Legionnaires' disease - reliability of urine antigen testing

A 58 year old male patient presents to the emergency room with shortness of breath for the last few days.  He also complains of chills, a cough, myalgia, and diarrhea.  His notable findings include WBC = 14 k/uL, Scr = 1.2 mg/dL, BUN = 27 mg/dL, BP = 132/76 mm Hg, RR = 30 breaths/minute, Tmax = 38.5⁰C, and O2sat = 92% on room air.  His chest x-ray reveals a patchy infiltrate suggestive of pneumonia.  Upon further questioning, the patient tells you he lives across the street from an apartment building where several people recently were diagnosed with Legionnaires' disease.  He has no recent exposure to any health care settings, has taken no antibiotics, was not recently incarcerated, is not immunocompromised, and has not recently traveled.  Can we use urine antigen testing to help guide our treatment of this patient's pneumonia?

Cause of Legionnaires' disease

Legionnaires' disease is essentially pneumonia caused by Legionella bacteria.  There are 20 different Legionella species that infect humans with Legionnella pneumophila being responsible for 90% of infections.  Within L. pneumophila there are 16 serogroups with serogroup 1 causing 70-90% of cases.  Serogroup 1 can further be differentiated based on genotype, phenotype, and serologic differences the most common being Pontiac, causing 67-90% of cases.  Most laboratories can detect L. pneumophila and serogroup 1 but other species and serogroups are more difficult to detect and require more sophisticated techniques like DNA sequencing.

Legionella is an intracellular Gram-negative bacilli (rod) that is an obligate aerobe (cannot live without oxygen) and is ubiquitous in nature.  It is found in freshwater lakes, streams, mud, coastal water, and can live inside protozoas which can encyst and have a biofilm enabling it to survive in harsh conditions.  One amebal cyst can easily contain more than 1000 Legionella bacteria, enabling inhalation of one cyst to deliver more than enough bacteria to cause disease.  Another notable characteristic of Legionella is its hydrophobic lipopolysaccharide component of the cell wall - this is the reason why it is not as virulent as some other Gram-negative bacilli but does avail it to distribution by aerosolization.  It grows best at 35⁰C in humidified air making cooling towers, air-conditioning systems, faucets, and shower heads systems for dispersal.

Urine antigen testing

Ideally, a urine antigen test would be best if it was both highly sensitive and highly specific but this is unfortunately not the case.  Here are some of the pros and cons about the test:

Pros	Cons
Easy to collect urine compared to lower respiratory tract or blood Does not require special laboratory skills Highly specific (>99%) Remains positive for days after antimicrobials initiated	Poor sensitivity:      90% for L. pneumophila serogroup type 1 Pontiac type      60% for other L. pneumophila serogroup type 1      <5% for other L. pneumophila serogroups and species

This poor sensitivity was further analyzed by a study of 317 patients with culture-proven Legionnaires' disease.  They found that about 94% of patients with travel-associated Legionnaires' diseases had positive urine antigen test but only 81% with community-acquired disease and 45% with nosocomial disease tested positive.  The possible explanation for these results are that nosocomial disease is more likely to be caused by other species and serogroups that are not detected in the urine (as are immunocompromised patients and some people from Australia).

Lastly, severity of disease is positively correlated with positive test results (mild-moderately ill patients are more likely to have false negatives) and patients with extensive bilateral disease may excrete urinary antigen for weeks to months after recovery (when it is the testable species, serogroup, and subtype).

Back to the patient case

Based at the patient's initial presentation, he has a CURB-65 score of 2 (elevated BUN and RR) and should therefore most likely be hospitalized for management of this infection.  His pneumonia presentation includes several findings concerning for Legionnaires' diseases, namely the respiratory symptoms, diarrhea, myalgias, chest radiography findings, and proximity to known cases.  As we learned above, urine antigen testing is not very effective for ruling out Legionnaires' disease due to its low sensitivity and a negative result should not supersede our high clinical suspicion.  He should initially be empirically treated for community-acquired pneumonia with a first dose in the emergency department of either a respiratory fluoroquinolone or a combination beta-lactam/macrolide.  Either a fluoroquinolone or beta-lactam/macrolide combination are good options because fluoroquinolones, macrolides, and tetracyclines have an intracellular mechanism of action.  

Take home points:

• Urine antigen testing for Legionnaires' disease only detects one subtype of one serogroup of one species (although it is the most common) that causes human infections
• A negative Legionella urine antigen test should not warrant discontinuation of antibiotics if there is clinical concern
• Sensitivity of urine antigen testing is relatively low
• Severe disease tends to be caused by other serogroups or species so false negatives frequently occur

References:
Ryan KJ, Ray C. Legionella and Coxiella.  In: Ryan KJ, Ray C. eds. Sherris Medical Microbiology, 6e.  New York, NY: McGraw-Hill; 2014.
Edelstein PH, Cianciotto NP.  Legionella.  In: Mandell GL, Bennett JE, et al eds. Infectious Diseases, 7e. Philadelphoa, PA: Elsevier; 2010.
Helbig JH, Uldum SA, Bernander S, et al.  Clinical utility of urinary antigen detection for diagnosis of community-acquired, travel-associated, and nosocomial Legionaires' disease.  J Clin Microbiol  2003:41(2):838-40.

photo from here