DEDICATÓRIA
Gostaria de agradecer ao Professor António Sarmento pelo empenho e disponibilidade demonstrados ao longo da elaboração deste trabalho.
Gostaria também de agradecer aos meus pais e à minha família pelo apoio constante ao longo dos anos e quilómetros.
FACULDADE DE MEDICINA DA UNIVERSIDADE DO PORTO
MESTRADO INTEGRADO EM MEDICINA
ANO LECTIVO 2017/18
DISSERTAÇÃO/ MONOGRAFIA
TRABALHO ELABORADO DE ACORDO COM AS NORMAS DA REVISTA
“INFECÇÃO E SEPSIS”
ORIENTADOR: PROF. ANTÓNIO SARMENTO
TITLE
A systematic review on serious infections by the intracellular bacterial pathogens
Legionella, Listeria, and Salmonella in patients receiving anti-TNF therapy
TÍTULO
Revisão sistemática das infecções graves pelas bactérias patogénicas intracelulares
AUTHORS/ TITLES/ DEPARTMENT/ CONTACT INFO
Luis Bicheiro, PhD
Faculty of Medicine, University of Porto, Portugal lbicheiro@igc.gulbenkian.pt
António Sarmento, MD, PhD
Department of Infectious Diseases, Hospital S. João, Portugal Faculty of Medicine, University of Porto, Portugal
ABSTRACT
Anti-TNF- agents are widely used in inflammatory diseases and have been associated with serious intracellular infections. This study is aimed at characterising the clinical presentation, analysing the treatment options, and assessing the different outcomes of infections by the intracellular bacteria Legionella, Listeria, and Salmonella in patients treated with anti-TNFs.
PubMed/MEDLINE was used to search for peer-reviewed papers of relevance. This study found 70 papers which fulfilled the criteria, in which 31 cases of serious infection by
Legionella, 57 cases of serious infection by Listeria, and 16 cases of serious infection by Salmonella were described.
The overwhelming majority of the patients taking anti-TNFs with serious infection were also receiving concomitant immunosuppressive drugs, especially steroids. The typical patient is a male in his 50s, suffering from RA, and taking Infliximab. All of the patients infected with Legionella had pneumonia and were treated with either a quinolone, or a macrolide, or a combination involving at least one of them. The majority of patients infected with Listeria had bacteremia and/ or meningitis and/ or CNS involvement; they were mainly treated with ampicillin +/- gentamicin or amoxicillin +/- gentamicin. The majority of patients infected with Salmonella had bacteremia, being septic arthritis also very common; most were treated with fluoroquinolones. Altogether, 17 patients died, and others developed complications.
A very important step towards successfully treating these patients is to achieve an accurate diagnosis quickly; instituting effective empirical antibiotic therapy is also paramount.
RESUMO
Os agentes anti-TNF- são muito usados em doenças inflamatórias e estão associados a infecções intracelulares graves. Este trabalho tem por objectivo a
caracterização da apresentação clínica, a análise das opções de tratamento e a avaliação das consequências das infecções pelas bactérias intracelulares Legionella, Listeria e Salmonella em doentes tratados com anti-TNFs.
Neste trabalho recorreu-se ao PubMed/MEDLINE para a procura de artigos revistos por pares relevantes, tendo sido encontrados 70 artigos que cumpriram os critérios e que apresentavam 31 casos de infecção grave por Legionella, 57 casos de infecção grave por
Listeria e 16 casos de infecção grave por Salmonella.
A maioria dos doentes medicados com agentes anti-TNF e que sofreram infecção grave estavam a tomar outros fármacos imunossupressores, especialmente esteróides. O doente típico é homem, com mais de 50 anos de idade, com artrite reumatóide e medicado com infliximab. Todos os doentes infectados com Legionella apresentaram pneumonia e foram tratados com uma quinolona, ou um macrólido, ou uma combinação com pelo menos um deles. A maioria dos doentes com infecção por Listeria apresentaram bacteremia e/ ou meningite e/ ou envolvimento do SNC, tendo sido a maior parte das vezes tratados com ampicilina +/- gentamicina ou amoxicilina +/- gentamicina. A maioria dos doentes com infecção por Salmonella apresentou bacteremia, sendo a artrite séptica uma apresentação também bastante comum; a maioria foi tratada com fluoroquinolonas. Ao todo, morreram 17 doentes, tendo outros desenvolvido complicações.
Um passo muito importante para o tratamento eficaz destes doentes é chegar ao diagnóstico correcto rapidamente; igualmente importante é instituir terapêutica antibiótica empírica adequada.
KEYWORDS
Adalimumab, Certolizumab, Etanercept, Golimumab, Infliximab, Legionellosis, Listeriosis, and Salmonellosis.
PALAVRAS-CHAVE
Adalimumab, Certolizumab, Etanercept, Golimumab, Infliximab, Legionelose, Listeriose e Salmonelose.
INTRODUCTION
Tumor necrosis factor alpha (TNF-) is a key regulator of Th1 responses to intracellular pathogens, playing an equally important role in the regulation of innate immunity and induction of the inflammatory response. TNF- is synthesized by activated macrophages and T cells, being subsequently cleaved to form soluble TNF-. Biologically active TNF- requires aggregation of three TNF- monomers, which then act by binding TNFR1 or TNFR2, which stimulate production of inflammatory cytokines, chemokines and endothelial adhesion molecules[1].
TNF- is important for recruitment of neutrophils and macrophages, differentiation of monocytes into macrophages, activation of phagosome and macrophages, formation and maintenance of granuloma integrity. Mycobacterium species, Histoplasma capsulatum and other intracellular pathogens are not readily killed by the host’s immune system; they are sequestered in granulomas, which are made of a central core of macrophages,
multinucleated giant cells and necrotic debris enveloped by macrophages and lymphocytes[2].
In excess, TNF- leads to inadequate inflammation and tissue damage, thus, dysregulated TNF- can contribute to several pathological conditions, namely rheumatoid arthritis (RA), ankylosing spondylitis (AS), psoriatic arthritis, psoriasis, Crohn’s disease (CD) and ulcerative colitis (UC)[1]. Studies concerning the role of TNF- in these diseases led to the development of therapies based on TNF- blockage.
Presently there are five TNF- inhibitors (anti-TNFs) approved for the treatment of a variety of inflammatory diseases. Adalimumab is a human monoclonal anti-TNF
antibody; it binds both monomeric and trimeric TNF-. Certolizumab is the antigen-binding fragment of a humanized monoclonal antibody coupled to polyethylene glycol; the
antibody-dependent cellular cytotoxicity. Etanercept is a fusion protein consisting of two TNFR2 coupled to the constant region of IgG1, acting as a soluble TNF- receptor, binding to trimeric TNF- and lymphotoxin; it has the shortest half-life of the five (3 days versus 8-14 days). Golimumab is a human monoclonal anti-TNF antibody. Infliximab is a mouse-human chimeric monoclonal anti-TNF antibody; it binds both monomeric and trimeric TNF-; it is the only of the five which is administered intravenously[3].
The five anti-TNFs bind both the soluble (sTNF) and transmembrane (mTNF) bioactive forms of TNF-. Binding to mTNF can have an agonistic action, initiating reverse signalling leading to cytokine suppression, cell cycle arrest and/ or apoptosis. Binding to mTNF can also lead to complement-dependent-cytotoxicity and antibody-dependent cell-mediated cytotoxicity (ADCC). It is thought the therapeutic consequences of the anti-TNFs come from sequestration of sTNF, accelerated efflux of cells from target sites, induction of apoptosis (but not with Certolizumab), ADCC (but not with
Certolizumab), or a mix of these. Etanercept has reduced potential to disrupt granuloma but also reduces the number of memory B cells, comparing to the other four anti-TNFs; at least in part, this is due to binding the mTNF with decreased affinity or avidity, unlike the other anti-TNFs[3].
