opportunistic infections in patients with inflammatory bowel disease - prvention and diagnosis 2008

doi:10.1136/gut.2006.114660 2008;57;549-558; originally published online 4 Jan 2008; Gut Colombel N Viget, G Vernier-Massouille, D Salmon-Ceron, Y Yazdanpanah and J-F diagnosis inflammatory bowel disease: prevention and Opportunistic infections in patients with http://gut.bmj.com/cgi/content/full/57/4/549 Updated information and services can be found at: These include: References http://gut.bmj.com/cgi/content/full/57/4/549#otherarticles 1 online articles that cite this article can be accessed at: http://gut.bmj.com/cgi/content/full/57/4/549#BIBL This article cites 107 articles, 20 of which can be accessed free at: service Email alerting the top right corner of the article Receive free email alerts when new articles cite this article - sign up in the box at Notes http://journals.bmj.com/cgi/reprintform To order reprints of this article go to: http://journals.bmj.com/subscriptions/ go to: GutTo subscribe to on 11 August 2008 gut.bmj.comDownloaded from Opportunistic infections in patients with inflammatory bowel disease: prevention and diagnosis N Viget, 1 G Vernier-Massouille, 2 D Salmon-Ceron, 3 Y Yazdanpanah, 1,4,5 J-F Colombel 2 1 Service des Maladies Infectieuses et du Voyageur, Centre Hospitalier de Tourcoing, France; 2 Service d’He´pato- gastroente´rologie, Hoˆpital Claude Huriez, Centre Hospitalier Universitaire de Lille, Lille France; 3 Service des Maladies Infectieuses, Universite´ Paris V, Faculte´ Cochin, Paris, France; 4 EA 2694, Faculte´deMe´decine de Lille, France; 5 Laboratoire de Recherches E ´ conomiques et Sociales, CNRS URA 362, Lille, France Correspondence to: Professor J-F Colombel, Service d’He´pato-gastroente´rologie, Hoˆpital Claude Huriez, CHRU de Lille, 59037 Lille Cedex, France; jfcolombel@chru-lille.fr Revised 13 November 2007 Accepted 21 November 2007 Published Online First 4 January 2008 ABSTRACT Because of the increasing use of immunosuppressive and biological drugs, the occurrence of opportunistic infections has become a key safety issue for patients with inflammatory bowel disease (IBD). Consequently, improvement of healthcare workers’ knowledge of this domain is urgent. In this review, the preventive measures that would help to reduce the rate of opportunistic infections in patients with IBD are listed, and the management of situations frequently confronting doctors is considered. In the absence of national and international recommendations, the information given here should help doctors to optimise patient outcomes. Over the past 10 years, the treatment of inflam- matory bowel disease (IBD) has been marked by the increasing use of immunosuppressors, mainly azathioprine (AZA)/6-mercaptopurine (6-MP) and methotrexate (MTX), and by the advent of biological therapies. The increasing evidence in favour of immunosuppressors means that they are being used more often and earlier in the course of the disease. Recent data have shown that once initiated, maintenance therapy with AZA should be continued. 1 The introduction of biological agents, especially inhibitors of the key proinflam- matory cytokine tumour necrosis factor a (TNFa) ushered in a new therapeutic era, and the use of these agents has become increasingly widespread since their introduction in 1998. 2 Any treatment or medication can cause unto- ward events, and its benefit has to be weighed against the risk of side effects. As regards immu- nosuppressors and TNF antagonists, key safety considerations for patients with IBD certainly include the prevention of opportunistic infections. These infections may either be due to an organism which does not usually cause disease but which may, under certain conditions, become pathogenic, or they may constitute an unusually severe infection by an organism which normally causes mild disease only. Because, in different ways, immunosuppressors and TNF antagonists inhibit immune system activity, their association with opportunistic infections can be viewed as an extension of their normal, intended therapeutic activity. Opportunistic infections pose a difficult problem for doctors because they are often hard to recognise and are associated with significant morbidity and mortality, as they are frequently serious and hard to treat effectively. It is important to improve gastroenterologists’ knowledge of opportunistic infections, because this might provide a new approach to optimising patient outcomes by introducing new strategies for prevention or early diagnosis. EPIDEMIOLOGICAL ASPECTS IBD is associated with conditions that may predispose to opportunistic infections, such as the lack of an appropriate innate immune response to infectious agents (a response that may be inherent in the disease), malnutrition, surgery and immu- nosuppressive medication. The prevalence of opportunistic infections in patients with IBD is not known, but they have been regularly stated to be a cause of death in this population in various reports, including case reports, open series, pla- cebo-controlled randomised clinical trials, post- approval databases and registries. 