Original article 1247
Listeria monocytogenes infection in inflammatory bowel disease patients: case series and review of the literature José Miranda-Bautistaa, Camilo Padilla-Suáreza, Emilio Bouzab, Patricia Muñozb, Luis Menchéna,c,d and Ignacio Marín-Jiméneza,d Background Listeria monocytogenes (LM) is a grampositive intracellular bacillus that in immunodeficient patients, children, geriatric patients, pregnant women, and even in healthy individuals can cause central nervous system infection, bacteremia, and other clinical manifestations, becoming a relevant pathogen.
treatment, one patient died from a cause related to the infection, that is, rombencephalitis. Increased incidence of LM bacteremia was found in IBD patients, compared with the general population (12.2 bacteremias/100 000 IBD patient-years, compared with 1.6 bacteremias/100 000 person-years), with an odds ratio of 7.4.
Materials and methods From the Microbiology Service data of ‘Gregorio Marañón’ Hospital, we selected all positive biological sample cultures for LM from inflammatory bowel disease (IBD) patients, from January 1986 until January 2011. These cases were included in an SPSS database, analyzing several basal clinical characteristics and factors related to the infection.
Conclusion IBD patients may be at risk for more frequent and serious LM infection compared with the general population. Eur J Gastroenterol Hepatol 26:1247–1252 © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.
Results Three patients diagnosed with IBD had positive cultures for LM during this period. All of them were male, and also all of them had a diagnosis of Crohn’s disease. Every patient had a corticosteroid cumulated dose of more than 400 mg (equivalency in methylprednisolone doses), adding anti-tumor necrosis factor-α treatment (certolizumab) in one patient. Prior colonoscopy with biopsy was performed in two patients. Clinical presentation of the infection was bacteremia in two patients, accompanied by central nervous system infection in one patient. One patient had isolated meningoencephalitis. Despite correct empiric
Introduction Inflammatory bowel disease (IBD), which includes Crohn’s disease (CD) and ulcerative colitis, is a chronic inflammatory disease of the gastrointestinal tract and is characterized by recurrent ulceration of different parts of the bowel [1]. IBD treatment is continuously changing, with new molecules that target different steps of the inflammatory cascade being developed. This, added to chronic disease behavior, malnutrition, and comorbidities, can reduce the ability of the organism to fight against micro-organisms, leading to an increase in the risk for infections in IBD patients, even those whose pathogenic capacity is minimal or inexistent under ordinary circumstances. These opportunistic infections represent a difficult challenge for clinicians, concerning early diagnosis, adequate treatment, and an effort to improve immunity without harming clinically controlled IBD. Morbidity and mortality of these opportunistic infections are not 0954-691X © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
European Journal of Gastroenterology & Hepatology 2014, 26:1247–1252 Keywords: Anti-tumor necrosis factor-α drugs, colonoscopy, inflammatory bowel disease, Listeria a
Digestive Diseases Service, bMicrobiology and Infectious Diseases Services, “Gregorio Marañón” General University Hospital, Health Investigation Institute “Gregorio Marañón” (IISGM), cOn-line Hepatic and Digestive Diseases Research Centre (CIBERehd), Carlos III Health Institute and dDepartment of Medicine, “Complutense” University, Madrid, Spain Correspondence to Ignacio Marín, MD, Digestive Diseases Service, “Gregorio Marañón” General University Hospital, Health Investigation Institute “Gregorio Marañón” (IISGM), C/Dr, Esquerdo 46, 28007 Madrid, Spain Tel: + 34 915 868 300; fax: + 34 915 868 018; e-mail: [email protected] Received 28 May 2014 Accepted 18 July 2014
negligible; hence, increasing the knowledge on these entities is mandatory for current clinical practice. Listeria monocytogenes (LM) is a gram-positive bacillus that in immunodeficient patients, children or geriatric patients, and in pregnant women can cause central nervous system infection, bacteremia, and other clinical manifestations, becoming a relevant pathogen [2]. Prior colonoscopy is another risk factor for the development of LM infection [3,4]. We hypothesize that IBD patients are a subgroup of high-risk patients with a high incidence of IBD.
Materials and methods From Microbiology Service data of ‘Gregorio Marañón’ Hospital, we selected retrospectively all positive cultures for LM in normally sterile body fluids from IBD patients, including blood, cerebrospinal fluid (CSF), amniotic fluid, and other biological samples, from January 1986 until January 2011. The methods used for sampling, transporting, and processing blood cultures and for identification of isolates were standard. Blood culture DOI: 10.1097/MEG.0000000000000188
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Table 1
European Journal of Gastroenterology & Hepatology 2014, Vol 26 No 11
Resumed patients’ history and evolution
Case (n) Age/Sex
IBD
Anti-TNF
Dose/Time Prior of treatment Corticosteroids IMM Comorbidity colonoscopy
1
47/M
CD (A2L1B3p) Certolizumab 4/2 months
Yes
No
No
2 3
67/M 15/M
CD CD (A2L2B1)
Yes Yes
No No
No No
No No
Syndrome
Outcome
Yes (2 days Bacteremia Recovered before) No Bacteremia + romboencephalitis Death Yes (12 days Meningoencephalitis Recovered before)
CD, Crohn’s disease; IBD, inflammatory bowel disease; IMM, immunomodulatory therapy; M, male.
laboratory processing systems varied during this period. From 1986 to 1995, BACTEC NR-640 was used (Johnston Laboratories Inc., Towson, Maryland, USA). From 1995 to 2011, blood cultures were processed using BACTEC 9240 (Becton Dickinson Microbiology Systems, Towson, Maryland, USA), which is more automatic and includes continuous shaking. All positive samples were subcultured and Gram stained. These cases were included in an SPSS software package (SPSS 20.0; SPSS Inc., Chicago, Illinois, USA), analyzing clinical basal characteristics (age, sex, type of IBD, Montreal Classification, comorbidity using Mc Cabe and Jackson criteria, type and doses of IBD treatment) and factors related to the infection (time of presentation, clinical manifestation, positive cultures, treatment, and outcome). On the basis of data from the ‘Gregorio Marañón’ database IBD registry, those from the Health Ministry on the population attended to in our hospital area, and those from the Microbiology Service registry, we calculated the incidence of bacteremia in the general population of our health area and compared it with the incidence in the IBD population. A review of the literature was performed, searching the PubMed database for ‘Inflammatory Bowel Disease’, ‘Listeria’, ‘Anti TNF’, ‘Infliximab’, ‘Adalimumab’, ‘Certolizumab’ and ‘Colonoscopy’. Cases reported were analyzed, focusing on the following data: age, sex, type of IBD, ongoing treatment [anti-tumor necrosis factor (TNF)-α, corticosteroids, immunosuppressive agents], prior colonoscopy, clinical presentation, comorbidity, and outcome.