Skin reactions characterized by itching, pain, redness, irritation, bruising, or swelling at the site of injection are common but usually minor problems with subcutaneously administered agents (Adalimumab, Certolizumab, Etanercept and
Golimumab). Infliximab is associated with non-allergic acute (<24h) and delayed (1-14d) infusion reactions such as skin rash, joint pain, myalgia and fatigue[2]. Other adverse effects
of the anti-TNFs include mild neutropenia, infections, demyelinating disease, heart failure, malignancy and induction of autoimmunity[2].
The importance of TNF in host defense has led to an awareness of potential infection risk. The incidence of serious infection (infection requiring intravenous
antibiotics or hospitalisation) has been reported to be significantly higher in patients taking anti-TNFs when compared to patients taking glucocorticoids or other non-anti-TNF
immunosuppressors[4]. The risk of tuberculosis reactivation with anti-TNF therapy is well established and the original findings led to the development of screening and prophylaxis protocols before the start of anti-TNF therapy[5],[6]. As expected, there is an enhanced risk of infection with other intracellular bacteria as well (such as Listeria, Salmonella,
Legionella, and Nocardia), with fungi (such as Candida albicans, Aspergillus fumigatus, Pneumocystis jirovecii, Cryptococcus, Coccidioides, and Histoplasma capsulatum), and
with virus (such as hepatitis B and herpes zoster virus) [7],[8].
As TNF- is important for the maintenance of granuloma, TNF- inhibitors allow the breakdown of granuloma and subsequent reactivation and dissemination of the
pathogens. Also, TNF- neutralization with monoclonal antibodies results in a reduced synthesis of interferon (IFN)-γ, which leads to a reduced expression of Toll-like receptor 4 (TLR-4) and defective cellular immune response. As recognition of microorganisms by TLR-4 and activation of macrophages by IFN-γ are fundamental mechanisms for the defense against intracellular pathogens, their inhibition by anti-TNFs leads to increased infections by these agents[9].
Pathogenic bacteria, which can cause disease, may be able to infect their host in an acute or chronic fashion. Intracellular bacteria are characterised by entering host cells’, usually macrophages, using this intracellular habitat in order to avoid antibody responses, among others. Considering macrophages are notorious for their pathogen detection and killing functions, this is somewhat of a paradox. In fact, living in such a hostile
environment requires the use of different strategies, namely influencing host processes such as membrane trafficking, signalling pathways, metabolism, autophagy and apoptosis[10].
Among the obligatory intracellular pathogenic bacteria we find Chlamydia,
Ehrlichia, and Rickettsia. Among the facultative intracellular pathogenic bacteria we find
Legionella pneumophila (a Gram negative [G-]), Listeria (G+), Mycobacterium,
Salmonella (G-), Neisseria (G-), Brucella (G-), Nocardia (G+), Francisella (G-) and Yersinia pestis (G-).
The broad grouping of intracellular bacteria colonizes two topologically distinct regions of the host cell, being thus subdivided into cytosolic and intravacuolar bacteria[11]. Cytosolic bacteria, such as Francisella tularensis and Listeria monocytogenes, escape from the endocytic pathway and replicate in the host cytosol. Intravacuolar bacteria, such as
Brucella spp, L. pneumophila, Mycobacterium tuberculosis and Salmonella enterica, reside
and replicate within the host endomembrane system; this is accompanied by expansion of the vacuolar membrane and has the added benefit of being protected from the host
cytosolic innate immune defenses[10].
Following entry, vacuoles containing invading bacteria diverge from the
phagolysosomal pathway; bacteria will then target multiple host’s components in order to maintain the integrity of the vacuole. One of the main challenges intravacuolar bacteria face is to exert actions beyond the vacuolar membrane; this is accomplished by secreting effectors outside of it through secreting systems, such as Salmonella’s type III secretion system (T3SS), and L. pneumophila’s type IV secretion system (T4SS). Furthermore, secretion systems are also involved in invasion of the host’s cells and the evasion of the phagolysosome. L. pneumophila segregates from the endocytic route, recruit endoplasmic reticulum-derived vesicles, and form ribosome-studded specialized vacuoles in a T4SS-dependent manner. S. enterica replicates in a late endosome-like compartment that
excludes lysosomal degradation enzymes; the S. enterica containing vacuole migrates to the microtubule-organizing centre and forms Salmonella-induced filaments along microtubules in a T3SS-dependent manner. Manipulation of autophagy and apoptosis occurs[10].
For entry into host epithelial cells, L. monocytogenes, a cytosolic bacterium, requires interaction between E-cadherin and internalin A (a bacterial surface protein). L.
monocytogenes escapes the phagolysosomal pathway using the type II secretion system
(T2SS) effectors listeriolysin and phospholipase C (PLC), which promote vacuolar
membrane disruption. In the cytosol, L. monocytogenes manipulates host sensing pathways to avoid detection, autophagy and cell death, replicating rapidly and hijacking the host actin polymerization machinery to move within and between cells[10].
A review of the Adverse Event Reporting System of the US Food and Drug Administration (AERSUSFDA) between 1998-2002 revealed a high frequency of granulomatous infections in patients taking Infliximab or Etanercept. On the
aforementioned period, there were 38 serious infections by Listeria and 11 by Salmonella in patients receiving anti-TNFs reported to the AERSUSFDA[7]. Similarly, between 1999 and 2010, 80 cases of serious infection by Legionella in patients receiving anti-TNFs, were reported to the AERSUSFDA. These three agents were found to be the top bacterial
pathogens, excluding Mycobacterium sp, in the population of anti-TNF takers, causing high morbidity and mortality. In fact, perhaps more important than the numbers were the
uncommon presentations of these infections that soon after started to be described in the peer-reviewed literature.
Given the increased risk of serious infection by the intracellular bacteria Legionella,
analysing the treatment options, and assessing the different outcomes of these infections in patients treated with anti-TNFs.
METHODS
PubMed/MEDLINE was used to search for records of relevance for this review. The search queries included medical subject headings and keywords where appropriate; the terms “anti-TNF”, “Adalimumab”, “Certolizumab”, “Etanercept”, “Golimumab”, “Infliximab” were combined with each of the pathogenic agents or causative disease: “Legionella” or “Legionellosis”, “Listeria” or “Listeriosis”, and “Salmonella” or
“Salmonellosis”. The last search was conducted on 30 September 2017. Some records were identified through the reference section of previously query-identified papers. In short, after identifying records of potential interest, these were put to a process of selection as indicated in Figure 1: randomized controlled trials (RCTs), observational studies (OSs) and case reports reporting infection with either Legionella, Listeria or Salmonella in humans receiving anti-TNFs were to be retrieved and used in this systematic review, while records without access to full text, without comprehensible language or without data on the patients or data on the course of the infection were to be excluded. Altogether, 70 papers were found that fulfilled the criteria: 19 papers reporting legionellosis in anti-TNF-treated humans were included in this review (Table 1); 37 papers reporting listeriosis in anti-TNF-treated humans were included in this review (Table 2); 15 papers reporting salmonellosis in anti-TNF-treated humans were included in this review (Table 3) one paper is included in both Table 2 and Table 3.
RESULTS AND DISCUSSION
Legionellosis
Legionellosis refers to Pontiac fever (acute and self-limited illness) and Legionnaire´s disease (pneumonia), which are the two human diseases caused by
Legionella sp; L. pneumophila is responsible for 80-90% of the cases[82].
This study has found 31 cases of serious infection by L. pneumophila in patients taking anti-TNF medication published in the peer-reviewed literature (Table 1). Of these, 55% of the patients were male and 45% were female. The mean age of the patients was 54 years, while the youngest was 26 and the oldest 78 years old. Infliximab was associated to 55% of the cases, Adalimumab to 35% and Etanercept to 10%; Certolizumab and
Golimumab were not associated to any of the cases. Interestingly, a study which used the national registry of France on biotherapies found there is a higher risk for legionellosis in patients taking anti-TNFs than the general french population[5] and another study found there is a higher risk for legionellosis in patients taking Infliximab or Adalimumab, versus Etanercept[83]. The same study also found that patients taking anti-TNF medication in general have a risk for L. pneumophila infection 13,1 times higher than the general
population. That study also found that patients taking anti-TNF medication who developed Legionnaire’s disease were younger and had a lower mortality rate than the general
population who developed Legionnaire’s disease; in both populations there were more men than women developing Legionnaire’s disease[83].
