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Journal ArticleDOI

Fulminant Legionellosis in Two Patients Treated with Infliximab for Crohn’s Disease: Case Series and Literature Review

Adam Hofmann1, Yanick Beaulieu, Francis Bernard, Philippe Rico 
01 Dec 2009-Canadian Journal of Gastroenterology & Hepatology (Hindawi Publishing Corporation)-Vol. 23, Iss: 12, pp 829-833

TL;DR: Two cases of fulminant pulmonary legionellosis are described, complicated by prolonged intensive care unit stays and acute respiratory distress syndrome, and who were recently treated with infliximab for Crohn's disease, and Physicians prescribing anti-TNF-alpha drugs should be aware of this association.

AbstractTwo cases of fulminant pulmonary legionellosis, complicated by prolonged intensive care unit stays and acute respiratory distress syndrome, and who were recently treated with infliximab for Crohn’s disease, are described. A review of the literature revealed three additional cases in patients with inflammatory bowel disease, and a total of 22 cases of Legionella pneumophila pneumonia in the context of treatment with antitumour necrosis (TNF)-alpha medications. The median age of the patients was 49 years, and men and women were affected equally. The case fatality rate was 14% (three of 22). Early recognition and treatment of this anti-TNF-alpha-related complication would likely result in reduced mortality and morbidity. Physicians prescribing anti-TNF-alpha drugs should be aware of this association.

Topics: Infliximab (55%), Case fatality rate (54%), Fulminant (54%), Inflammatory bowel disease (54%), Crohn's disease (54%)

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Journal ArticleDOI
TL;DR: The therapeutic modulation of TNF now moves into the era of personalized medicine with society's challenging expectations of durable treatment success and of achieving long-term disease remission.
Abstract: Tumor Necrosis Factor (TNF), initially known for its tumor cytotoxicity, is a potent mediator of inflammation, as well as many normal physiological functions in homeostasis and health, and anti-microbial immunity. It also appears to have a central role in neurobiology, although this area of TNF biology is only recently emerging. Here, we review the basic biology of TNF and its normal effector functions, and discuss the advantages and disadvantages of therapeutic neutralization of TNF - now a commonplace practice in the treatment of a wide range of human inflammatory diseases. With over ten years of experience, and an emerging range of anti-TNF biologics now available, we also review their modes of action, which appear to be far more complex than had originally been anticipated. Finally, we highlight the current challenges for therapeutic intervention of TNF: (i) to discover and produce orally delivered small molecule TNF-inhibitors, (ii) to specifically target selected TNF producing cells or individual (diseased) tissue targets, and (iii) to pre-identify anti-TNF treatment responders. Although the future looks bright, the therapeutic modulation of TNF now moves into the era of personalized medicine with society's challenging expectations of durable treatment success and of achieving long-term disease remission.

520 citations


Journal ArticleDOI
TL;DR: The consensus group developed a working definition for OIs as ‘indicator’ infections, defined as specific pathogens or presentations of pathogens that ’indicate’ the likelihood of an alteration in host immunity in the setting of biologic therapy.
Abstract: No consensus has previously been formed regarding the types and presentations of infectious pathogens to be considered as 'opportunistic infections' (OIs) within the setting of biologic therapy. We systematically reviewed published literature reporting OIs in the setting of biologic therapy for inflammatory diseases. The review sought to describe the OI definitions used within these studies and the types of OIs reported. These findings informed a consensus committee (infectious diseases and rheumatology specialists) in deliberations regarding the development of a candidate list of infections that should be considered as OIs in the setting of biologic therapy. We reviewed 368 clinical trials (randomised controlled/long-term extension), 195 observational studies and numerous case reports/series. Only 11 observational studies defined OIs within their methods; no consistent OI definition was identified across studies. Across all study formats, the most numerous OIs reported were granulomatous infections. The consensus group developed a working definition for OIs as 'indicator' infections, defined as specific pathogens or presentations of pathogens that 'indicate' the likelihood of an alteration in host immunity in the setting of biologic therapy. Using this framework, consensus was reached upon a list of OIs and case-definitions for their reporting during clinical trials and other studies. Prior studies of OIs in the setting of biologic therapy have used inconsistent definitions. The consensus committee reached agreement upon an OI definition, developed case definitions for reporting of each pathogen, and recommended these be used in future studies to facilitate comparison of infection risk between biologic therapies.