Ethical considerations Verbal and informed consent was obtained, and the informed consent form was signed by the investigator and patient before the patients were included in the study (when possible). This study was approved by the Ethical Committee of Gregorio Marañón and was in accordance with the current laws on patient data protection and medical behavior.
Results Three IBD patients had positive cultures for LM from January 1986 until January 2011 (Table 1).
All of them were male, and all of them had a diagnosis of CD. McCabe and Jackson criteria were used for analyzing comorbidity, obtaining a score of 1 in all individuals. Age at hospitalization with infection was 15, 47, and 67 years. All patients showed colon involvement, and one of them had perianal disease. All patients had a corticosteroid cumulated dose of more than 400 mg (of equivalent methylprednisolone); one patient was under anti-TNF-α treatment (subcutaneous certolizumab pegol, 400 mg at weeks 0, 2, and 4, and 400 mg 4 weeks later). None of them were under classical immunosuppressive therapy (e.g. azathioprine or methotrexate). Biological samples with LM isolates were taken before 48 h of hospitalization (what we denominated ‘out-of-hospital’ infection) in two patients. All patients were also admitted with digestive symptoms resembling IBD exacerbation. Clinical presentation of the infection was bacteremia in two patients, one with isolated bacteremia and the other with accompanying central nervous system infection (one patient developed rhombencephalitis, without positivity of the CSF culture). The other patient presented with meningoencephalitis without bacteremia. Antibiotics were initiated according to the etiological agent (ampicillin plus gentamicin or cotrimoxazol), and despite correct empiric treatment, one patient died from a cause related to the infection, that is, rombencephalitis refractory to medical treatment (patient 2, Table 1). In-hospital and 30-day mortality rate was 33%. Two patients had undergone colonoscopy in the previous 15 days before infection (12 and 2 days, respectively). The incidence of bacteremia due to LM in patients with IBD was calculated and compared with that in the general population in the same area, and an elevated incidence was observed in IBD patients (12.2 bacteremias/100 000 IBD patients/year, compared with 1.6 bacteremias/100 000 person-years), with an odds ratio (OR) of 7.4 in the IBD group compared with the general population.
Discussion Infections are probably the most important complication in IBD patients, being the second most common cause of death in this group of patients [5]. Several factors play a role in this situation, including chronic evolution of the disease, disease severity, treatment, malnutrition status, and surgical complications [6]. Immunomodulatory therapy, including corticosteroids, thiopurines, methotrexate, calcineurin inhibitors, anti-TNF-α,
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Listeria monocytogenes and IBD Miranda-Bautista et al. 1249
and other biological agents, increases the risk for infection. This can be related, among several reasons, to the common use of combination therapy with these agents. There is also an increased risk, depending on the number of therapies used concomitantly. A combination of immunomodulators increases the relative risk of presenting an infection compared with a single immunomodulator [OR 14.5 (95% confidence interval (CI) 4.9–43) and OR 2.9 (95% CI 1.5–5.3), respectively] [7]. A recent meta-analysis of randomized controlled trials [8] including 4135 patients who received anti-TNF-α therapy and 2919 patients administered placebo revealed opportunistic infections in 39 (0.9%) and nine (0.3%) patients, respectively, with a relative risk (RR) in the treatment group of 2.05 (95% CI 1.10–3.85). LM is a gram-positive intracellular obligated bacterium, identified in 0.8–3.4% of the asymptomatic population on stool analysis [9]. After ingestion, the bacteria reaches the intestinal mucosa and invades it, establishing systemic infection. Immunity against LM is mediated by activation of lymphocytes, T lymphokines, and macrophages [10,11]. The incidence of infection in the global population is between 0.25 [12] and 1.2 cases/100 000 people/ year [13], currently increasing in several European countries [2,14]. Sporadic disease is much more frequent when compared with outbreaks [15–18]. Most LM infections occur in patients with one or several risk factors: age [2,19], neoplasia, glucocorticoids and organ receptors [20], pregnancy [19], AIDS [11], treatment with anti-TNF-α drugs [21], diabetes mellitus [22–24], chronic renal dysfunction [25], iron overload [26,27], prior colonoscopy [3,4], liver disease, and alcoholism [24]. A recent review [28] has shown that of 266 published cases of LM infection among patients under anti-TNF-α therapies, 38% were IBD patients, and IFX was the most common drug used in these patients (95%); thus, it seems that the incidence of LM infection is increased among patients under anti-TNF-α therapy, especially among those under combined immunosuppressive therapies and during the first year after initiating treatment. Clinical manifestations are gastroenteritis and central nervous system infection. The incidence of positive cerebrospinal fluid cultures in patients affected with rombencephalitis was lower than that of positive blood cultures (41 vs. 61%) [13]. Eight of every 10 patients with meningitis had positive blood cultures [29], with varying percentages depending on the number of samples extracted. Hly gene, which codes for listeriolysin O, can be detected by PCR and has been approved for LM diagnosis in CSF samples [19]. Ampicillin plus gentamicin or trimethoprim sulfamethoxazole is considered first-line treatment, although combination therapy does not seem to have an impact on mortality and increases toxicity [2]. Overall, mortality is estimated between 15 and 30% [15,30–32].