Of the 31 cases retrieved in this study, 17 (55%) had RA, 5 (16%) had CD, and the remaining patients had either psoriasis, psoriatic arthritis, SLE, UC, Behcet’s disease or pyoderma gangrenosum as indication for administration of the anti-TNF therapy. Only 4 patients were not taking any other immunosuppressive drug at the time of the infection. Of those receiving concomitant immunosuppressive drugs, corticosteroids were the most
common, with 58% taking them, either alone or with other immunosuppressive drugs; 48% of the patients were taking MTX; and other patients were taking azathioprine,
sulphasalazine, 6-mercaptopurine and/ or others. The dosage, timing and duration of anti-TNF and other immunosuppressive therapies has been discussed elsewhere[5],[7],[83],[84] and
is not the focus of this study.
Most of the patients identified had several co-morbidities, apart from the condition which was the reason for anti-TNF treatment and apart from immunosuppression. The most common issue with these patients is a long history of smoking, while some had COPD, diverting colostomy, enterocutaneous fistula, and others. In fact, immunosuppression, chronic lung disease, tobacco, >65 years old, and discharge from hospital around 10 days before first pneumonia symptoms are risk factors for Legionnaire’s disease; in 28% of cases with Legionnaire’s disease, these risk factors are not present[85].
At the time of legionellosis diagnosis none of the papers reported continuation of anti-TNF therapy. Stopping anti-TNF therapy is a sound initial approach towards infection treatment in these patients and should be recommended. Anti-TNF therapy was restarted in 5 patients[14],[26],[28],[29],[30], some 6 weeks, others one year after the end of the infection treatment; two papers reported discontinuation of anti-TNF therapy[15],[21]; and the remaining papers did not mention whether anti-TNF therapy was restarted or not. In one case[26], the patient experienced a second episode of Legionnaire’s disease after
re-introduction of Infliximab. The decision to re-introduce anti-TNF should be worked out case by case, measuring risk versus benefit, but this limited sample does not warrant permanent absence of anti-TNF treatment based on legionellosis.
Most of the cases decribed here are community-acquired pneumonia, but there are also three cases of hospital-acquired pneumonia[20],[23]. Legionella is in the top 4 causes of
patients with nosocomial pneumonia[82]. The natural habitats for L. pneumophila are aquatic rivers and lakes, but they proliferate more after entering man-made aquatic
reservoirs. Legionella infection may occur through aspiration or inhalation of contaminated aerosols produced by cooling towers, public baths, decorative fountains, humidifiers or faucets[82]. In most cases here described, the origin of the infection was never identified; in one case, the suspected source was a public bath. Guidelines for preventing legionellosis in patients taking anti-TNFs are not available; however, reducing exposure to aerosolized untreated water sources, such as fountains is reasonable; and also reasonable is minimizing exposure to public baths.
After entering the lungs, L. pneumophila attaches to host cells via bacterial type IV pili, heat-shock proteins, a major outer-membrane protein and complement. Macrophages phagocytose L. pneumophila and enhance neutrophil recruitment. L. pneumophila evades intracellular killing by inhibiting phagosome-lysosome fusion. The humoral immune system is activated against Legionella, with IgM and IgG antibodies measurable in the first weeks of infection[86]. In all cases retrieved by this study, the target organ was the lung, and the disease of presentation was pneumonia. Fever was present in all patients while some patients had shortness of breath, cough and chest pain. Many patients also developed extrapulmonary symptoms such as vomiting, abdominal pain, diarrhea, headache, myalgia, fatigue and others. All patients had abnormal chest radiograph’s showing pulmonary infiltrates; 16 patients had unilateral pneumonia, 7 had bilateral pneumonia, and 4 pleural effusion. CT chest scan revealed in many cases ground-glass opacity. Laboratory analysis revealed in many, but all cases, elevated CRP and elevated leucocyte count. Crackles and/ wheezes could be heard in many, but not all patients. These findings are also present in immunocompetent patients with Legionnaire’s disease and, as in such patients, are also nonspecific, not allowing to distinguish from pneumonia of other etiologies; however,
temperature > 39ºC, diarrhea, neurologic findings and unresponsiveness to beta-lactamic drugs (penicillins and cephalosporins) and aminoglycosides occur more frequently are thus suggestive clues of Legionnaire’s disease.
Early diagnosis is important in the treatment of pneumonia by L. pneumophila. In the papers analysed in this study, L. pneumophila was successfully identified in all but one case, in which bacteria from the genus Legionella was without doubt identified,
nonetheless. Laboratory confirmation of legionellosis can be achieved by antigen detection in urine, immunofluorescence testing, polymerase chain reaction, culture of respiratory secretions and serology. The urine antigen test is rapid and has high sensibility and specificity, making it the primary method for detection; however, it only works for serogroup 1 (SG1), while there are 16 SGs[87]. The non-reactivity of the urine antigen test towards other SGs markedly delays the diagnostic of pneumonia by Legionella as members of the Legionellaceae do not grow on routine microbiologic media; growing them in
Wadowsky-Yee-Okuda medium (which allows the detection of the other SGs) is the definitive method for diagnosis but requires a high degree of suspicion and takes 3-5 days. If this translates in a delay in instituting the appropriate antibiotics for Legionella
pneumonia, the mortality increases significantly. In the papers analysed in this study, the most used method of identification was the urinary antigen test (23 positively identified cases), but culture in Wadowsky-Yee-Okuda medium was also widely used. Also in this study, the main SG identified was SG1, with 74% of the reported cases; serogroups 2, 3, 4, 5, 6, 7, 8 and 10 were also identified; in 4 cases no data regarding the SG was reported. SG1 is globally responsible for 80-86% of Legionnaire´s disease.
All of the patients retrieved by this study were treated for Legionnaire’s disease with either a quinolone, or a macrolide, or a combination involving at least one of them. Roughly speaking, the patients were subjected to either quinolone alone (5 patients), or
macrolide alone (4 patients), or macrolide and quinolone (4 patients), or quinolone and rifampicin (7 patients), or macrolide and rifampicin (two patients), or quinolone and other non-macrolide nor rifampicin (4 patients); 5 patient’s data on antibiotic treatment are absent. Some of the quinolones used were levofloxacin, pazufloxacin, moxifloxacin and ofloxacin. Some of the macrolides used were azithromycin, erythromycin and
clarithromycin. The preferred route to administer the antibiotics was the intravenous one (IV) with a few patients receiving them orally (o). The majority of patients were treated for three weeks; some successfully treated patients received their antibiotics for as little as 10 days while others for as long as 9 weeks.
Most of the papers did not state which empirical therapy (if any) was given. At least 5 patients received empirical antibiotic treatment for pneumonia (before Legionella was identified as the pathogen). Four of these[17],[20],[21],[24] included a macrolide, and after positive identification of Legionella were switched anyway to specific treatment, which is listed in Table 1; one patient was initially treated with imipenem, which was switched two days later for vancomycin + levofloxacin; however, at day 7, the patient died of septic shock and multiorgan failure[27].
That particular case re-iterates the importance of a quick diagnosis of Legionnaire’s disease and the importance of an expedient administration of appropriate antimicrobial therapy. Since not always is possible to identify L. pneumophila (this was a case of SG4,10 hence the urinary antigen test came back negative), all patients with pneumonia who are being treated with anti-TNFs should receive first-line antibiotic therapy that is active against Legionella (such as a fluoroquinolone or a macrolide, as either is capable of attaining high intracellular concentrations). For instance, for community-acquired
pneumonia in non-ICU inpatients: moxifloxacin 400mg/24h (IV) or ceftriaxone 2g/24h (IV) + azithromycin 500mg/24h (IV) (the first dose should be doubled) is recommended by the
Infectious Diseases Society of America. Upon identification of L. pneumophila as the etiological agent, the antibiotic regimen should change to a macrolide, or a quinolone, or a combination of both; rifampicin may also be used, but always in association with one the first two. Initial therapy should be given by IV route. In the immunocompetent patient the total duration of therapy is 10-14 days, with clinical response occurring within 3-5 days and complete clearing of infiltrates requiring 1-4 months. For the immunosuppressed patient, as we have seen, administering a longer course of antibiotics (three weeks) seems to be the preferred alternative. Whether to administer monotherapy or a combination of antibiotics depends largely on the clinician’s evaluation of the severity of the pneumonia; for critically ill patients it is common practice to use combination regimens. Some of the recommended dosages are as follows: azithromycin 500mg/24h (IV) (the first dose should be doubled), levofloxacin 750mg/24h (IV), rifampicin 300-600mg/12h (o or IV)[86].
