Legionnaires' disease at a Dutch flower show: prognostic factors and impact of therapy - Research

Emerging Infectious Diseases, Dec, 2002 by Kamilla D. Lettinga, Annelies Verbon, Gerrit-Jan Weverling, Joop F.P. Schellekens, Jeroen W. Den Boer, Ed P.F. Yzerman, Jacobus Prins, Wim G. Boersma, Ruud J. van Ketel, Jan M. Prins, Peter Speelman

After a large outbreak of Legionnaires' disease in the Netherlands, we determined risk factors for intensive care unit (ICU) admission and death and the impact of adequate therapy on ICU-free survival among 141 hospitalized patients. Overall mortality rate was 13%, and ICU mortality rate was 36%. Smoking, temperature >38.5[degrees]C, and bilateral infiltrates shown on chest x-ray were independent risk factors for ICU admission or death (all p<0.05). Starting adequate therapy within 24 hours after admission resulted in a higher ICU-free survival rate compared to therapy initiation after 24 hours: 78% versus 54%, respectively (p=0.005). However, delay in providing therapy to patients with urinary antigen tests with negative results did not influence outcome. These data suggest that by using the urinary antigen test on admission a more tailored approach to patients with community-acquired pneumonia may be applied.

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Severe Legionnaires' disease has an overall mortality rate of 10% to 30% (1-3), and 30% to 50% of patients require admission to an intensive care unit (ICU) (1,4). One of the most important determinants of outcome is the early initiation of adequate therapy after admission (1,5). Administering appropriate antibiotics for Legionella pneumophila during the empiric treatment of patients with community acquired pneumonia has been advocated (6). Given the low frequency of Legionnaires' disease, this strategy is costly and leads to over-consumption of antibiotics. Therefore, many physicians have not adopted these guidelines in daily practice. Identifying those patients with community-acquired pneumonia caused by L. pneumophila is difficult.

In March 1999 one of the largest outbreaks of Legionnaires' disease since the first described outbreak in Philadelphia (7) occurred in the Netherlands. The outbreak originated at the Westfriesian Flora, an annual flower show combined with a consumer products exhibition, held February 19-February 28, 1999. The flower show was visited by 77,061 persons, and Legionnaires' disease developed in at least 188 (8). The size of the outbreak provided a unique opportunity to determine which clinical factors on hospital admission predict ICU admission or death (ICU/death). We also evaluated whether the rapid urinary antigen test can help identify those patients with Legionnaires' disease for whom adequate therapy cannot be delayed.

Patients and Methods

Study Group

On March 12, 1999, the Dutch population was alerted by newspapers and a special broadcast that a flower show was identified as probable origin of an outbreak of Legionnaires' disease (9). To collect clinical data, we obtained written informed consent from patients with Legionnaires' disease who had visited the flower show or their relatives. The study was approved by the medical ethical committee of the Academic Medical Center in Amsterdam.

The following definitions were used to categorize the patients: "confirmed Legionnaires' disease" was defined as the presence of a new infiltrate shown on the chest x-ray on admission and one or more of the following laboratory criteria: 1) isolation of L. pneumophila from a respiratory sample (28 patients), 2) detection of L. pneurnophila serogroup 1 antigen in a urine sample (Binax Now Legionella urinary antigen test; Binax, Portland, ME) (86 patients), 3) seroconversion to positive immunoglobulin (Ig)G or IgM (or both) antibody levels to L. pneumophila, or a fourfold rise in antibody titers to L. pneumophila in paired acute-phase and convalescent-phase sera (62 patients). Antibodies to L. pneumophila were determined by using a commercial enzyme linked immunosorbent assay (IgM cutoff>140 U/mL and IgG cutoff> 70 U/mL, serogroup 1-7; Serion, Institut Virion-serion GmbH, Wurzburg, Germany) or a microagglutination antibody assay (IgM, serogroup 1-12; Regional Laboratory of Public Health, Tilburg, the Netherlands). In three patients, a commercial enzyme immunoassay (Binax EIA, Binax; Biotest EIA, Biotest AG, Dreiech, Germany) was positive in concentrated urine, while other diagnostic tests were negative.

"Probable Legionnaires' disease" was defined as the presence of a new infiltrate shown on the chest x-ray on admission and either a single high antibody titer (microagglutination assay 1:>256; 2 patients) or a positive polymerase chain reaction analysis of sputum (1 patient) (10). Patients who visited the flower show and in whom radiologically confirmed pneumonia developed within 4 weeks were also considered to have probable Legionnaires' disease when no other cause of the pneumonia could be established (18 patients). Patients were excluded if the first symptoms occurred more than 4 weeks after they visited the flower show. None of the patients were hospitalized during the month preceding admission.

Data Collection and Definitions

Data on the following variables were collected from the medical chart (if data were missing, patients were interviewed by telephone):, 1) Premorbid conditions: age, sex, smoking [greater than or equal to] 1 cigarette per day), alcohol intake ([greater than or equal to] 2 units per day), use of immunosuppressive medication (ongoing treatment with chemotherapy or steroids >10 mg/day), underlying diseases such as chronic obstructive pulmonary disease, diabetes mellitus, chronic renal insufficiency, cancer (solid or hematologic neoplasm), and chronic cardiac disease (considered present if cardiac medication was used at the time of the flower show visit). 2) Day of visiting the flower show, first day of illness, and date of admission 3) Symptoms and results of physical examination on admission. 4) Routine biochemical and hematologic laboratory tests obtained on admission. 4) Urinary antigen test results collected from the microbiologic laboratory that performed the test. The overall agreement between the Binax NOW and the enzyme immunoassay Binax EIA (Binax Legionella Urinary Antigen EIA Kit: Binax) has been found to be 98% (11). 6) Chest radiograph results on admission and 48-72 hours later reviewed by attending hospital radiologist. Radiographic progression during this period was defined as an increase in density or size of infiltrate, or progression to multiple lobes. 7) Antibiotic treatment. Adequate therapy was considered a macrolide or a fluoroquinolone, with or without rifampicin. 8) Admission to the ICU, death, and renal insufficiency.

At the time of the patient's admission, Legionnaires' disease was defined as severe when two or more of the following conditions were present: 1) respiratory rate >30 breaths / minute, 2) chest radiograph showing bilateral involvement or involvement of multiple lobes, 3) shock (systolic blood pressure below 90 mmHg or diastolic blood pressure below 60 mmHg), 4) Pa[O.sub.2] <60 mmHg or arterial oxygen saturation <92%. For assessment of severity, we used the minor criteria for severity of community-acquired pneumonia described by the American Thoracic Society (12) since the major criteria are indicators for ICU admission by themselves.