After a review of the literature on LM infection and IBD, we found 6275 articles, with 61 finally selected as reviews or case reports including human patients and in English or Spanish. A total of 28 cases of LM infections in IBD patients (http://www.lareb.nl/LarebCorporateWebsite/media/ publicaties/kwb_2003_1_infli.pdf) [22,26,33–54] were found, which have been summarized in Table 2. Of the patients, 60% were male, between 17 and 78 years old, with a CD diagnosis in 57.1%. Twenty cases (71.4%) were on anti-TNF-α treatment, 19 with infliximab (IFX). Corticosteroids were being used at the time of infection in 23 patients (82.1%), and immunomodulatory therapy in 21 patients (75%), including 18 patients being treated with azathioprine (AZA) or 6-mercaptopurine. We also analyzed combination therapy, reporting triple immunosuppressive therapy in 13 patients (46.4%) and a combination of anti-TNF-α and any other drug in 20 patients (71.4%). Interestingly, none of the reported patients were on anti-TNF-α treatment alone. The remaining patients were under corticosteroid treatment (three), immunomodulatory therapy (two), or both (three). The majority had no comorbities. Prior colonoscopy had been performed in six patients (21.4%), although we could not find results on colonoscopy in four reports. Isolated bacteremia was the most common syndrome (10 cases, 35.7%), followed by bacteremia associated with central nervous system infection (eight cases, 28.5%), isolated central nervous system infection (seven cases, 25%), fulminant or subfulminant colitis (two cases), and bacteremia associated with a splenic abscess (one cases). Twenty-three patients (82.1%) recovered from the infection with treatment, three had neurologic sequelae, and two deaths were reported, all related to LM infection. Our case series is concordant with most features of the reported cases. We recognized a higher proportion of male (3 : 0) and CD patients (three); all patients showed colonic affection, with an important role of ongoing treatment. All patients were pharmacologically immunocompromised: two being treated with a single agent (corticosteroids) and one being treated with two agents (an anti-TNF drug plus corticosteroids). Notably, none of the patients were under azathioprine or 6-mercaptopurine treatment. The anti-TNF agent used was certolizumab at a habitual dosage during the 2 months of 400 mg at weeks 0, 2, and 4, and 200 mg 2 weeks later. The relationship between LM infection and exacerbation of IBD is a controversial issue. LM was confirmed in the resected colon of a patient with fulminant ulcerative colitis using PCR and subsequent Southern blot analysis and immunohistochemical analysis [34], although similar proportions of LM DNA in intestinal biopsies from IBD patients and non-IBD controls have been shown [55]. It is tempting to hypothesize that these patients had intestinal colonization of LM, and an inflammatory outbreak of the disease, in addition to immunosuppressive therapy and colonoscopy (if performed), can lead to an
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37/M 42/M 35/M 34/M
15 16 17 18
UC UC
CD CD UC UC UC UC
UC CD
IFX IFX
ADA/week IFX IFX No IFX No
No IFX
IFX IFX IFX IFX
IFX
IFX IFX IFX
IFX IFX IFX
No No No No IFX IFX No
Anti-TNF
2/5 weeks 3/9 weeks
1/0.2 week
Yes Yes
Yes No Yes Yes Yes No
Yes Yes
– 1/0.2 weeks 10/12 weeks 3/9 weeks 1/0.2 week
Yes Yes No No
Yes
Yes Yes Yes
Yes Yes Yes
Yes No Yes Yes Yes Yes Yes
Corticosteroids
2/5 weeks 2/2 weeks 2/4 weeks 12/46 weeks
2/4 weeks
1/1 week 1/1 week 1/0.2 week
1/2 weeks 1/1 week 3/6 weeks
3/7 weeks 1/0.5 weeks
Dose/Time of treatment Comorbidity
No No
MTX AZA 6MP AZA AZA AZA
AZA 6MP
AZA No AZA AZA
AZA
AZA No AZA
No No No No No Ischemic cardiopathy, AF No HIV on ART
No No
DM, ischemic cardiopathy, arthropathy No No No No
No No No
Citotoxic No ACTH No No No AZA No 6MP No No Ischemic cardiopathy, 40 cg/d smoker AZA No 6MP No 6MP No
IMM
Yes No
No No No No No No
Yes No
No No No No
No
Unknown Yes No
No Unknown Unknown
Unknown Yes Yes Yes No No No
Prior colonoscopy
Bacteremia + meningoencephalitis Bacteremia + meningitis
Bacteremia + meningitis Bacteremia Bacteremia + meningitis Meningitis Bacteremia Bacteremia
Bacteremia Meningoencefalitis
Bacteremia + meningitis Meningitis Meningitis Bacteremia + meningitis
Bacteremia
Meningitis Bacteremia + splenic abscess Meningitis
Meningitis Bacteremia Bacteremia + meningitis
Bacteremia Bacteremia Fulminant colitis Bacteremia Bacteremia Bacteremia + meningitis Toxic megacolon
Syndrome
Recovered Recovered
Recovered Recovered Recovered Alive/ventriculoatrial shunt/amnesia Recovered Alive/pulmonary microembolism Recovered Recovered Recovered Recovered Recovered Recovered
Recovered
Recovered Recovered Alive/paralysis of one eye Death Recovered Recovered
Death Recovered Recovered Recovered Recovered Recovered Recovered
Outcome
ADA, adalimumab; AF, atrial fibrillation; ART, antiretroviral therapy; AZA, azathioprine; CD, Crohn’s disease; DM, diabetes mellitus; F, female; IFX, infliximab; IMM, immunomodulatory therapy; M, male; 6MP, 6-mercaptopurine; MTX, methotrexate; UC, ulcerative colitis.
27 Abreu et al. [52] 28 Abreu et al. [52]
51/F 69/M
19/M 50/F 17/M 64/F 76/M 62/M
21 22 23 24 25 26
Gil et al. [48] Ramos et al. [49] Chuang et al. [50] Triantafillidis and Panteris [54] Katsanos and Zois [53] Kassalik et al. [51]
78/M 50/F
19 Minami et al. [46] 20 Izbéki et al. [47]
CD CD CD CD
CD
67/M
Williams et al. [42] Dederichs et al. [43] Osuna Molina et al. [44] Ramanampamonjy et al. [45]
CD CD CD
20/M 48/M 43/F
CD CD CD
UC UC UC UC CD CD UC
11 Slifman et al. [39] 12 Tweezer-Zaks et al. [40] 13 Lareb database (http://www.lareb.nl/ LarebCorporateWebsite/media/ publicaties/kwb_2003_1_infli.pdf) 14 De la Fuente et al. [41]
45/F 56/F 59/M 49/F 67/M 17/M 77/M
Age/Sex IBD
41/F 64/F 39/F
Samra et al. [22] Shemesh et al. [33] Chiba et al. [34] Witlox et al. [26] Morelli and Wilson [35] Kamath et al. [36] Jover Díaz et al. [37]
Reference
Previously reported cases of Listeria monocytogenes infection in inflammatory bowel disease patients
8 Joosten et al. [38] 9 Slifman et al. [39] 10 Slifman et al. [39]
1 2 3 4 5 6 7
N
Table 2
1250 European Journal of Gastroenterology & Hepatology 2014, Vol 26 No 11
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Listeria monocytogenes and IBD Miranda-Bautista et al. 1251
