Chest
Volume 144, Issue 3, September 2013, Pages 990-998
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Original Research
Chest Infections
Incidence and Risk Factors of Legionella pneumophila Pneumonia During Anti-Tumor Necrosis Factor Therapy: A Prospective French Study

https://doi.org/10.1378/chest.12-2820Get rights and content

Objective

Our objective was to describe the incidence and risk factors of legionellosis associated with tumor necrosis factor (TNF)-α antagonist use.

Methods

From February 1, 2004, to January 31, 2007, we prospectively collected all cases of legionellosis among French patients receiving TNF-α antagonists in the Research Axed on Tolerance of Biotherapies (RATIO) national registry. We conducted an incidence study with the French population as a reference and a case-control analysis with four control subjects receiving TNF-α antagonists per case of legionellosis.

Results

Twenty-seven cases of legionellosis were reported. The overall annual incidence rate of legionellosis for patients receiving TNF-α antagonists, adjusted for age and sex, was 46.7 (95% CI, 0.0-125.7) per 100,000 patient-years. The overall standardized incidence ratio (SIR) was 13.1 (95% CI, 9.0-19.1; P < .0001) and was higher for patients receiving infliximab (SIR, 15.3 [95% CI, 8.5-27.6; P < .0001]) or adalimumab (SIR, 37.7 [95% CI, 21.9-64.9; P < .0001]) than etanercept (SIR, 3.0 [95% CI, 1.00-9.2; P = .06]). In the case-control analysis, exposure to adalimumab (OR, 8.7 [95% CI, 2.1-35.1]) or infliximab (OR, 9.2 [95% CI, 1.9-45.4]) vs etanercept was an independent risk factor for legionellosis.

Conclusions

The incidence rate of legionellosis for patients receiving TNF-α antagonists is high, and the risk is higher for patients receiving anti-TNF-α monoclonal antibodies than soluble TNF-receptor therapy. In case of pneumonia occurring during TNF-α antagonist therapy, specific urine antigen detection should be performed and antibiotic therapy should cover legionellosis.

Section snippets

Materials and Methods

The RATIO registry was designed to prospectively collect all cases of microbiologically documented opportunistic and severe bacterial infections, including legionellosis, from February 1, 2004, to January 31, 2007, in patients who were receiving or had received TNF-α antagonists (see methodological details described in Tubach et al5). This study was authorized by the ethics committee of AP-HP, GHU Nord (Institutional Review Board of Paris North Hospitals, Paris 7 University, AP-HP;

Description of L pneumophila Pneumonia Cases

Twenty-seven cases of L pneumophila pneumonia were reported to the RATIO registry and were confirmed by the validation committee. All cases were confirmed as sporadic and community acquired and came from 18 different hospitals, with four sites that notified two or more cases. Patients' characteristics are listed in Table 1. Sixty percent of patients who received infliximab had received only this TNF-α antagonist, 64% of patients who received adalimumab had received only this TNF-α antagonist,

Discussion

Meta-analyses and most registries have revealed that severe infection is higher in patients receiving TNF-α antagonists than placebo or other classic treatments used for the management of chronic inflammatory diseases.19, 20, 21, 22 The most frequent severe infection is bacterial pneumonia. TNF-α antagonist use also exposes patients to increased risk of less-frequent intracellular bacterial infections, such as those caused by Mycobacterium tuberculosis, Listeria monocytogenes, L pneumophila,

Acknowledgments

Author contributions: Dr Lortholary had full access to all data and final responsibility for the decision to submit for publication.

Dr Lanternier: contributed to co-coordination of the writing committee and collection of data.

Dr Tubach: contributed to study design, statistical analysis, manuscript writing, and collection of data.

Dr Ravaud: contributed to study design and manuscript writing.

Dr Salmon: contributed to study design, cases validation, and manuscript review.

Dr Dellamonica:

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    This article was presented in part at the 50th Interscience Conference on Antimicrobial Agents and Chemotherapy, September 12-15, 2010, Boston, MA, Abstract L1-1988.

    Funding/Support: The RATIO was supported by a research grant from INSERM [A-02-02-PRO-AX-11-ed.3] (Réseau de recherche clinique 2003 and 2006) and by an unrestricted grant from Abbott Laboratories [convention ratio/hum/2007-2009], Schering-Plough (now Merck & Co, Inc), and Wyeth [convention 0711RC26, 0611RC19, 0911RC02, 0511RC03, 0411RC08, 0811RC02] (now Pfizer Inc).

    Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.

    *

    A list of RATIO participants is located in e-Appendixes 1 and 2.

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