77 citations


Journal ArticleDOI
01 Sep 2013-Chest
TL;DR: The incidence and risk factors of legionellosis associated with tumor necrosis factor (TNF)-α antagonist use are described and the risk is higher for patients receiving anti-TNF-α monoclonal antibodies than soluble TNF-receptor therapy.
Abstract: 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 P P 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. Trial registry ClinicalTrials.gov; No.: NCT00224562; URL: www.clinicaltrials.gov

65 citations


Journal ArticleDOI
TL;DR: The impact of T2S on lung infection is a combination of at least three factors: the promotion of growth in macrophages, the facilitation ofrowth in epithelia, and the dampening of the chemokine and cytokine output from infected host cells.
Abstract: The type II secretion (T2S) system of Legionella pneumophila is required for the ability of the bacterium to grow within the lungs of A/J mice. By utilizing mutants lacking T2S (lsp), we now document that T2S promotes the intracellular infection of both multiple types of macrophages and lung epithelia. Following infection of macrophages, lsp mutants (but not a complemented mutant) elicited significantly higher levels of interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α), IL-10, IL-8, IL-1β, and MCP-1 within tissue culture supernatants. A similar result was obtained with infected lung epithelial cell lines and the lungs of infected A/J mice. Infection with a mutant specifically lacking the T2S-dependent ProA protease (but not a complemented proA mutant) resulted in partial elevation of cytokine levels. These data demonstrate that the T2S system of L. pneumophila dampens the cytokine/chemokine output of infected host cells. Upon quantitative reverse transcription (RT)-PCR analysis of infected host cells, an lspF mutant, but not the proA mutant, produced significantly higher levels of cytokine transcripts, implying that some T2S-dependent effectors dampen signal transduction and transcription but that others, such as ProA, act at a posttranscriptional step in cytokine expression. In summary, the impact of T2S on lung infection is a combination of at least three factors: the promotion of growth in macrophages, the facilitation of growth in epithelia, and the dampening of the chemokine and cytokine output from infected host cells. To our knowledge, these data are the first to identify a link between a T2S system and the modulation of immune factors following intracellular infection.

52 citations


Cites background from "Fulminant Legionellosis in Two Pati..."

  • ...Fourth, in humans, anti-TNF agents given to treat inflammatory diseases are a risk factor for Legionnaires’ disease (12, 56)....

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Journal ArticleDOI
TL;DR: The pathogenesis of Crohn’s disease has been regarded as the consequence of a dysregulated T-cell-mediated response to intestinal microbes, but recent molecular biological and clinical investigations indicate that CD is actually a primary immunodeficiency.
Abstract: The pathogenesis of Crohn's disease (CD) has widely been regarded as the consequence of a dysregulated T-cell-mediated response to intestinal microbes, and the majority of the worldwide research effort has focused on characterizing and treating the chronic inflammatory phase of the disease. However, recent molecular biological and clinical investigations indicate that CD is actually a primary immunodeficiency. At first counter-intuitive, the apparent paradox of a pathogenic innate immune defect can be linked mechanistically to the granulomatous chronic inflammation characteristic of the disease. Genome-wide association studies have corroborated the involvement of innate immune dysfunction in the pathogenesis of CD, but less than 20% of the heritable risk is accounted for. By contrast, in vitro and in vivo stimulation of the immune system has highlighted novel areas of interest that may lead to the development of targeted therapeutic and diagnostic tools.