invasive LM infection, by traversing the weakened intestinal barrier. Most patients (66% in our series) were admitted to the hospital with an infection, and most patients (100% in our series) presented several clinical symptoms resembling IBD activity, not always accompanied by nervous system alterations. Hence, it is mandatory to extract blood cultures from IBD patients arriving at Emergency Services with fever or a suspicion of systemic infection. By identifying risk factors for LM infection (see above), clinicians may be able to recognize high-risk patients. In these cases, in which a suspected infected IBD patient is suffering an unfavorable evolution despite usual antibiotics (e.g. ciprofloxacin and metronidazole), infrequent infectious agents might not have been taken into account, and a change in treatment is mandatory. Prior colonoscopies with biopsies had been performed in two cases in our series (66%), compared with 21.4% described in the literature. Both of them were CD patients on corticosteroid treatment, which was combined with certolizumab in one case. The pathophysiological explanation might be bacterial translocation through the intestinal barrier during an aggression against colonic mucosa, in a probable LM-colonized colon. All cases in which a prior colonoscopy was reported in the literature had recovered from the infection (six in the revision, two in our series). No data has been published on prophylactic therapy in IBD patients with multiple risk factors, or before a colonoscopy in IBD patients. However, because of the potential severity, it may be acceptable to design a study essaying primary prophylaxis, for example, with TMP–SMX, in those patients with several risk factors (double or triple immunomodulatory therapy, > 65 years, pregnancy), or before colonoscopy, to decontaminate intestinal flora that may potentially lead to the development of systemic infection. Physicians should consider recommending these subgroups of patients to avoid foods that are potentially sources of LM (soft cheese, unpasteurized milk) and to reheat until steaming some readyto-eat foods (hot dogs, cold cuts) before eating [56]. However, the relationship between asymptomatic intestinal carriage and invasive disease observed in immunocompromised patients is not known. Secondary prophylactic treatment may also be acceptable, although the low incidence may make it difficult to perform a prospective study. The incidence of LM bacteremia in IBD patients seems to be increased compared with the general population, as shown in our results [12.2 bacteremias/100 000 IBD patient-years, compared with 1.6 bacteremiad/100 000 person-years, RR = 7.6 (95% CI 1.5–39.5)]. We also compared IBD patients under anti-TNF therapy during the period between 1986 and 2011 (n = 190) with IBD controls without biologic therapy (n = 899). The incidence
rate in the anti-TNF-α group was 21.1 listeriosis/100 000 patient-years, compared with 8.9 listeriosis/100 000 patient-years in the control group (RR = 2.33, 95% CI 0.21–25.57). The difference was not statistically different, probably because of the small number of cases, one and two cases, respectively. Finally, in our hospital area, from January 1986 to December 2007, 111 listeriosis cases were diagnosed in an average population of 657 972 individuals; 96 of them were LM bacteremias. The incidence is low as some long-term studies on IBD patients do not report cases of LM infection. This is the reason why collecting data from individual case series is the best way of understanding the real impact of this disease, and efforts in multicenter databases are warranted. Postmarketing safety of anti-TNF-α drugs was evaluated by Deepak et al. [57], who reviewed neurological events related to anti-TNF-α therapy reported to The Food and Drug Administration Adverse Event Reporting System. From January 2000 to December 2009, 772 neurological adverse events were identified, 140 of which were in IBD patients; only two cases of LM meningitis were reported, both in patients on infliximab therapy. A standardized registry is needed to prospectively collect data on all cases of LM infection in IBD patients and to individualize therapeutic and prophylaxis techniques, which may improve survival and decrease morbidity, as it is a growing entity in European countries, which can be potentially fatal. Our series emphasized a different point of view on LM infections in IBD patients. We include two more cases of LM infection after colonoscopy, and special attention should be paid in case symptoms that develop after this exploration; the first case was reported in a patient on certolizumab therapy. More studies are needed to develop recommendations on the management and prevention of LM infection in patients at risk for IBD.
Acknowledgements The authors thank specialists from ‘Servicio de Microbiología Hospital Gregorio Marañón’, who facilitated the recruitment of patients. Conflicts of interest
There are no conflicts of interest.
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32 33
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34 Chiba M, Fukushima T, Koganei K, Nakamura N, Masamune O. Listeria monocytogenes in the colon in a case of fulminant ulcerative colitis. Scand J Gastroenterol 1998; 33:778–782. 35 Morelli J, Wilson FA. Does administration of infliximab increase susceptibility to listeriosis? Am J Gastroenterol 2000; 95:841–842. 36 Kamath BM, Mamula P, Baldassano RN, Markowitz JE. Listeria meningitis after treatment with infliximab. J Pediatr Gastroenterol Nutr 2002; 34:410–412. 37 Jover Diaz F, Laveda Cano R, Martinez Egea A, et al. Listeria monocytogenes and ulcerative colitis. Rev Clin Esp 2002; 202:123–125. 38 Joosten AA, van Olffen GH, Hageman G. Meningitis due to Listeria monocytogenes as a complication of infliximab therapy. Ned Tijdschr Geneeskd 2003; 147:1470–1472. 39 Slifman NR, Gershon SK, Lee JH, Edwards ET, Braun MM. Listeria monocytogenes infection as a complication of treatment with tumor necrosis factor alpha-neutralizing agents. Arthritis Rheum 2003; 48:319–324. 40 Tweezer-Zaks N, Shiloach E, Spivak A, Rapoport M, Novis B, Langevitz P. Listeria monocytogenes sepsis in patients treated with anti-tumor necrosis factor-alpha. Isr Med Assoc J 2003; 5:829–830. 41 de la Fuente Penco B, Marcó Piella A, Riera Mestre A, Boadas Mir J. Sepsis caused by Listeria monocytogenes related with the use of infliximab. Med Clin (Barc).; 2005. 124:p. 398. 42 Williams G, Khan AA, Schweiger F. Listeria meningitis complicating infliximab treatment for Crohn’s disease. Can J Infect Dis Med Microbiol 2005; 16:289–292. 43 Dederichs F, Pinciu F, Gerhard H, Eveld K, Stallmach A. Listeria meningitis in a patient with Crohn’s disease – a seldom, but clinically relevant adverse event of therapy with infliximab. Z Gastroenterol 2006; 44:657–660. 44 Osuna Molina R, Ferrer Rios T, Gallego Gallegos R, Ramos Lora M, Ynfante Ferrús M, Figueruela López B. Listeria meningitis as complication of treatment with infliximab in a patient with Crohn’s disease. Rev Esp Enferm Dig 2006; 98:60–61. 45 Ramanampamonjy RM, Laharie D, Bonnefoy B, Amouretti M. Infliximab therapy in Crohn’s disease complicated by Listeria monocytogenes meningoencephalitis. Gastroenterol Clin Biol 2006; 30:157–158. 