaires’ disease is reported between 5-30%

What-if scenarios

Legionella urinary antigen is the recommended initial diagnostic test as it has rapid turnover of results and high specificity. If a clinician maintains strong suspicion of legionnaires’ disease despite a negative urinary antigen test, he or she should still initiate empiric antibiotic treatment with Levofloxacin or Azithromycin as 10% or more of infections are caused by non-serotype 1 Legionella species. In addition, legionella does not grow well on standard culture medium, so one must request culture on BCYE agar.

How do you contract Legionella and how frequent is this disease?

Mode of spread: Inhalation of aerosolized fresh water source particularly human-made with temperatures higher than ambient temperature (cooling towers, whirlpools/spas, potable water sources). Legionella is not contracted through person-person spread.

Incidence: For nosocomial infection, incidence does not change over annual period. With community-acquired cases in the United States, there is increased incidence of infection during summer and fall months when cooling towers tend to run. In addition, travel-related outbreaks occur in hotels, on cruise ships, and in resorts.

Epidemiology studies: Cases reported in North and South America, Asia, Australia, New Zealand, Europe, and Africa. Although substantially underdiagnosed and underreported, Legionella spp are thought to cause 2-9% of cases of community-acquired pneumonia. In the United States, 8000-18,000 people are hospitalized for pneumonia due to Legionella spp per year. However, this is unlikely to reflect true incidence as many patients receive empiric antibiotics for community-acquired pneumonia without a reported diagnosis.

Zoonotic transmissions: no current documentation of spread from animal to human or animal to animal.

What pathogens are responsible for this disease?

Legionella pneumophila: most pathogenic. Serotype 1 is responsible for 90% of infections in humans and is associated with community/hospital outbreaks of infection. Serotypes 1 and 6 most commonly associated with legionnaires’ disease.

Non-Legionella pneumophila: less common, tends to occur in immunocompromised patients (HIV, solid organ transplant, hematologic malignancy), and incidence is sporadic (not outbreak-associated). Clinical picture is similar to pneumonia due to L. pneumophila. L longbeachae potting soil and soil conditioners have been associated with infection.

How do these pathogens cause disease?

Legionella species are intracellular parasites that live in fresh water protozoa with optimal growth at 35°C. The organism also forms biofilms within the water source. Infection is transmitted through inhalation from a fresh water source or soil. The bacterium then enters mammalian cells through phagocytosis and by inhibiting phagosome-lysosome fusion multiplies intracellularly within the phagosome, ultimately leading to host cell necrosis. Host response relies mainly on a cell-mediated immunity response, which is why solid organ transplant recipients tend to develop more aggressive disease. Legionella pneumophila, Serotype 1, is the primary pathogen responsible for infection. It possesses significant virulence factors and flagella. Surface antigens of Serotype 1, recognized by a particular monoclonal antibody, may propagate more severe infection.

What other clinical manifestations may help me to diagnose and manage legionella infection?

No single clinical manifestation distinguishes legionella infection from other types of pneumonia.

Patient often experiences 2-14 days of symptoms. History can sometimes note exposure to a local known outbreak or documents possible travel exposure.

Physical exam is notable for fever and signs of lung consolidation.

What other additional laboratory findings may be ordered?

Blood cultures
Direct fluorescent antibody (DFA): performed on respiratory and tissue samples. Rapid results obtained (within 2-4 hours). Less sensitive than respiratory culture as it requires more organisms to visualize positive test.
Antibody: positive test requires 4-fold increase in serum titers between acute phase and convalescent phase; single titer in patient with acute pneumonia of greater than or equal to 1:128 is presumptive evident of infection. Subsequent titer of greater than or equal to 1:256 in comparison is definitive evidence of infection.
Polymerase chain reaction (PCR): can identify different serotypes rapidly within urine, bronchoalveolar lavage, or serum. Tests possesses increased specificity can be more sensitive than respiratory culture. Six commercial assays exist but only one has been approved by the US Food and Drug Administration (BD ProbeTec ET Legionella pneumophila amplified DNA assay) but it is not yet marketed in the United States.

How can legionella infection be prevented?

Proper maintenance of aerosol-generating devices, including decontamination with higher temperatures (approximately >50°C) to inhibit Legionella growth.

Performing routine culture of water samples and taking swab samples of biofilms can be done if several cases occur in a given location. Antibiotic prophylaxis against legionella is not recommended, and no vaccine is approved for use in humans exists.

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