29 citations


References
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Journal ArticleDOI
TL;DR: In patients with active RA, anti-TNF therapy was not associated with increased risk of overall serious infection compared with DMARD treatment, after adjustment for baseline risk, but the rate of serious skin and soft tissue infections was increased, suggesting an important physiologic role of TNF in host defense in the skin andsoft tissues beyond that in other tissues.
Abstract: Objective To determine whether the rate of serious infection is higher in anti–tumor necrosis factor (anti-TNF)–treated rheumatoid arthritis (RA) patients compared with RA patients treated with traditional disease-modifying antirheumatic drugs (DMARDs). Methods This was a national prospective observational study of 7,664 anti-TNF–treated and 1,354 DMARD-treated patients with severe RA from the British Society for Rheumatology Biologics Register. All serious infections, stratified by site and organism, were included in the analysis. Results Between December 2001 and September 2005, there were 525 serious infections in the anti-TNF–treated cohort and 56 in the comparison cohort (9,868 and 1,352 person-years of followup, respectively). The incidence rate ratio (IRR), adjusted for baseline risk, for the anti-TNF–treated cohort compared with the comparison cohort was 1.03 (95% confidence interval 0.68–1.57). However, the frequency of serious skin and soft tissue infections was increased in anti-TNF–treated patients, with an adjusted IRR of 4.28 (95% confidence interval 1.06–17.17). There was no difference in infection risk between the 3 main anti-TNF drugs. Nineteen serious bacterial intracellular infections occurred, exclusively in patients in the anti-TNF–treated cohort. Conclusion In patients with active RA, anti-TNF therapy was not associated with increased risk of overall serious infection compared with DMARD treatment, after adjustment for baseline risk. In contrast, the rate of serious skin and soft tissue infections was increased, suggesting an important physiologic role of TNF in host defense in the skin and soft tissues beyond that in other tissues.

715 citations


Journal ArticleDOI
TL;DR: The British Society for Rheumatology established a register of patients newly treated with biological agents, the BSR Biologics Register (BSRBR), which became active in January 2002 and is recruiting a comparison cohort of patients with rheumatoid arthritis treated with standard disease modifying antirheumatic drugs.
Abstract: The British Society for Rheumatology (BSR) established a register of patients newly treated with biological agents, the BSR Biologics Register (BSRBR), which became active in January 2002. The goal is to register all patients in the United Kingdom with rheumatic diseases, newly starting treatment with these agents and to follow them up to determine the incidence of any short and long term hazards to health. The Register is also recruiting a comparison cohort of patients with rheumatoid arthritis treated with standard disease modifying antirheumatic drugs to determine the relative contributions of disease factors and other treatments apart from biological agents on any risks observed.

566 citations


"Fulminant Legionellosis in Two Pati..." refers background in this paper

  • ...The association of L pneumophila pneumonia with antitumour necrosis factor (TNF)-alpha has been reported previously in the literature (2-10) and twice before in patients receiving infliximab for Crohn’s disease (4,5)....

    [...]