In the cases reviewed by this study, many patients developed acute respiratory distress syndrome and a few developed pulmonary abscess, bacteremia, septic shock and multiorgan failure. Those that survived, recovered fully. Altogether, 7 patients died (23%). For instance, in immunocompetent patients, mortality rates from community-acquired Legionnaire’s disease usually go no further than 11%[86], which makes the mortality in
patients treated with anti-TNFs a high mortality rate. Immunosuppression is a known risk factor for negative outcome; however the timing of administration of appropriate
antimicrobial therapy, the patient’s underlying disease, and the severity of pneumonia also influence prognosis[86].
Let’s take a closer look at other cases which also resulted in death. In the case described by Hayashi et al[15], the patient was successfully treated with pazufloxacin 1g IV daily for 10 days and discharged; however, the L. pneumophila pneumonia relapsed at day 55, this time with deep mycosis, and the patient died 24 days later. In the case described by
Kaku2013, the patient died within 24h after admission; post-mortem blood culture revealed bacteremia as well. In the case of the 59 year old man described by Hofmann et al[20], the pulmonary infiltrates found on the initial inspection evolved to abscess formation over the next days (at this time he was being treated with piperacillin-tazobactam 3,375g IV every 6h and ciprofloxacin 400mg every 12h, the etiological agent of the pneumonia having not yet been identified); the patient was indicated to open lung biopsy, although the
identification of L. pneumophila was achieved first through the urinary antigen test; while staying in the ICU he developed candidemia, and cytomegalovirus, Pseudomonas
aeruginosa and vancomycin-resistant Enterococcus sp were also identified in the patient’s
samples; he was treated with azithromycin 500mg IV daily as well as adequate antibiotics for the other pathogens; however the patient’s status worsened and he died. In the case described by Kohn et al[23] the patient died 8 days after admission by septic shock; he had developed pulmonary abscess. As we can see from these cases, death as an outcome of L.
pneumophila pneumonia seems to be more likely when Legionnaire’s disease is fulminant
or severe, complicated by concomitant infections, pulmonary abscess or bacteremia. This further highlights the need to act preventively and act promptly.
Listeriosis
This study has found 57 cases of serious infection by Listeria in patients taking anti-TNF medication published in the peer-reviewed literature (Table 2). Of these, 54% of the patients were male and 46% were female. The mean age of the patients was 56 years, while the youngest was 17 and the oldest 87 years old. Infliximab was associated with 79% of the cases, Etanercept with 12%, Adalimumab with 7% and Certolizumab with 2%; Golimumab was not associated with any of the cases. These percentages are very similar to the ones found in a 2013 study which included case reports and adverse reaction databases data, heralding 266 cases of Listeria infection in patients taking biologicals (anti-TNFs and
others)[88]: Infliximab was associated with 77% of the cases, Etanercept with 12% and Adalimumab with 10%. Serious infection with Listeria does seem to be much more common in Infliximab-treated patients than in patients taking any other anti-TNF.
Indications for the use of anti-TNFs in the 57 patients included in this study are as follows: 25 (44%) had RA, 18 (32%) had CD, 6 (11%) had UC, 4 (7%) had psoriatic arthritis, and the remaining patients had AS, Still’s disease, or unstated disease. Eighty-four percent of these patients were receiving concomitant immunosuppressive drugs, especially steroids (70%), MTX (40%) and/ or azathioprine (16%); fifty-six percent of patients were taking two or more distinct immunosuppressors apart from the anti-TNF. The dosage, timing and duration of anti-TNF and other immunosuppressive therapies and its relation with the onset of infection has been approached elsewhere[42],[88] and is not the focus of this study.
None of the papers report continuation of anti-TNF therapy during the severe infection episode. Stopping anti-TNF therapy is a sound initial approach towards infection treatment in these patients and should be recommended. There are 8 cases in which the fate of TNF therapy is clearly stated; of these, 5 authors opted for non-reintroducing anti-TNF therapy while three patients received further anti-anti-TNF therapy after finishing infection treatment; none of these three were reported to suffer from infection recurrence. The
decision to re-introduce anti-TNF should be worked out case by case, measuring risk versus benefit; this study does not warrant permanent exclusion of anti-TNF treatment based on one episode of listeriosis.
L. monocytogenes can present as several clinical syndromes, such as gastroenteritis,
bacteremia, meningitis and/ or focal CNS infection. In this study, bacteremia was found to be the most common type of serious infection, affecting 31 patients (54%); meningitis, affecting 25 patients (44%), was the second most common; other patients had
meningoencephalitis, rhombencephalitis, brain abscess, encephalitis, hydrocephalus, septic arthritis, cholecystitis, and/ or others; indeed, 17 patients (30%) had more than one
manifestation of Listeria infection. L. monocytogenes infection with involvement of the meningeal membranes (meningitis or meningoencephalitis), rhombencephalitis or brain abscess may occur in up to 47% of infected patients[89].
Symptoms of listeriosis overlap greatly with those of other infectious diseases. However, immunocompetent patients frequently present with nonspecific flu-like symptoms, lymphadenopathy, and gastrointestinal symptoms, while immunosuppressed patients are more prone to develop bacteremia and/ or meningitis[90]. Bacteremic
presentation typically has fever, chills and myalgia/ arthralgia. Meningitic presentation is more frequently subacute than in other bacterial etiologies, but CSF does show elevated white blood cell count, elevated protein levels, and low glucose levels. Rhombencephalitis caused by L. monocytogenes may affect equally healthy, immunocompetent patients; it typically has a biphasic presentation with a prodrome of headache, nausea, vomiting, and fever, although elderly and/ or immunosuppressed patients with meningoencephalitis may not manifest a fever; neurologic signs signify the end of the prodrome[91]; CSF can be normal or can more frequently show pleocytosis and elevation in protein; CT imaging can demonstrate small brainstem abscesses, brainstem hypodensities, widening of the brainstem, or hydrocephalus or can be normal; MR imaging can show increased intensities on T2 sequences[92].
Diagnosing in time requires considering the disease in the following risk
groups: >65 years old, pregnant women, neonates, immunosuppressed, and patients with certain chronical conditions (diabetes, renal disease, etc.). Meningitis in those over 60 years of age should trigger consideration of L. monocytogenes as the etiological agent, regardless of immunosuppression. In UC or CD patients with active disease, fever may not result from
infection but from non-infectious inflammatory process, turning more difficult to tell apart infection from a flare of the underlying illness; these patients provide additional diagnostic challenge within the anti-TNF-treated population. Clinicians must be able to identify early signs of this serious infection in patients taking anti-TNFs. If these patients show headache, fever or new-onset neurological signs, clinicians should go for a thourough assessment; immediate empirical antibiotic therapy should be started, and Listeria should be considered as the possible etiological agent. The diagnosis is usually achieved by CSF or blood
culture[86].