3–13 A large num- ber of opportunistic infections have been attrib- uted to IBD therapies (see list in Table 1). Their description is outside the scope of this article, but some important points are worth mentioning. All kinds of infection have been associated with the use of corticosteroids, AZA/6-MP, MTX, cyclos- porin and TNF antagonists, even though some specific effects may be due to their mechanism of action. 14 For instance, by leading to T lymphocyte apoptosis, AZA/6-MP metabolites may, in parti- cular, predispose to infection by viruses such as cytomegalovirus (CMV), varicella zoster virus (VZV) or Epstein–Barr virus (EBV). 14 15 In the case of TNF antagonists, the risk of reactivating granulomatous diseases and infections, in which host defences are particularly macrophage depen- dent, is of particular concern. The prevalence and awareness of specific infections may vary from country to country, as it does, for instance, for Histoplasmosis in endemic or non-endemic regions. 3 16–18 Recent safety concerns have focused on biological drugs, but it should be remembered that older traditional therapies have been less well scrutinised and that they all carry risks. It is difficult to attribute the causes of adverse effects such as opportunistic infections to a specific drug. Because these infections are rare, large cohorts are needed to determine their precise incidence in IBD Recent advances in clinical practice Gut 2008;57:549–558. doi:10.1136/gut.2006.114660 549 on 11 August 2008 gut.bmj.comDownloaded from patients, and also to establish the excess risk associated with the use of a specific medication. Other sources of bias in assessing the actual risk include the ‘‘learning curve’’ inherent in new drug use, and exposure to multiple agents. Doctors should be aware that the combination of immu- nosuppressors, including steroids, and TNF antago- nists may substantially increase the risk of opportunistic infections. In a recent case–control study from the Mayo Clinic, the odds ratio for opportunistic infections associated with the use of corticosteroids, AZA/6-MP or infliximab was 2.6 (95% CI 1.4 to 4.7), and increased to 12.9 (95% CI 4.5 to 37.0) when two or more drugs were used. 17 PREVENTION Admittedly, there are no universal recommenda- tions for the management of opportunistic infec- tions, and the following statements merely reflect either guidelines from national scientific societies or authors’ opinions. The present method for prevention of opportunistic infections rests on a thorough clinical and laboratory work-up before starting the administration of immunosuppressors and/or TNF antagonists, and on vaccinations, chemoprophylaxis and, when indicated, appropri- ate control of underlying chronic viral infections. Clinical and laboratory work-up (Box) Patients should be questioned about their history of bacterial infections, especially frequent infec- tions such as those involving the urinary tract. 19 20 The risk of latent or active tuberculosis is evaluated from the following information: date of the last BCG vaccination, previous contacts with infected patients, country of origin, prolonged stays in countries where tuberculosis is endemic, and any history of latent or active tuberculosis and the treatment received. In addition, patients must report any history of infection by VZV and herpes simplex virus (HSV), especially primary varicella in childhood and HSV recurrences in recent years. Lastly, immunisation status against tetanus, diphtheria, poliomyelitis, rubella, measles, mumps and hepatitis B should be determined. The possible presence should be actively explored of various systemic and/or local symp- toms of infection such as fever, sweating, chills, weight loss, cough, dyspnoea, haemoptysis, chest pain, cardiac murmur, dysuria and increased frequency or urgency of urination. Dental status needs to be evaluated and appropriate dental care performed. 21 To reduce the risk of Candida septicaemia, fungal infections such as oral and vaginal candidosis or intertrigo should be identified and appropriately treated. In connection with this, an increased incidence of abnormal Papanicolaou (Pap) smears and cervical dysplasia, probably due to the enhancement of chronic cervical infection by human papillomavirus (HPV), was recently reported in women with IBD treated with immu- nosuppressors. 22 23 Gynaecological examination and cervical cancer screening should therefore be systematically planned for women with IBD before and during treatment with immunosuppressors and TNF antagonists. 21–23 Patients with a history of urinary tract infection or urinary symptoms should have a urine test. According to present recommendations, neutro- phil and lymphocyte cell counts should be performed before starting IBD treatment, and regularly monitored thereafter. Immuno-suppres- sive therapy may lower the neutrophil count, 14 possibly causing neutropenia, which is associated with rapidly progressing life-threatening infec- tions. 14 In neutropenic patients, any infections must be urgently evaluated, and prompt empirical antimicrobial therapy administered. A heightened index of suspected infection is essential, because symptoms of infection may be minimal in this population, due to a blunted inflammatory response. Long-term systemic corticosteroid ther- apy (.1 month) induces dose-dependent lympho- cyte depletion and, when combined with other immunosuppressive agents, has a cumulative adverse effect on lymphocytopenia. A lymphocyte count ,600/mm 3 and, more specifically, a CD4 cell count ,300/mm 3 are predictive of infection. 