  • ...Table 1 - CONTINueD author (reference) age, years Sex anti-TNFalpha drug Treatment duration Indication Concomitant immunosuppressive therapy Comorbidities Clinical and radiological features Communityacquired (C) or nosocomial (N) Diagnostic modality (serogroup) antibiotic therapy Outcome Tubach et al (5) 45 F ALMB (40 mg biweekly) 36 weeks JRA MTX (15mg/ week), prednisone (5 mg/day) Smoker UL pneumonia, delirium C LPAg-positive (LP1) Macrolide, then FLQ Recovered Tubach et al (5) 66 F ALMB (40 mg biweekly) 45 weeks RA MTX (15 mg/week) None Abdominal pain, BL interstitial pneumonia, ARDS, acute kidney damage C LP6, seroconversion FLQ, ceftriaxone Recovered Tubach et al (5) 47 M ALMB (40 mg biweekly) 50 weeks RA Prednisone (5 mg/day) Smoker, watercleaning system worker BL upper lobe pneumonia, ARDS, pneumothorax C LPAg-positive (LP1), BAL culture Rifampicin, FLQ Admitted to ICU, recovered Tubach et al (5) 69 F ETCP (25 mg twice weekly); IFMB (3 mg/kg) 45 weeks RA MTX (7.5 mg/ week), prednisone (5 mg/day) None BL diffuse interstitial pneumonia, dyskinesia, delirium, diarrhea C LPAg-positive (LP1) FLQ Recovered Dixon et al (10) 49 M IFMB 16 weeks RA N/A N/A N/A N/A N/A N/A N/A Dixon et al (10) 59 M IFMB 128 weeks RA N/A N/A N/A N/A N/A N/A N/A Eisendle and Fritsch (9) 56 M IFMB (5 mg/kg, two doses) 2 weeks EP Prednisolone 20 mg/day Diabetes mellitus and steroid myopathy UL pneumonia, septic shock C LPAgnegative, BAL and postmortem culture for serogroup 4 and 10 FLQ Death from multiorgan failure Li Gobbi et al (6) 38 F IFMB (3mg/ kg; total 200 mg) 2 weeks RA MTX (15 mg/week) None UL pneumonia C LPAg-positive (LP1) Macrolide Recovered Mancini et al (3) 30 M IFMB (5 mg/kg) 4 weeks Behçet’s disease MTX Pulmonary TB from previous cycle of IFMB UL pneumonia, pleural and pericardial effusions C LPAg-positive (LP1) FLQ, rifampicin Recovered Albert et al (8) 73 F IFMB (150 mg bimonthly) 72 weeks RA MTX (15 mg/ week), prednisone (5 mg/day) None UL pneumonia C LPAgnegative, BAL culture positive (serogroup 1) FLQ Recovered, resumed IFMB therapy with no sequelae ALMB Adalimumab; ARDS Acute respiratory distress syndrome; BAL Bronchoalveolar lavage; BL Bilateral; CD Crohn’s disease; COPD Chronic obstructive pulmonary disease; EP Erythrodermic psoriasis; ETCP Etanercept; F Female; FLQ Fluoroquinolone; HFOV High-frequency oscillation ventilation; IBD Inflammatory bowel disease; ICU Intensive care unit; IFMB Infliximab; IV Intravenous; JRA Juvenile-onset rheumatoid arthritis; LP Legionella pneumophila; LPAg L pneumophila antigen; M Male; MP 6-mercaptopurine; MTX Methotrexate; N/A Information not available; NSAID Nonsteroidal anti-inflammatory drugs; PCR Polymerase chain reaction; PD Pyoderma gangrenosum; RA Rheumatoid arthritis; TB Tuberculosis; UC Ulcerative colitis; UL Unilateral Can J Gastroenterol Vol 23 No 12 December 2009832...

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  • ...Dixon et al (10) 59 M IFMB 128 weeks RA N/A N/A N/A N/A N/A N/A N/A...

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  • ...Dixon et al (10) 49 M IFMB 16 weeks RA N/A N/A N/A N/A N/A N/A N/A...

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Journal ArticleDOI
TL;DR: Severe ulcerative colitis is a life‐threatening disorder, despite i.v. glucocorticoids treatment, and infliximab has been proposed as a safe rescue therapy.
Abstract: Background Severe ulcerative colitis is a life-threatening disorder, despite i.v. glucocorticoids treatment. Infliximab has been proposed as a safe rescue therapy. Aim To evaluate short- and long-term effectiveness and safety of infliximab in severe refractory ulcerative colitis. Methods Eighty-three patients with severe ulcerative colitis (i.v. glucocorticoids treatment-refractory) were treated with infliximab in 10 Italian Gastroenterology Units. Patients underwent one or more infusions according to the choice of treating physicians. Short-term outcome was colectomy/death 2 months after the first infusion. Long-term outcome was survival free from colectomy. Safety data were recorded. Results Twelve patients (15%) underwent colectomy within 2 months. One died of Legionella pneumophila infection 12 days after infliximab. Early colectomy rates were higher in patients receiving one infusion (9/26), compared with those receiving two/more infusions (3/57, P = 0.001, OR = 9.53). Seventy patients who survived colectomy and did not experience any fatal complications were followed-up for a median time of 23 months; 58 patients avoided colectomy during the follow-up. Forty-two patients were maintained on immunosuppressive drugs. No clinical features were associated with outcomes. Conclusions Infliximab is an effective and relatively safe therapy to avoid colectomy and maintain long-term remission for patients with severe refractory ulcerative colitis. In the short term, two or more infusions seem to be more effective than one single infusion.