Of the cases retrieved by this systematic review, thirty patients were treated with ampicillin, either alone (11 patients) or in combination. Amoxicillin was given to 8 patients, either alone or in combination. Gentamicin was given to 21 patients, but always in
combination with another antibiotic, mainly ampicillin (15 patients). Altogether, 10 patients received only the combination ampicillin + gentamicin. Meropenem, benzylpenicillin, co-trimoxazole, and others were also used. The treatment of septic arthritis was, in all cases, completed with arthroscopic lavage and debridement. Similarly, the treatment of cholecystitis was, in all cases, completed with cholecystectomy. Most of the papers do not state what, if any, empiric therapy was administered; meropenem was given empirically to 3 patients with meningitis/ CNS involvement; one patient under 65 years old with meningitis received ceftriaxone, which was changed after identification of
Listeria; in fact, in all these cases, once the pathogen was identified, empirical therapy was
changed to the one stated in Table 2. All patients received their antibiotics via IV, at least on the first days of specific treatment; while some later changed to oral antibiotics, others finished the course with IV antibiotics as well. The duration of therapy varied from as little as 10 days to as much as 18 weeks; typically, a patient with bacteremia was treated for two
weeks, a patient with meningitis for three weeks, and a patient with CNS involvement for at least 4 weeks.
L. monocytogenes is susceptible to all common antibiotics (in vitro), but not to
cephalosporins. Antibiotic regimens used have included a combination of ampicillin 2g/6h (IV) and gentamicin 80mg tds (IV), or amoxicillin 2g qds (IV) and gentamicin, although optimal therapy has not been established in controlled clinical trials; the addition of an aminoglycoside is recommended in serious infection because the penicillins alone are not bactericidal against this organism; as such, gentamicin is usually added due to its
synergistic bactericidal effect. Meropenem and penicillin have good in vitro activity against
L. monocytogenes, and are occasionally used[93]. For the penicillin-allergic patient, the
bactericidal co-trimoxazole is an alternative, and erythromycin another[38],[39]. Treatment takes two weeks for bacteremia, three weeks for meningitis, and 6-8 weeks for other types of CNS involvement. For meningitis in the immunosuppressed, some suggest three weeks of IV treatment plus three weeks of oral treatment[39]. Empirical treatment for meningitis in
all those over 60 years is ampicillin + cefotaxime or ceftriaxone, which covers L.
monocytogenes. In those taking anti-TNFs, L. monocytogenes should be considered as
possible etiological agent and, as such, these patients should also receive empirical treatment that covers this agent, regardless of age. Optimal treatment of prosthetic joint infection includes debridement and resection of infected tissues within the first weeks of symptoms, prosthesis removal, antimicrobial therapy for 6 weeks, and re-implantation of a new prosthesis[48].
Of the 57 patients with Listeria infection described in this systematic review, 8 died, which corresponds to 14%. This percentage is very similar to the 16% mortality rate found in the 2013 study with 266 cases of Listeria infection previously mentioned[88]. In the
two Etanercept was the anti-TNF. Although rarer occurrences, encephalitis,
rhombencephalitis and meningoencephalitis are associated with three deaths; meningitis is associated with 4 deaths; and bacteremia, either alone or associated with one of the former is also associated with fatalities. Furthermore, this study also shows that infections with involvement of the CNS resulted in a few cases of survival with permanent neurological sequelae. It has been shown that CNS involvement is an independent risk factor for mortality in L. monocytogenes infections[94]. The development of CNS sequelae, which is rare in the general population, is partially dependent on infected macrophages spreading the intracellular bacterium cell-to-cell within neurons[95].
Human infections with L. monocytogenes occur mainly via ingestion of contaminated processed and unprocessed foods of animal and plant origin. L.
monocytogenes induces its own internalization by cells that are not normally phagocytic.
An essential determinant of its pathogenicity is listeriolisin, which mediates the rupture of the phagosomal membrane formed after phagocytosis. Bacteria that survive the bactericidal activity of macrophages grow in the cytosol and spread from cell to cell. Another important protein, ActA, allows the bacteria to move intra- and extra-cellularly via nucleation of the host’s actin filaments. Neutrophils are fundamental to host defense during the first 24h of infection; later on, migration of activated macrophages from the bone marrow is crucial. DCs also play a role in the early steps of enteral L. monocytogenes infection; furthermore, DCs, along with macrophages, are a major cellular constituent of the outer ring wall of suppurative granulomas in human listeriosis. Immunity is cell-mediated (CD8+ T cells doing the recognition and lysing the infected cells); humoral immunity plays no role[96]. L.
monocytogenes is reportedly capable of entering the CNS by: direct invasion of endothelial
cells, transport across the bloodbrain barrier within leukocytes, and migration into the brain within the axons of cranial nerves[95].
Use of co-trimoxazole prophylaxis against Pneumocystis jirovecii is recommended if patients are prescribed triple immunosuppression including either a calcineurin inhibitor or an anti-TNF; in cases of dual immunosuppression, prophylaxis should still be considered, particularly with use of a calcineurin inhibitor[97]. As co-trimoxazole may also be of use in
the prophylaxis against Listeria, Legionella and Toxoplasma[98], its use could potentially reduce the number of cases of Listeria in high risk individuals. Furthermore, patients taking anti-TNFs should be advised to avoid certain foods such as unpasteurized dairy products and to reheat until steaming processed meats, as a way to minimise the risk of acquiring this infection[32],[33].
Salmonellosis
This study has found 16 cases of serious infection by Salmonella in patients taking anti-TNF medication published in the peer-reviewed literature (Table 3). Of these, 69% of the patients were male and 31% were female. The mean age of the patients was 57 years, while the youngest was 31 and the oldest 74 years old. Infliximab was associated with 63% of the cases, Etanercept to 19%, Adalimumab to 12% and Certolizumab to 6%; Golimumab was not associated with any of the cases.
Of the 16 cases retrieved in this study, 11 (69%) had RA, 3 (19%) had CD, and the remaining patients had either psoriatic arthritis or IBD as indication for administration of the anti-TNF therapy. Only 2 patients were not taking any other immunosuppressive drug at the time of the infection. Of those receiving concomitant immunosuppressive drugs, MTX was the most common, with 6 patients taking it, either alone or with other
immunosuppressive drugs; 5 patients were taking corticosteroids; and other patients were taking azathioprine, 6-mercaptopurine and/ or hidroxichloroquine; 4 patients had no data reporting to concomitant immunosuppressive therapy. The dosage, timing and duration of anti-TNF and other immunosuppressive therapies is not the focus of this study.
Most of the patients had several co-morbidities, such as hypertension,
atherosclerosis, non-alcoholic steatohepatitis, total knee arthroplasty, cholecystectomy, partial colectomy, loop ileostomy and anti-acid therapy, apart from the condition which was the reason for anti-TNF treatment, and apart from immunosuppression. In fact, conditions that are reported to increase susceptibility to Salmonella infection include decreased stomach acidity and decreased intestinal integrity[86].
At the time of salmonellosis diagnosis none of the papers reported continuation of anti-TNF therapy. Stopping anti-TNF therapy is a sound initial approach towards infection treatment in these patients and should be recommended. Anti-TNF therapy was restarted in two patients[50],[76], after the end of the infection treatment; these two patients did not suffer from recurrence of Salmonella infection; three papers reported discontinuation of anti-TNF therapy[71],[72],[73]; and the remaining papers did not mention whether anti-TNF therapy was restarted or not. The decision to re-introduce anti-TNFs should be worked out case by case, measuring risk versus benefit, but this limited sample does not warrant permanent absence of anti-TNF treatment based on salmonellosis.
All members of Salmonella are now grouped into only two species: S. bongori and
S. enterica. S. enterica has 6 subspecies and each subspecies has associated serotypes. Most
of the human pathogenic Salmonella serotypes belong to the enterica subspecies; these serotypes include S. Typhi, S. Paratyphi, and nontyphoidal Salmonella (NTS) serotypes: S. Enteritidis, S. Typhimurium, S. Choleraesuis, and others. S. Typhi and S. Paratyphi, whose growth only occurs in humans, cause enteric (aka typhoid) fever. The remaining serotypes, which are able to colonize the gastrointestinal tracts of a wide range of animals, namely humans, may cause nontyphoidal salmonellosis. Over 16 million cases of enteric fever occur worldwide, with 500 000 fatalities per year, while NTS cases go up to 800 million, with 3 million fatalities[99]. Identification of serotypes can be helped by agglutination
testing, which defines specific O-antigen serogroups: A, B, C1, C2, D and E; strains in these serogroups cause nearly all Salmonella infections in humans; S. Enteritidis, S. Typhi and others are serogroup D, for instance[86].