24 25 Monitoring CD4 cell counts in patients with a total lymphocyte count (600/mm 3 may help to identify those at high risk of certain infections such Table 1 Opportunistic infections reported with immunosuppressant therapy in inflammatory bowel disease Factors that may predispose to infectious complications in IBD IBD (disease type and extension, disease duration) Malnutrition Immunosuppressive medications Leucopenia from immunosuppressive medications Surgery Concomitant disease Viral infections Virus Varicella zoster Virus Herpes simplex Cytomegalovirus Epstein–Barr virus Human papilloma virus Bacterial infections Escherichia coli Salmonella spp. Streptococcus pneumoniae Clostridium difficile Staphylococcus spp. Mycobacterium tuberculosis Legionella pneumophila Listeria monocytogenes Mycobacterium avium spp. or xenopi Nocardia Parasite and fungal infections Candida spp. Pneumocystis jiroveci (carinii) Aspergillus spp. Histoplasmosis Cryptococcus spp. Toxoplasma gondii* Coccidioides immitis Leishmania donovani Blastomycoses *Toxoplasma gondii has not been reported with immunosuppressant therapy in patients with IBD in the past, but may potentially occur. IBD, inflammatory bowel disease. Recent advances in clinical practice 550 Gut 2008;57:549–558. doi:10.1136/gut.2006.114660 on 11 August 2008 gut.bmj.comDownloaded from as Pneumocystis jiroveci, and to guide chemoprophy- laxis. Hepatitis C virus (HCV), hepatitis B virus (HBV) and HIV serologies are required before starting immunosuppressive therapy. Fatal cases of infec- tious mononucleosis and EBV-associated lym- phoma have been reported in patients on AZA, 6- MP and cyclosporin. 26–31 However, no reactivation of latent EBV infection was detected in patients with rheumatoid arthritis treated by infliximab. 32 Moreover, similar EBV viral loads have been found in patients with Crohn’s disease, with or without immunosuppressors, and in EBV-seropositive con- trols. 33 Consequently, serological tests for EBV should not be performed before starting immuno- suppression. In patients without a clear history of varicella immunisation, VZV titres should be tested. Those with negative titres are at risk of varicella and may require vaccination. Malignant varicella infections have indeed been reported in IBD patients on immunosuppressive therapy, especially anti-TNF blockers. 34 35 CMV reactivation has been described during MTX, AZA/6-MP and infliximab therapy. 36 37 CMV serology is useful to identify patients who have already been in contact with the virus (ie, who have positive IgG CMV titres), and are therefore at risk of CMV reactiva- tion. However, subsequent CMV serology in such cases is useless. In contrast, patients with negative IgG CMV titres will be at risk of primary CMV infection, and in that case serology may be useful for diagnosis. Every country has provided specific guidelines for managing the risk of tuberculosis in patients due to start treatment with a TNF antagonist. 38–44 Establishing a diagnosis of latent tuberculosis can Systematic work-up to consider before immunomodulatory agents and/or tumour necrosis factor antagonist initiation Detailed interview c History of travel and/or living in tropical areas or countries with endemic infections c History of bacterial infections, c History of fungal infections: oral and vaginal candidosis, intertrigo c Risk of latent or active tuberculosis: – date of the last BCG vaccination – history of contact with tuberculosis patients – country of origin, prolonged stay in countries where tuberculosis is endemic – history of latent or active tuberculosis and treatment given c History of VZV infection c History of herpes simplex virus infection: frequency and severity of recurrences c Immunisation status for tetanus, diphtheria and poliomyelitis, and date of vaccination (was the patient vaccinated against these diseases within the past 10 years?) c Immunisation status for rubella, measles and mumps, and date of vaccination c Immunisation status for hepatitis B and, in vaccinated patients, testing for the presence of hepatitis B antibodies c Future plans to travel abroad to endemic areas (to consider whether the patient may need live virus vaccines such as the one for yellow fever) Clinical examination c Identification of systemic and/or local possibly active infections c Evaluation of dental status c Gynaecological visit and pap smear Laboratory tests c Neutrophil count c Lymphocyte count and, in the case of lymphopenia, CD4 lymphocyte count c C-reactive protein c Urine analysis in patients with a history of urinary tract infection, and urinary symptoms c VZV serology in patients without a clear history of varicella immunisation c CMV serology c HCV, HBV and HIV serology* – In patients with HCV or HBV chronic viral infection, alanine aminotransferase (ALT) assay, and determination of the stage of liver fibrosis and of necroinflammatory activity – In patients with HIV, CD4 cell count and viral load c Eosinophil count, stool examination and strongyloidiasis serology for patients having lived in a tropical area Other procedures c Tuberculin skin test (according to each country’s specific guidelines) c Pulmonary chest x ray *Patients with a history of hepatitis B vaccination should be tested for the presence of hepatitis B antibodies. CMV, cytomegalovirus; HBV, hepatitis B virus; HCV, hepatitis C virus; VZV varicella zoster virus. Recent advances in clinical practice Gut 2008;57:549–558. doi:10.1136/gut.2006.114660 551 on 11 August 2008 gut.bmj.comDownloaded from be a problem because purified protein derivative (PPD) screening is difficult to interpret in patients with previous BCG vaccination, and because of frequent anergy in patients on concomitant immunosuppressive therapy. 