46 Minami M, Hasegawa T, Ando T, Maeda O, Ohkura T, Ohta M, Goto H. Postcolonoscopic listeria septicemia in ulcerative colitis during immunosuppressive therapy. Intern Med 2007; 46:2023–2027. 47 Izbéki F, Nagy F, Szepes Z, Kiss I, Lonovics J, Molnár T. Severe listeria meningoencephalitis in an infliximab-treated patient with Crohn’s disease. Inflamm Bowel Dis 2008; 14:429–431. 48 Gil C, Legido J, Cuenca C, Santamaría A, Sacristán MV, Salvatierra C, et al. Meningitis due to Listeria monocytogenes during adalimumab therapy. Gastroenterol Hepatol 2009; 32:587–588. 49 Ramos JM, García-Sepulcre MF, Masiá M, Brotons A, Grau MC, Gutiérrez F. Listeria monocytogenes infection in patients with inflammatory bowel diseases receiving anti-tumor necrosis factor therapy. Rev Esp Enferm Dig 2010; 102:614–616. 50 Chuang MH, Singh J, Ashouri N, Katz MH, Arrieta AC. Listeria meningitis after infliximab treatment of ulcerative colitis. J Pediatr Gastroenterol Nutr 2010; 50:337–339. 51 Kassalik M, Fry LC, Didowacz-Grollmann A, Mousalli S, Mönkemüller K. Listeria monocytogenes sepsis in ulcerative colitis. Endoscopy 2012; 44 (Suppl 2 UCTN):E219–E220. 52 Abreu C, Magro F, Vilas-Boas F, Lopes S, Macedo G, Sarmento A. Listeria infection in patients on anti-TNF treatment: report of two cases and review of the literature. J Crohns Colitis 2013; 7:175–182. 53 Katsanos KHKM, Zois CD. Listeria monocytogenes infection two days after infliximab initiation in a patient with ulcerative colitis. Ann Gastroenterol 2010; 23:209–210. 54 Triantafillidis JSM, Panteris V. Listeria meningitis in an immunocompromised patient with ulcerative colitis: a report of a case and review of the literature. Ann Gastroenterol 2010; 23:205–208. 55 Chen W, Li D, Paulus B, Wilson I, Chadwick VS. Detection of Listeria monocytogenes by polymerase chain reaction in intestinal mucosal biopsies from patients with inflammatory bowel disease and controls. J Gastroenterol Hepatol 2000; 15:1145–1150. 56 Dave M, Purohit T, Razonable R, Loftus EV Jr. Opportunistic infections due to inflammatory bowel disease therapy. Inflamm Bowel Dis 2014; 20:196–212. 57 Deepak P, Stobaugh DJ, Sherid M, Sifuentes H, Ehrenpreis ED. Neurological events with tumour necrosis factor alpha inhibitors reported to the Food and Drug Administration Adverse Event Reporting System. Aliment Pharmacol Ther 2013; 38:388–396.
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Listeria monocytogenes infection in inflammatory bowel disease patients: case series and review of the literature José Miranda-Bautistaa, Camilo Padilla-Suáreza, Emilio Bouzab, Patricia Muñozb, Luis Menchéna,c,d and Ignacio Marín-Jiméneza,d Background Listeria monocytogenes (LM) is a grampositive intracellular bacillus that in immunodeficient patients, children, geriatric patients, pregnant women, and even in healthy individuals can cause central nervous system infection, bacteremia, and other clinical manifestations, becoming a relevant pathogen.
treatment, one patient died from a cause related to the infection, that is, rombencephalitis. Increased incidence of LM bacteremia was found in IBD patients, compared with the general population (12.2 bacteremias/100 000 IBD patient-years, compared with 1.6 bacteremias/100 000 person-years), with an odds ratio of 7.4.
Materials and methods From the Microbiology Service data of ‘Gregorio Marañón’ Hospital, we selected all positive biological sample cultures for LM from inflammatory bowel disease (IBD) patients, from January 1986 until January 2011. These cases were included in an SPSS database, analyzing several basal clinical characteristics and factors related to the infection.
Conclusion IBD patients may be at risk for more frequent and serious LM infection compared with the general population. Eur J Gastroenterol Hepatol 26:1247–1252 © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.
Results Three patients diagnosed with IBD had positive cultures for LM during this period. All of them were male, and also all of them had a diagnosis of Crohn’s disease. Every patient had a corticosteroid cumulated dose of more than 400 mg (equivalency in methylprednisolone doses), adding anti-tumor necrosis factor-α treatment (certolizumab) in one patient. Prior colonoscopy with biopsy was performed in two patients. Clinical presentation of the infection was bacteremia in two patients, accompanied by central nervous system infection in one patient. One patient had isolated meningoencephalitis. Despite correct empiric
Introduction Inflammatory bowel disease (IBD), which includes Crohn’s disease (CD) and ulcerative colitis, is a chronic inflammatory disease of the gastrointestinal tract and is characterized by recurrent ulceration of different parts of the bowel [1]. IBD treatment is continuously changing, with new molecules that target different steps of the inflammatory cascade being developed. This, added to chronic disease behavior, malnutrition, and comorbidities, can reduce the ability of the organism to fight against micro-organisms, leading to an increase in the risk for infections in IBD patients, even those whose pathogenic capacity is minimal or inexistent under ordinary circumstances. These opportunistic infections represent a difficult challenge for clinicians, concerning early diagnosis, adequate treatment, and an effort to improve immunity without harming clinically controlled IBD. Morbidity and mortality of these opportunistic infections are not 0954-691X © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
European Journal of Gastroenterology & Hepatology 2014, 26:1247–1252 Keywords: Anti-tumor necrosis factor-α drugs, colonoscopy, inflammatory bowel disease, Listeria a
Digestive Diseases Service, bMicrobiology and Infectious Diseases Services, “Gregorio Marañón” General University Hospital, Health Investigation Institute “Gregorio Marañón” (IISGM), cOn-line Hepatic and Digestive Diseases Research Centre (CIBERehd), Carlos III Health Institute and dDepartment of Medicine, “Complutense” University, Madrid, Spain Correspondence to Ignacio Marín, MD, Digestive Diseases Service, “Gregorio Marañón” General University Hospital, Health Investigation Institute “Gregorio Marañón” (IISGM), C/Dr, Esquerdo 46, 28007 Madrid, Spain Tel: + 34 915 868 300; fax: + 34 915 868 018; e-mail: [email protected] Received 28 May 2014 Accepted 18 July 2014
negligible; hence, increasing the knowledge on these entities is mandatory for current clinical practice. Listeria monocytogenes (LM) is a gram-positive bacillus that in immunodeficient patients, children or geriatric patients, and in pregnant women can cause central nervous system infection, bacteremia, and other clinical manifestations, becoming a relevant pathogen [2]. Prior colonoscopy is another risk factor for the development of LM infection [3,4]. We hypothesize that IBD patients are a subgroup of high-risk patients with a high incidence of IBD.