Only one patient out of the 16 cases retrieved by this study developed infection with an enteric fever-causing serotype, S. Paratyphi. The most common serotype found in this study was S. Enteritidis, affecting 6 patients. Other NTS serotypes found include S.
Typhimurium (2 patients), S. Choleraesuis (one patient) and one other NTS serotype; there were also 3 patients with S. Group D, one patient with S. enterica and one patient with an undetermined species of Salmonella. In the USA, S. Typhimurium is the main serotype associated with salmonellosis, with 23% of infections, and S. Enteritidis is the second one, with 16% of infections. S. Choleraesuis is extremely rare in the USA, although it’s the second commonest Salmonella causing human disease in Taiwan[86],[69]. Enteric fever has become rare in developed countries, being transmitted via water or food which has become contaminated by feces from ill or asymptomatic chronic human carriers. NTS, on the other hand, is quite common in developed and underdeveloped countries alike, and is mostly associated with uncooked products of animal origin and other products contaminated with animal waste.
Six of the patients retrieved by this study had travelled to a developing country shortly before the onset of salmonellosis’ symptoms; many of these patients were also able to confirm consumption of undercooked foods. One patient, who never left the UK,
confirmed consumption of partially cooked eggs from a local free range farm[50]. In 9 papers there was no data available on the possible source of Salmonella infection.
Travellers to developing countries are advised to monitor their food and water intake and consider immunisation against S. Typhi. Patients under anti-TNF therapy should take extra care when travelling abroad, specially to developing countries. Although quality control of
food is an area of growing concern and improvement worldwide, these patients should take extra measures, such as avoid eating raw eggs, or undercooked meat products. Some authors have proposed screening for Salmonella fecal colonization[71], others considering even the possibility of routine co-trimoxazole prophylaxis[98].
Enteric fever serotypes, after reaching the small intestine, penetrate the mucus layer and traverse through M cells that reside within Peyer’s patches; after crossing the epithelial layer, they are phagocytosed by macrophages; they may disseminate throughout the body in macrophages via the lymphatics and colonize the reticuloendothelial system[86].
Comparatively, NTS gastroenteritis is characterized by polymorphonuclear leukocyte infiltration into the large- and small-bowel mucosa, while in enteric fever infiltration of mononuclear cells into the small-bowel mucosa occurs. Both enteric fever and NTS
serotypes can lie dormant in the reticuloendothelial system and eventually reactivating after immunosuppression. Salmonellosis can present in 5 major forms: enteric fever,
gastroenteritis, bacteremia, focal disease, and a carrier state. Enteric fever is a systemic disease characterized by abdominal pain and fever, being caused by dissemination of S. Typhi or S. Paratyphi; other common symptoms include headache, anorexia, chills, cough, diarrhea, sweating, nausea, myalgia, vomiting and others. Infection with NTS usually leads to gastroenteritis indistinguishable from that caused by other enteric pathogens,
characterized by nausea, vomiting, diarrhea, abdominal cramping and fever[86]. Bacteremia
occurs in as much as 8% of patients with NTS gastroenteritis and up to 10% of these develop localized infections; both these complications are more common in the young, the old, and the immunocompromised. Chronic asymptomatic carriers occur with both enteric and NTS serotypes, in as up to 0,6% of patients previously infected with Salmonella, carriage being more common in females, the young, and persons with biliary
In the present study, bacteremia was found to be the most common type of serious infection, affecting 9 patients (56%); septic arthritis was the second most common, affecting 8 patients (two patients were found with septic arthritis and bacteremia). Other patients had urosepsis, pleural empyema and/ or soft tissue infection. The most affected joint in the septic arthritis subgroup was the knee, with 5 cases; other sites include the elbow, pubic symphysis and a Baker’s cyst. Whereas most NTS cause self-limited gastroenteritis with only 5% of patients developing bacteremia, some serotypes are particularly aggressive; for instance, S. Choleraesuis has the higheest predilection among
Salmonella serotypes to cause primary bacteremia (which it does in up to 70% of patients),
focal invasive extra intestinal disease (which it does in up to 50% of patients) and
recurrence; and this with little or no gastrointestinal symptoms; these manifestations occur especially in the immunosuppressed (the most significant risk factor for invasive
salmonellosis, others being age over 50 years, liver cirrhosis, IBD, SLE, and diabetes mellitus); mycotic aneurysms, osteomyelitis, and pleuropulmonary infections are the commonest focal infections reported[100]. Salmonella septic arthritis comes by way of haematogenous spread instead of direct inoculation into the joint; still, septic arthritis is an uncommon complication of Salmonella bacteremia (<1% of patients); joint infections that occur over three months after joint arthroplasty are haematogenous in origin[71]. The risk of septic arthritis in Salmonella infection is associated with young and old age, RA, CD, SLE, HIV, diabetes mellitus, prosthetic joint transplant, and others[70]. It was also shown that anti-TNF therapy poses a higher risk of septic arthritis than non-biological DMARD therapy, and that Etanercept poses a higher risk of septic arthritis than Adalimumab or Infliximab[101].
Most of the patients found by this systematic review showed non-specific
either some time before the severe infection episode, or concomitant to it, symptoms that are consistent with gastroenteritis, such as nausea, vomiting, abdominal pain and diarrhea; interestingly, three patients showed no gastrointestinal symptoms at all. On the other hand, many patients showed extra-abdominal symptoms, such as headache, somnolence,
tachycardia, acute renal failure, sweating, cough, shortness of breath, myalgia; all the patients who presented with septic arthritis showed, if not all, at least some symptoms of joint inflammation, such as joint pain, swelling, stiffness, erythema and increased warmth. On ultrasound, septic arthritis showed itself via synovial thickening and excessive fluid in most of patients. Laboratory analysis revealed in many, but not all of the 16 cases of serious infection by Salmonella, elevated CRP, elevated erythrocyte sedimentation rate and elevated leukocyte count with neutrophilia. Although joint infection is a rheumatology emergency that requires early diagnosis, the onset of septic arthritis in RA patients is more insidious and may be mistaken for a flare of RA; the presentation may be even more subtle in patients on immunosuppressor therapy. This may account for a delay in diagnosis, when a quick diagnosis is essential to prevent joint destruction; as such, for patient’s on anti-TNF therapy one must consider the possibility of septic arthritis. The identification of
Salmonella, and subsequent diagnosis of salmonellosis is based on isolation of the bacteria
from stool, blood or synovial fluid. All cases retrieved by this systematic review identified
Salmonella via culture and most of them followed that with serotyping. Gram staining was
also widely used. It is not enough to stress out that because the rates of morbidity and mortality associated with salmonellosis are highest among the old, the young, and the immunosuppressed, while the clinical presentation is relatively non-specific, taking the necessary steps to identify the pathogen quickly is fundamental to implement successful therapy to quench the infection. Also important is assessing antibiotic susceptibility as multidrug resistant strains of Salmonella have been emerging since the 1980s, with some
being resistant to ampicillin, chloramphenicol, streptomycin, sulfonamides, tetracyclines, trimethoprim-sulfamethoxazole (TMP-SMZ, TMP-SMX, co-trimoxazole) or ciprofloxacin; assessing antibiotic susceptibility was also undertaken in the vast majority of cases here reported.