160 citations


"Fulminant Legionellosis in Two Pati..." refers background or methods in this paper

  • ...One death is documented in a clinical trial (4), in which the patient died of complications of his infection 11 days after the first dose of infliximab....

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  • ...Kohn et al (4) 71 M IFMB 11 days UC Mesalazine, IV glucocorticoids N/A N/A N PCR of sputum sample N/A Death from septic shock...

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  • ...The association of L pneumophila pneumonia with antitumour necrosis factor (TNF)-alpha has been reported previously in the literature (2-10) and twice before in patients receiving infliximab for Crohn’s disease (4,5)....

    [...]

  • ...Can J Gastroenterol Vol 23 No 12 December 2009830 Table 1 Clinical characteristics of tumour necrosis factor (TNF)-alpha antagonist-associated legionellosis patients author (reference) age, years Sex anti-TNFalpha drug Treatment duration Indication Concomitant immunosuppressive therapy Comorbidities Clinical and radiological features Communityacquired (C) or nosocomial (N) Diagnostic modality (serogroup) antibiotic therapy Outcome Inflammatory bowel disease-associated clinical cases Case A 26 M IFMB (5 mg/kg) 4 weeks CD MP, Prednisone Smoker BL pneumonia, ARDS requiring HFOV, acute kidney damage requiring hemodialysis N LPAgpositive (LP1) Macrolide Admitted to ICU, severe hypoxia, hemodialysisdependent, recovered Case B 59 M IFMB (5 mg/kg, two doses) 4 weeks CD Methylprednisolone Smoker BL pneumonia with abscess formation, ARDS requiring HFOV N LPAgpositive (LP1) Macrolide Admitted to ICU, died as a result of complications of his ICU stay, and sequelae of a massive vertebrobasilar stroke Beigel et al (2) 58 M IFMB CD Azathioprine, mesalamine, prednisolone Smoker UL pneumonia, respiratory failure requiring ICU admission C BAL culture, LPAgpositive (LP1) FLQ Admitted to ICU, 2 weeks of mechanical ventilation, complete recovery Kohn et al (4) 71 M IFMB 11 days UC Mesalazine, IV glucocorticoids N/A N/A N PCR of sputum sample N/A Death from septic shock Tubach et al (5) 27 F IFMB (250 mg) 1 week CD Azathioprine (200 mg/ day), prednisone 15 mg/day) None ARDS, UL pneumonia C LPAgpositive (LP1), BAL culture Rifampicin, FLQ Recovered, experienced second episode with reintroduction of IFMB Clinical cases associated with other rheumatic conditions or other inflammatory condition indications for anti-TNF-alpha therapy Tubach et al (5) 43 M ALMB (40 mg biweekly) 71 weeks RA MTX, Prednisone Diabetes mellitus BL pneumonia, vomiting C LPAgpositive (LP1) FLQ Recovered Tubach et al (5) 55 F ALMB (40 mg monthly) 26 weeks RA MTX (7.5 mg/ week), prednisone (8 mg/day) None UL pneumonia C LPAgpositive (LP1) Macrolide, rifampicin Recovered Tubach et al (5) 67 M ETCP (25 mg twice weekly) 16 weeks RA MTX (12.5 mg/week), prednisolone (10 mg/day) Tobaccorelated COPD UL multilobar pneumonia, ARDS, acute kidney damage requiring hemodialysis C LPAg positive (LP1) and BAL culture Rifampicin, FLQ Admitted to ICU, recovered Tubach et al (5) 46 F IFMB 73 weeks PD Prednisone (10 mg/day), pipobroman (75 mg/day) Primary thrombocythemia BL lower lobe pneumonia, pleural effusion, ARDS, nausea C LPAgpositive (LP1) Macrolide, rifampicin Admitted to ICU, alive at discharge Tubach et al (5) 58 M IFMB (5 mg/kg) 3 weeks Psoriasis None Smoker (15 packyears) UL upper lobe pneumonia, small pleural effusion C LPAg-positive (LP1) and PCR-positive sputum samples Macrolide, FLQ Recovered Tubach et al (5) 40 M ALMB (40 mg biweekly) 34 weeks RA Sulfasalazine (2 g/day), betamethasone (2 mg/day) Diabetes mellitus, tobaccorelated COPD UL bilobar pneumonia, myalgia, vomiting C LPAgpositive (LP1) Rifampicin, FLQ Recovered Continued on next page Can J Gastroenterol Vol 23 No 12 December 2009 831 young man with no wasting or dermatological abnormalities....