Materials and methods From Microbiology Service data of ‘Gregorio Marañón’ Hospital, we selected retrospectively all positive cultures for LM in normally sterile body fluids from IBD patients, including blood, cerebrospinal fluid (CSF), amniotic fluid, and other biological samples, from January 1986 until January 2011. The methods used for sampling, transporting, and processing blood cultures and for identification of isolates were standard. Blood culture DOI: 10.1097/MEG.0000000000000188
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1248
Table 1
European Journal of Gastroenterology & Hepatology 2014, Vol 26 No 11
Resumed patients’ history and evolution
Case (n) Age/Sex
IBD
Anti-TNF
Dose/Time Prior of treatment Corticosteroids IMM Comorbidity colonoscopy
1
47/M
CD (A2L1B3p) Certolizumab 4/2 months
Yes
No
No
2 3
67/M 15/M
CD CD (A2L2B1)
Yes Yes
No No
No No
No No
Syndrome
Outcome
Yes (2 days Bacteremia Recovered before) No Bacteremia + romboencephalitis Death Yes (12 days Meningoencephalitis Recovered before)
CD, Crohn’s disease; IBD, inflammatory bowel disease; IMM, immunomodulatory therapy; M, male.
laboratory processing systems varied during this period. From 1986 to 1995, BACTEC NR-640 was used (Johnston Laboratories Inc., Towson, Maryland, USA). From 1995 to 2011, blood cultures were processed using BACTEC 9240 (Becton Dickinson Microbiology Systems, Towson, Maryland, USA), which is more automatic and includes continuous shaking. All positive samples were subcultured and Gram stained. These cases were included in an SPSS software package (SPSS 20.0; SPSS Inc., Chicago, Illinois, USA), analyzing clinical basal characteristics (age, sex, type of IBD, Montreal Classification, comorbidity using Mc Cabe and Jackson criteria, type and doses of IBD treatment) and factors related to the infection (time of presentation, clinical manifestation, positive cultures, treatment, and outcome). On the basis of data from the ‘Gregorio Marañón’ database IBD registry, those from the Health Ministry on the population attended to in our hospital area, and those from the Microbiology Service registry, we calculated the incidence of bacteremia in the general population of our health area and compared it with the incidence in the IBD population. A review of the literature was performed, searching the PubMed database for ‘Inflammatory Bowel Disease’, ‘Listeria’, ‘Anti TNF’, ‘Infliximab’, ‘Adalimumab’, ‘Certolizumab’ and ‘Colonoscopy’. Cases reported were analyzed, focusing on the following data: age, sex, type of IBD, ongoing treatment [anti-tumor necrosis factor (TNF)-α, corticosteroids, immunosuppressive agents], prior colonoscopy, clinical presentation, comorbidity, and outcome.
Ethical considerations Verbal and informed consent was obtained, and the informed consent form was signed by the investigator and patient before the patients were included in the study (when possible). This study was approved by the Ethical Committee of Gregorio Marañón and was in accordance with the current laws on patient data protection and medical behavior.
Results Three IBD patients had positive cultures for LM from January 1986 until January 2011 (Table 1).
All of them were male, and all of them had a diagnosis of CD. McCabe and Jackson criteria were used for analyzing comorbidity, obtaining a score of 1 in all individuals. Age at hospitalization with infection was 15, 47, and 67 years. All patients showed colon involvement, and one of them had perianal disease. All patients had a corticosteroid cumulated dose of more than 400 mg (of equivalent methylprednisolone); one patient was under anti-TNF-α treatment (subcutaneous certolizumab pegol, 400 mg at weeks 0, 2, and 4, and 400 mg 4 weeks later). None of them were under classical immunosuppressive therapy (e.g. azathioprine or methotrexate). Biological samples with LM isolates were taken before 48 h of hospitalization (what we denominated ‘out-of-hospital’ infection) in two patients. All patients were also admitted with digestive symptoms resembling IBD exacerbation. Clinical presentation of the infection was bacteremia in two patients, one with isolated bacteremia and the other with accompanying central nervous system infection (one patient developed rhombencephalitis, without positivity of the CSF culture). The other patient presented with meningoencephalitis without bacteremia. Antibiotics were initiated according to the etiological agent (ampicillin plus gentamicin or cotrimoxazol), and despite correct empiric treatment, one patient died from a cause related to the infection, that is, rombencephalitis refractory to medical treatment (patient 2, Table 1). In-hospital and 30-day mortality rate was 33%. Two patients had undergone colonoscopy in the previous 15 days before infection (12 and 2 days, respectively). The incidence of bacteremia due to LM in patients with IBD was calculated and compared with that in the general population in the same area, and an elevated incidence was observed in IBD patients (12.2 bacteremias/100 000 IBD patients/year, compared with 1.6 bacteremias/100 000 person-years), with an odds ratio (OR) of 7.4 in the IBD group compared with the general population.