Although antibiotic treatment is usually not recommended in NTS gastroenteritis (fluid and electrolyte replacement is, if dehydration is an issue), pre-emptive antibiotic treatment should be considered for patients with increased risk of invasive salmonellosis (such as patients younger than three months, patients older than 50 years with
atherosclerosis, immunosuppressed patients, patients with endovascular abnormalities, and patients with joint prosthesis); treatment should consist of ciprofloxacin 500mg bid (o) or ofloxacin 400mg bid (o); immunocompromised patients may require 7-14 days of therapy, while non-immunocompromised patients 2-3 days. Because of the increasing antibiotic resistance, empirical treatment for focal disease or bacteremia should include a third
generation cephalosporin or a fluoroquinolone. In case of bacteremia, ceftriaxone 2g/d (IV) or ciprofloxacin 400mg q12h (IV) are recommended for 7-14 days. In case of arteritis, ceftriaxone 2g/d (IV) or ciprofloxacin 400mg q8h (IV) are recommended for 42 days, plus surgical resection; ampicillin is suggested by some. In case of septic arthritis, the same antibiotics of arteritis are recommended, plus surgical drainage of the affected area. In case of enteric fever, the empiric treatment is ceftriaxone 2g/d (IV) for 10-14 days, or another third-generation cephalosporin, or azithromycin; for treatment of fully-susceptible enteric fever, fluoroquinolones (such as ciprofloxacin) are the most effective class of agents, but azithromycin, amoxicillin, chloramphenicol or co-trimoxazole can also be used; for treatment of multidrug- and quinolone-resistant strains, ceftriaxone, azithromycin or ciprofloxacin are used. In case of chronic carriage, treatment for 4-6 weeks with oral ciprofloxacin, oral amoxicillin, or others is advised[86].
In this systematic review 10 patients were found to be treated with fluoroquinolones, ciprofloxacin being the one most used (in 7 patients); levofloxacin (in two patients) and ofloxacin (in one patient) were also used. Ceftriaxone was given to 5 patients. Amoxiclav, oxacillin, minocycline and amoxicillin were also used to treat salmonellosis. Furthermore, other antibiotics were used as well, either empirically, or after complications emerged. Most of the papers do not state what, if any empiric therapy was administered. For instance, out of the 8 cases of septic arthritis, only three authors reported the empiric treatment: two patients received vancomycin and levofloxacin, while one patient received meropenem. Once the pathogen was identified and/ or antibiotic susceptibility ascertained, antibiotic was changed as indicated in Table 3. The treatment of septic arthritis was, in all cases, completed with non-antibiotic therapy, including arthroscopic lavage and debridement; continuous closed irrigation suction; open arthrotomy and synovectomy (with retention or reconstruction of prosthesis). Most patients received their antibiotics via IV while admitted and, after discharge, would continue with oral therapy. The duration of therapy varied widely; of the papers which report its length, there are patients who received antibiotics for as little as 10 days, and others for as many as 6 months; the septic arthritis cases were the ones which required the longest course of action (from one to 6 months), while bacteremia, unless complicated by mycotic aneurism, required usually under one month.
In the cases retrieved by this study, 4 patients developed mycotic
aneurism[9],[72],[75],[79], while three patients experienced recurrence of Salmonella
infection[69],[71],[79], and only one patient had to go through joint reconstruction[80]. Two of the patients that eventually developed mycotic aneurism were initially not given
fluoroquinolones or cephalosporins; in one of these cases, and despite later changing the antibiotic treatment to ceftriaxone, the patient died. Similar to septic arthritis, treatment of mycotic aneurism included non-antibiotic therapy, such as surgical resection with or
without placement of bypass, or placement of endovascular prosthesis. Antibiotic treatment after identification of mycotic aneurism complication involved ciprofloxacin and a long course therapy with co-trimoxazole, in one successful case.
Altogether, two patients died (12%), and both of them had developed mycotic aneurism. Mycotic aneurism development is facilitated by atherosclerosis and
immunosuppression, which are common in the 16 patients retrieved by this study.
Recurrence after appropriate and adequate antimicrobial therapy is a feared complication in patients with infection by some serotypes of Salmonella; some of the risk factors for
recurrence include atherosclerotic plaques, diseased joints, and diseased bones. In patients with mycotic aneurysms, in addition to antibiotics, surgery may prevent recurrence[100].
GENERAL DISCUSSION AND CONCLUSIONS
The discussion on whether anti-TNFs pose an elevated risk of infection is far from being over; for instance, in IBD, biological drugs, even when taken in combination with other immunosuppressive drugs, were not found to confer a higher risk of serious infection than other treatment options[102]. Similarly, in psoriasis, no increased risk of infection was observed in patients taking anti-TNFs[103]. However, in RA, standard-dose biological drugs were associated with an increase in serious infections compared with traditional
immunosuppressive drugs[104],[105]. Curiously, the magnitude of the risk of serious infection in RA patients was not determined by the type of biological agents, having patient-specific risk factors more impact[106]. Perhaps these reports reflect more of a difference in
methodology, (with clinical trials concluding that biological drugs do not increase serious infections, while registries, which include the typical patients, showing different results) than of fundamental differences between RA-patients versus IBD- and psoriasis-patients. Regardless, it is clear that infection in patients taking anti-TNFs poses additional
challenges, both in terms of diagnosis and treatment.
Between the different anti-TNFs, Infliximab seems to present a higher risk of infection. For instance, the previously mentioned review of the AERSUSFDA showed there was a 3,25-fold greater risk of developing granulomatous infections in patients under Infliximab than in those under Etanercept; for Listeria, there were 15,5 infections per 100 000 patients on Infliximab versus 1,8 infections per 100 000 patients on Etanercept; while for Salmonella there were 3 infections per 100 000 patients on Infliximab and 3,5
infections per 100 000 patients on Etanercept[7]. Comparing between different anti-TNFs should take in consideration that they have been in use for different periods and in different diseases. In RA, the FDA approved Etanercept in 1998, Infliximab in 1998, Adalimumab in
2002, Certolizumab in 2009, and Golimumab in 2009[105]. Infliximab and Adalimumab are also approved for CD and UC, Certolizumab for CD, and Golimumab for UC[107].
The infection risk should not forbid anti-TNF treatment. The risk of serious infections in patients taking anti-TNF therapy can be managed by testing and treating existing latent infections; adequate precautions prior and during treatment should also be undertaken. In IBD, it is recommended to discontinue anti-TNF treatment during infection with Legionella, Listeria, and Salmonella[97]. The American College of Rheumatology also recommends that anti-TNF therapy be withheld when active bacterial infections or bacterial infections requiring antibiotic therapy are present; it further recommends RA patients who have a history of serious infections to use combination of DMARDs over anti-TNFs[108]. However, in these patients, treatment may continue if the risk/benefit ratio is favourable; the decision to continue treatment should be personalized and based on the medical history of the patient, causality of the adverse event, and whether the adverse event is a recurrence of a prior similar event, among others.
In this study, we searched the peer-reviewed literature and found 104 cases of serious infection by Legionella, Listeria, and Salmonella in patients who were under anti-TNF therapy. In the overwhelming majority of these cases the patients were receiving concomitant immunosuppressive drugs, especially steroids. The typical patient is a male in his 50s, suffering from RA, and taking Infliximab. All of the patients infected with
Legionella had pneumonia and were treated with either a quinolone, or a macrolide, or a
combination involving at least one of them. The majority of patients infected with Listeria had bacteremia and/ or meningitis and/ or CNS involvement; they were mainly treated with ampicillin +/- gentamicin or amoxicillin +/- gentamicin. The majority of patients infected with Salmonella had bacteremia, being septic arthritis also very common; most were treated with fluoroquinolones. Altogether, 17 patients died. Others experienced
complications, namely recurrence of infection, a rare event nonetheless, occurring after resuming anti-TNF therapy; many patients never did resume it. Patients can minimize the risk of infection with these agents by taking care with what they eat, and where they go. A very important step towards successfully treating these patients is to achieve an accurate diagnosis quickly; instituting effective empirical antibiotic therapy is also paramount.
This study has relied mainly on case reports; however, some cases were taken from RCTs and OSs as well. Case reports inform on which particular issues arise while treating specific patients, allowing emphasis on the narrative aspect, and detecting novelties; however, they lack the ability to generalize and suffer from publication bias. RCTs provide balanced groups for analysis of conditions; however, they usually involve a small number of patients and selected populations. OSs such as clinical registries capture the long-term benefit of drugs in routine care although lacking controls and randomization. However, both OSs and RCTs most often don’t show the information this study required for
characterising the patients and their clinical evolution; while case reports may have sketchy data, and collecting it turns to a laborious process, a deeper understanding of the issue at hand may emerge.