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Journal ArticleDOI
TL;DR: In patients receiving anti-TNF-alpha who develop pneumonia, legionellosis should be systematically investigated, and first-line antibiotic therapy should be efficient against L. pneumophila.
Abstract: Background Patients treated with tumor necrosis factor-alpha (TNF-alpha) antagonists have an increased risk of infection, but infection due to Legionella pneumophila has rarely been described in patients receiving such therapy. Methods A registry involving 486 clinical departments in France was designed by a multidisciplinary group (Recherche Axee sur la Tolerance des Biotherapies [RATIO]) to collect data on opportunistic and severe infections occurring in patients treated with TNF-alpha antagonists. All cases are reported to RATIO in accordance with national health authorities and validated by infectious disease experts. The legionellosis rate among patients treated with TNF-alpha antagonists was compared with the rate in France overall. Results We report a 1-year consecutive series of 10 cases of L. pneumophila pneumonia in France in 2004, including 6 cases treated with adalimumab, 2 treated with etanercept, and 2 treated with infliximab. The median patient age was 51 years (range, 40-69 years). Eight patients were treated for rheumatoid arthritis, 1 was treated for cutaneous psoriasis, and 1 was treated for pyoderma gangrenosum. The median duration of TNF-alpha antagonist treatment at onset of infection was 38.5 weeks (range, 3-73 weeks). Eight patients were receiving concomitant treatment with corticosteroids, and 6 were receiving treatment with methotrexate. The relative risk of legionellosis when receiving treatment with a TNF-alpha antagonist, compared with the relative risk in France overall, was estimated to be between 16.5 and 21.0. We also report a second episode of confirmed legionellosis following the reintroduction of infliximab therapy. Conclusions L. pneumophila pneumonia is a potentially severe but curable infection that might complicate anti-TNF-alpha therapy. In patients receiving anti-TNF-alpha who develop pneumonia, legionellosis should be systematically investigated, and first-line antibiotic therapy should be efficient against L. pneumophila.

129 citations


Journal ArticleDOI
TL;DR: New findings are described that demonstrate that various cytokines that define Th1 vs Th2 helper cell activity also are important in regulating resistance versus susceptibility to this ubiquitous microorganism.
Abstract: Legionella pneumophila is a ubiquitous intracellular bacterium found widely in the environment and is the cause of sporadic outbursts of opportunistic infection, mainly in immunocompromised individuals, including young children as well as aged persons. The host response to this organism is similar to responses to other opportunistic intracellular microbes and features both innate and adoptive immune mechanisms. Innate immunity includes the responses of a variety of host cells and cytokines, including those produced by macrophages stimulated by microbial antigens. Adoptive immunity consists of activated lymphocytes and the cytokines they produce, such as interferon and other cytokines that activate macrophages to restrict the growth and spread of intracellular bacteria. The role of cytokines specifically in resistance and immunity to Legionella is exemplified by studies concerning the nature and mechanism whereby interferon produced by activated T lymphocytes influences macrophages to resist infection by this bacterium, not only by restricting growth but also killing this bacterium. This cytokine is considered to have a key role in activating macrophages in adoptive immunity to Legionella and other intracellular bacteria. In particular, interferon is known to have a crucial role in activating macrophages to resist infection by L. pneumophila . This review also describes newer findings that demonstrate that various cytokines that define Th1 vs Th2 helper cell activity also are important in regulating resistance versus susceptibility to this ubiquitous microorganism. Copyright 2002, Elsevier Science (USA). All rights reserved.

97 citations


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