Discussion Infections are probably the most important complication in IBD patients, being the second most common cause of death in this group of patients [5]. Several factors play a role in this situation, including chronic evolution of the disease, disease severity, treatment, malnutrition status, and surgical complications [6]. Immunomodulatory therapy, including corticosteroids, thiopurines, methotrexate, calcineurin inhibitors, anti-TNF-α,
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Listeria monocytogenes and IBD Miranda-Bautista et al. 1249
and other biological agents, increases the risk for infection. This can be related, among several reasons, to the common use of combination therapy with these agents. There is also an increased risk, depending on the number of therapies used concomitantly. A combination of immunomodulators increases the relative risk of presenting an infection compared with a single immunomodulator [OR 14.5 (95% confidence interval (CI) 4.9–43) and OR 2.9 (95% CI 1.5–5.3), respectively] [7]. A recent meta-analysis of randomized controlled trials [8] including 4135 patients who received anti-TNF-α therapy and 2919 patients administered placebo revealed opportunistic infections in 39 (0.9%) and nine (0.3%) patients, respectively, with a relative risk (RR) in the treatment group of 2.05 (95% CI 1.10–3.85). LM is a gram-positive intracellular obligated bacterium, identified in 0.8–3.4% of the asymptomatic population on stool analysis [9]. After ingestion, the bacteria reaches the intestinal mucosa and invades it, establishing systemic infection. Immunity against LM is mediated by activation of lymphocytes, T lymphokines, and macrophages [10,11]. The incidence of infection in the global population is between 0.25 [12] and 1.2 cases/100 000 people/ year [13], currently increasing in several European countries [2,14]. Sporadic disease is much more frequent when compared with outbreaks [15–18]. Most LM infections occur in patients with one or several risk factors: age [2,19], neoplasia, glucocorticoids and organ receptors [20], pregnancy [19], AIDS [11], treatment with anti-TNF-α drugs [21], diabetes mellitus [22–24], chronic renal dysfunction [25], iron overload [26,27], prior colonoscopy [3,4], liver disease, and alcoholism [24]. A recent review [28] has shown that of 266 published cases of LM infection among patients under anti-TNF-α therapies, 38% were IBD patients, and IFX was the most common drug used in these patients (95%); thus, it seems that the incidence of LM infection is increased among patients under anti-TNF-α therapy, especially among those under combined immunosuppressive therapies and during the first year after initiating treatment. Clinical manifestations are gastroenteritis and central nervous system infection. The incidence of positive cerebrospinal fluid cultures in patients affected with rombencephalitis was lower than that of positive blood cultures (41 vs. 61%) [13]. Eight of every 10 patients with meningitis had positive blood cultures [29], with varying percentages depending on the number of samples extracted. Hly gene, which codes for listeriolysin O, can be detected by PCR and has been approved for LM diagnosis in CSF samples [19]. Ampicillin plus gentamicin or trimethoprim sulfamethoxazole is considered first-line treatment, although combination therapy does not seem to have an impact on mortality and increases toxicity [2]. Overall, mortality is estimated between 15 and 30% [15,30–32].
After a review of the literature on LM infection and IBD, we found 6275 articles, with 61 finally selected as reviews or case reports including human patients and in English or Spanish. A total of 28 cases of LM infections in IBD patients (http://www.lareb.nl/LarebCorporateWebsite/media/ publicaties/kwb_2003_1_infli.pdf) [22,26,33–54] were found, which have been summarized in Table 2. Of the patients, 60% were male, between 17 and 78 years old, with a CD diagnosis in 57.1%. Twenty cases (71.4%) were on anti-TNF-α treatment, 19 with infliximab (IFX). Corticosteroids were being used at the time of infection in 23 patients (82.1%), and immunomodulatory therapy in 21 patients (75%), including 18 patients being treated with azathioprine (AZA) or 6-mercaptopurine. We also analyzed combination therapy, reporting triple immunosuppressive therapy in 13 patients (46.4%) and a combination of anti-TNF-α and any other drug in 20 patients (71.4%). Interestingly, none of the reported patients were on anti-TNF-α treatment alone. The remaining patients were under corticosteroid treatment (three), immunomodulatory therapy (two), or both (three). The majority had no comorbities. Prior colonoscopy had been performed in six patients (21.4%), although we could not find results on colonoscopy in four reports. Isolated bacteremia was the most common syndrome (10 cases, 35.7%), followed by bacteremia associated with central nervous system infection (eight cases, 28.5%), isolated central nervous system infection (seven cases, 25%), fulminant or subfulminant colitis (two cases), and bacteremia associated with a splenic abscess (one cases). Twenty-three patients (82.1%) recovered from the infection with treatment, three had neurologic sequelae, and two deaths were reported, all related to LM infection. Our case series is concordant with most features of the reported cases. We recognized a higher proportion of male (3 : 0) and CD patients (three); all patients showed colonic affection, with an important role of ongoing treatment. All patients were pharmacologically immunocompromised: two being treated with a single agent (corticosteroids) and one being treated with two agents (an anti-TNF drug plus corticosteroids). Notably, none of the patients were under azathioprine or 6-mercaptopurine treatment. The anti-TNF agent used was certolizumab at a habitual dosage during the 2 months of 400 mg at weeks 0, 2, and 4, and 200 mg 2 weeks later. The relationship between LM infection and exacerbation of IBD is a controversial issue. LM was confirmed in the resected colon of a patient with fulminant ulcerative colitis using PCR and subsequent Southern blot analysis and immunohistochemical analysis [34], although similar proportions of LM DNA in intestinal biopsies from IBD patients and non-IBD controls have been shown [55]. It is tempting to hypothesize that these patients had intestinal colonization of LM, and an inflammatory outbreak of the disease, in addition to immunosuppressive therapy and colonoscopy (if performed), can lead to an
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37/M 42/M 35/M 34/M
15 16 17 18
UC UC
CD CD UC UC UC UC
UC CD
IFX IFX
ADA/week IFX IFX No IFX No
No IFX
IFX IFX IFX IFX
IFX
IFX IFX IFX
IFX IFX IFX
No No No No IFX IFX No
Anti-TNF
2/5 weeks 3/9 weeks
1/0.2 week
Yes Yes
Yes No Yes Yes Yes No
Yes Yes
– 1/0.2 weeks 10/12 weeks 3/9 weeks 1/0.2 week
Yes Yes No No
Yes
Yes Yes Yes
Yes Yes Yes
Yes No Yes Yes Yes Yes Yes
Corticosteroids
2/5 weeks 2/2 weeks 2/4 weeks 12/46 weeks
2/4 weeks
1/1 week 1/1 week 1/0.2 week
1/2 weeks 1/1 week 3/6 weeks
3/7 weeks 1/0.5 weeks
Dose/Time of treatment Comorbidity
No No
MTX AZA 6MP AZA AZA AZA
AZA 6MP
AZA No AZA AZA
AZA
AZA No AZA
No No No No No Ischemic cardiopathy, AF No HIV on ART
No No
DM, ischemic cardiopathy, arthropathy No No No No
No No No
Citotoxic No ACTH No No No AZA No 6MP No No Ischemic cardiopathy, 40 cg/d smoker AZA No 6MP No 6MP No
IMM
Yes No
No No No No No No
Yes No
No No No No
No
Unknown Yes No
No Unknown Unknown
Unknown Yes Yes Yes No No No
Prior colonoscopy
Bacteremia + meningoencephalitis Bacteremia + meningitis
Bacteremia + meningitis Bacteremia Bacteremia + meningitis Meningitis Bacteremia Bacteremia
Bacteremia Meningoencefalitis
Bacteremia + meningitis Meningitis Meningitis Bacteremia + meningitis
Bacteremia
Meningitis Bacteremia + splenic abscess Meningitis
Meningitis Bacteremia Bacteremia + meningitis
Bacteremia Bacteremia Fulminant colitis Bacteremia Bacteremia Bacteremia + meningitis Toxic megacolon
Syndrome
Recovered Recovered
Recovered Recovered Recovered Alive/ventriculoatrial shunt/amnesia Recovered Alive/pulmonary microembolism Recovered Recovered Recovered Recovered Recovered Recovered
Recovered
Recovered Recovered Alive/paralysis of one eye Death Recovered Recovered
Death Recovered Recovered Recovered Recovered Recovered Recovered
Outcome
ADA, adalimumab; AF, atrial fibrillation; ART, antiretroviral therapy; AZA, azathioprine; CD, Crohn’s disease; DM, diabetes mellitus; F, female; IFX, infliximab; IMM, immunomodulatory therapy; M, male; 6MP, 6-mercaptopurine; MTX, methotrexate; UC, ulcerative colitis.