Finally, as biologic therapies are increasing in use, one should be aware of the potential challenges they pose and how to best overcome them.
ACKNOWLEDGEMENTS
We thank Elsa Sousa and Inge De Landtsheer for their insightful takes on RA and flemish/dutch papers, respectively.
REFERENCES
[1] Silva LC, Ortigosa LC, Benard G. Anti-TNF-α agents in the treatment of immune-mediated inflammatory diseases: mechanisms of action and pitfalls.
Immunotherapy. 2010 Nov;2(6):817-33.
[2] Kirkham B. Tumor necrosis factor-alpha inhibitors: An overview of adverse effects. UpToDate. 2016 Sep 12.
[3] Thalayasingam N, Isaacs JD. Anti-TNF therapy. Best Pract Res Clin Rheumatol. 2011 Aug;25(4):549-67.
[4] Singh JA, Wells GA, Christensen R, et al. Adverse effects of biologics: a network meta-analysis and Cochrane overview. Cochrane Database Syst Rev. 2011 Feb 16;(2):CD008794.
[5] Mariette X, Gottenberg JE, Ravaud P, Combe B. Registries in rheumatoid
arthritis and autoimmune diseases: data from the French registries. Rheumatology (Oxford). 2011 Jan;50(1):222-9.
[6] Duarte R, Campainha S, Cotter J, et al. Position paper on tuberculosis screening in patients with immune mediated inflammatory diseases candidates for biological therapy. Acta Reumatol Port. 2012 Jul-Sep;37(3):253-9.
[7] Wallis RS, Broder MS, Wong JY, et al. Granulomatous infectious diseases associated with tumor necrosis factor antagonists. Clin Infect Dis. 2004 May 1;38(9):1261-5.
[8] Winthrop KL. Tumor necrosis factor-alpha inhibitors: Bacterial, viral, and fungal infections. UpToDate. 2017 Oct 09.
[9]: Netea MG, Radstake T, Joosten LA, et al. Salmonella septicemia in rheumatoid arthritis patients receiving anti-tumor necrosis factor therapy: association with decreased
interferon-gamma production and Toll-like receptor 4 expression. Arthritis Rheum. 2003 Jul;48(7):1853-7.
[10] Mitchell G, Chen C, Portnoy DA. Strategies Used by Bacteria to Grow in Macrophages. Microbiol Spectr. 2016 Jun;4(3).
[11] Kaufmann SH. Immunity to intracellular bacteria. Annu Rev Immunol. 1993;11:129-63.
[12] Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. J Clin Epidemiol. 2009 Oct;62(10):1006-12.
[13] Kunimoto K, Mikita N, Kanazawa N, Furukawa F. Case of Legionella
pneumophila pneumonia (legionellosis) developed in a psoriatic arthritis patient receiving adalimumab. J Dermatol. 2017 Aug;44(8):982-983.
[14] Giassi Kde S, Furlanetto V Jr, Fialho S, et al. [Legionella pneumonia after infliximab in a patient with rheumatoid arthritis]. Rev Bras Reumatol. 2014 Sep-Oct;54(5):397-9.
[15] Hayashi M, Kuraishi H, Masubuchi T, et al. A Fatal Case of Relapsing Pneumonia Caused by Legionella pneumophila in a Patient with Rheumatoid Arthritis After Two Injections of Adalimumab. Clin Med Insights Case Rep. 2013 Jun 12;6:101-6.
[16] Kaku N, Yanagihara K, Morinaga Y, et al. Detection of Legionella pneumophila serogroup 1 in blood cultures from a patient treated with tumor necrosis factor-alpha inhibitor. J Infect Chemother. 2013 Feb;19(1):166-70.
[17] Wuerz TC, Mooney O, Keynan Y. Legionella pneumophila serotype 1 pneumonia in patient receiving adalimumab. Emerg Infect Dis. 2012 Nov;18(11):1872-4.
[18] Aringer M, Houssiau F, Gordon C, et al. Adverse events and efficacy of TNF-alpha blockade with infliximab in patients with systemic lupus erythematosus: long-term follow-up of 13 patients. Rheumatology (Oxford). 2009 Nov;48(11):1451-4.
[19] Beigel F, Jürgens M, Filik L, et al. Severe Legionella pneumophila pneumonia following infliximab therapy in a patient with Crohn's disease. Inflamm Bowel Dis. 2009 Aug;15(8):1240-4.
[20] Hofmann A, Beaulieu Y, Bernard F, Rico P. Fulminant legionellosis in two patients treated with infliximab for Crohn's disease: case series and literature review. Can J Gastroenterol. 2009 Dec;23(12):829-33.
[21] Jinno S, Pulido S, Pien BC. First reported United States case of Legionella pneumophila serogroup 1 pneumonia in a patient receiving anti-tumor necrosis factor-alpha therapy. Hawaii Med J. 2009 Jun;68(5):109-12.
[22] Vinter H, Nielsen HI. [Legionella pneumonia in patients treated with infliximab]. Ugeskr Laeger. 2009 Jan 19;171(4):247.
[23] Kohn A, Daperno M, Armuzzi A, et al. Infliximab in severe ulcerative colitis: short-term results of different infusion regimens and long-term follow-up. Aliment
Pharmacol Ther. 2007 Sep 1;26(5):747-56.
[24] Lagier JC, Andriamanantena D, Damiano Jet al. [Anti-TNF alpha therapy: a risk factor for legionella infection]. Rev Mal Respir. 2007 Nov;24(9):1159-60.
[25] Mancini G, Erario L, Gianfreda R, et al. Tuberculosis and Legionella pneumophila pneumonia in a patient receiving anti-tumour necrosis factor-alpha (anti-TNF-alpha) treatment. Clin Microbiol Infect. 2007 Oct;13(10):1036-7.
[26] Tubach F, Ravaud P, Salmon-Céron D, et al. Emergence of Legionella
pneumophila pneumonia in patients receiving tumor necrosis factor-alpha antagonists. Clin Infect Dis. 2006 Nov 15;43(10):e95-100.
[27] Eisendle K, Fritsch P. Fatal fulminant legionnaires' disease in a patient with severe erythodermic psoriasis treated with infliximab after long-term steroid therapy. Br J Dermatol. 2005 Mar;152(3):585-6.
[28] Li Gobbi F, Benucci M, Del Rosso A. Pneumonitis caused by Legionella pneumoniae in a patient with rheumatoid arthritis treated with anti-TNF-alpha therapy (infliximab). J Clin Rheumatol. 2005 Apr;11(2):119-20.
[29] Albert C, Vandenbos F, Brocq O, et al. [Legionellosis in patient treated with infliximab]. Rev Med Interne. 2004 Feb;25(2):167-8.
[30] Wondergem MJ, Voskuyl AE, van Agtmael MA. A case of legionellosis during treatment with a TNFalpha antagonist. Scand J Infect Dis. 2004;36(4):310-1.
[31] Kroesen S, Widmer AF, Tyndall A, Hasler P. Serious bacterial infections in patients with rheumatoid arthritis under anti-TNF-alpha therapy. Rheumatology (Oxford). 2003 May;42(5):617-21.
[32] Stratton L, Caddy GR. Listeria Rhombencephalitis Complicating Anti-TNF Treatment during an Acute Flare of Crohn's Colitis. Case Rep Gastrointest Med.
2016;2016:6216128.
[33] Parihar V, Maguire S, Shahin A, et al. Listeria meningitis complicating a patient with ulcerative colitis on concomitant infliximab and hydrocortisone. Ir J Med Sci. 2016 Nov;185(4):965-967.
[34] Mathews BK, Chuang C, Rawal A, Gertner E. Listeria rhomboencephalitis in a patient on a tumor necrosis factor α inhibitor (etanercept). J Clin Rheumatol. 2014
Sep;20(6):325-7.
[35] Miranda-Bautista J, Padilla-Suárez C, Bouza E, et al. Listeria monocytogenes infection in inflammatory bowel disease patients: case series and review of the literature. Eur J Gastroenterol Hepatol. 2014 Nov;26(11):1247-52.