27 Abreu et al. [52] 28 Abreu et al. [52]
51/F 69/M
19/M 50/F 17/M 64/F 76/M 62/M
21 22 23 24 25 26
Gil et al. [48] Ramos et al. [49] Chuang et al. [50] Triantafillidis and Panteris [54] Katsanos and Zois [53] Kassalik et al. [51]
78/M 50/F
19 Minami et al. [46] 20 Izbéki et al. [47]
CD CD CD CD
CD
67/M
Williams et al. [42] Dederichs et al. [43] Osuna Molina et al. [44] Ramanampamonjy et al. [45]
CD CD CD
20/M 48/M 43/F
CD CD CD
UC UC UC UC CD CD UC
11 Slifman et al. [39] 12 Tweezer-Zaks et al. [40] 13 Lareb database (http://www.lareb.nl/ LarebCorporateWebsite/media/ publicaties/kwb_2003_1_infli.pdf) 14 De la Fuente et al. [41]
45/F 56/F 59/M 49/F 67/M 17/M 77/M
Age/Sex IBD
41/F 64/F 39/F
Samra et al. [22] Shemesh et al. [33] Chiba et al. [34] Witlox et al. [26] Morelli and Wilson [35] Kamath et al. [36] Jover Díaz et al. [37]
Reference
Previously reported cases of Listeria monocytogenes infection in inflammatory bowel disease patients
8 Joosten et al. [38] 9 Slifman et al. [39] 10 Slifman et al. [39]
1 2 3 4 5 6 7
N
Table 2
1250 European Journal of Gastroenterology & Hepatology 2014, Vol 26 No 11
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Listeria monocytogenes and IBD Miranda-Bautista et al. 1251
invasive LM infection, by traversing the weakened intestinal barrier. Most patients (66% in our series) were admitted to the hospital with an infection, and most patients (100% in our series) presented several clinical symptoms resembling IBD activity, not always accompanied by nervous system alterations. Hence, it is mandatory to extract blood cultures from IBD patients arriving at Emergency Services with fever or a suspicion of systemic infection. By identifying risk factors for LM infection (see above), clinicians may be able to recognize high-risk patients. In these cases, in which a suspected infected IBD patient is suffering an unfavorable evolution despite usual antibiotics (e.g. ciprofloxacin and metronidazole), infrequent infectious agents might not have been taken into account, and a change in treatment is mandatory. Prior colonoscopies with biopsies had been performed in two cases in our series (66%), compared with 21.4% described in the literature. Both of them were CD patients on corticosteroid treatment, which was combined with certolizumab in one case. The pathophysiological explanation might be bacterial translocation through the intestinal barrier during an aggression against colonic mucosa, in a probable LM-colonized colon. All cases in which a prior colonoscopy was reported in the literature had recovered from the infection (six in the revision, two in our series). No data has been published on prophylactic therapy in IBD patients with multiple risk factors, or before a colonoscopy in IBD patients. However, because of the potential severity, it may be acceptable to design a study essaying primary prophylaxis, for example, with TMP–SMX, in those patients with several risk factors (double or triple immunomodulatory therapy, > 65 years, pregnancy), or before colonoscopy, to decontaminate intestinal flora that may potentially lead to the development of systemic infection. Physicians should consider recommending these subgroups of patients to avoid foods that are potentially sources of LM (soft cheese, unpasteurized milk) and to reheat until steaming some readyto-eat foods (hot dogs, cold cuts) before eating [56]. However, the relationship between asymptomatic intestinal carriage and invasive disease observed in immunocompromised patients is not known. Secondary prophylactic treatment may also be acceptable, although the low incidence may make it difficult to perform a prospective study. The incidence of LM bacteremia in IBD patients seems to be increased compared with the general population, as shown in our results [12.2 bacteremias/100 000 IBD patient-years, compared with 1.6 bacteremiad/100 000 person-years, RR = 7.6 (95% CI 1.5–39.5)]. We also compared IBD patients under anti-TNF therapy during the period between 1986 and 2011 (n = 190) with IBD controls without biologic therapy (n = 899). The incidence
rate in the anti-TNF-α group was 21.1 listeriosis/100 000 patient-years, compared with 8.9 listeriosis/100 000 patient-years in the control group (RR = 2.33, 95% CI 0.21–25.57). The difference was not statistically different, probably because of the small number of cases, one and two cases, respectively. Finally, in our hospital area, from January 1986 to December 2007, 111 listeriosis cases were diagnosed in an average population of 657 972 individuals; 96 of them were LM bacteremias. The incidence is low as some long-term studies on IBD patients do not report cases of LM infection. This is the reason why collecting data from individual case series is the best way of understanding the real impact of this disease, and efforts in multicenter databases are warranted. Postmarketing safety of anti-TNF-α drugs was evaluated by Deepak et al. [57], who reviewed neurological events related to anti-TNF-α therapy reported to The Food and Drug Administration Adverse Event Reporting System. From January 2000 to December 2009, 772 neurological adverse events were identified, 140 of which were in IBD patients; only two cases of LM meningitis were reported, both in patients on infliximab therapy. A standardized registry is needed to prospectively collect data on all cases of LM infection in IBD patients and to individualize therapeutic and prophylaxis techniques, which may improve survival and decrease morbidity, as it is a growing entity in European countries, which can be potentially fatal. Our series emphasized a different point of view on LM infections in IBD patients. We include two more cases of LM infection after colonoscopy, and special attention should be paid in case symptoms that develop after this exploration; the first case was reported in a patient on certolizumab therapy. More studies are needed to develop recommendations on the management and prevention of LM infection in patients at risk for IBD.
Acknowledgements The authors thank specialists from ‘Servicio de Microbiología Hospital Gregorio Marañón’, who facilitated the recruitment of patients. Conflicts of interest
There are no conflicts of interest.
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