45 Two new immuno- logical methods T-SPOT TB (Oxford Immunotec, Abingdon, UK) and QuantiFERON TB Gold (QFT- G; Cellestis, Carnegie, Australia) have become available for the diagnosis of active and latent tuberculosis. 45 46 Both are based on interferon c ex vivo assays involving gene products in the Mycobacterium tuberculosis genome that are absent in BCG and most environmental mycobacteria. In particular, these tests seem to be more specific than the PPD test for the diagnosis of latent tuberculosis in immunocompetent patients. 47 Nevertheless, there are only limited data concerning their sensitivity in immunocompromised patients and, moreover, recent publications have pointed out a higher frequency of indeterminate results with these tests in immunocompromised patients. 48–50 Consequently, further clinical studies are needed to establish the performance of these tests in IBD patients. Preventive strategies Education The education of patients is essential for the prevention and treatment of opportunistic infec- tions. Patients need to be taught about them, and how to recognise early symptoms. Rapid 24 h access to a clinical team is mandatory. Because cases of listeriosis have been described during treatment with TNF antagonists, recommenda- tions have been made to avoid certain foods implicated in listerosis transmission, such as those made from unpasteurised milk, as well as processed foods such as soft cheese, cold cuts of meat—that is, delicatessen processed meats, hot dogs and refrigerated paˆte´s. 51 52 Salmonella infections have also been reported in patients taking TNF blockers. Salmonella is harboured by raw or undercooked eggs, poultry and meats. Advising patients to avoid eating high-risk foods when they start treatment with TNF antagonists may reduce the incidence of emerging opportunistic infections. 51 52 Vaccinations (Table 2) Vaccines are certainly underutilised in patients with IBD. In the USA, in 2005, only 76 out of 169 patients with IBD (45%) remembered that they had been immunised against tetanus within the past 10 years, 47 (28%) reported regularly receiving flu shots and 15 (9%) said they had had a pneumococcal vaccine injection. 56 Adult patients with IBD should undergo combined vaccination against tetanus, diphtheria and inactivated polio- myelitis every 10 years. There are no recommenda- tions regarding vaccination against pertussis. However, given the current resurgence of this disease, 57 vaccination is now recommended in some countries such as the USA in combination with vaccination against tetanus, poliomyelitis and diphtheria. 54 Patients with IBD should be vaccinated against influenza annually. Vaccine for pneumococ- cal disease with the 23-valent strain should be administered every 5 years. IBD patients with no detectable hepatitis B surface (HBs) antibodies should be vaccinated against hepatitis B, using a three-dose immunisation schedule. For patients with no clear history of varicella, immunisation should be tested and varicella vaccine considered for those who are immunologically naı¨v e . 56 Nevertheless, doctors should keep in mind that this vaccine is a live attenuated virus vaccine and cannot be admini- strated if the patient is on immunosuppressive therapy, or if immunosuppressors should be urgently initiated. When varicella vaccine is con- sidered, a two-dose vaccination schedule (with at least 4 weeks between doses) is recommended for adults, because their seroconversion rates are lower than those of children. 58 On account of the growing concern regarding HPV infections in young women with IBD, 22 23 a place may be accorded in the future to the new recombinant HPV vaccine in this population. However, no data are currently available for immune response to such vaccination or for its duration in immune-compromised patients in gen- eral and in patients with IBD in particular. 55 Lastly, one should check that all IBD patients were immunised in childhood against rubella, measles and mumps. When this is not the case, it is not yet clear whether the combined vaccine against these diseases needs to be administered to adults, given the low risk of acquiring them in industrialised coun- tries. In addition to safety issues, the use of immuno- suppressive agents, alone or in combination, may affect the natural immune response to vaccine immunisation, and therefore its efficacy. For example, after vaccination against hepatitis B, IBD patients treated with long-term immunosup- pressive agents may exhibit a suboptimal serologi- cal response. 62 63 Testing for serological immunity should therefore be performed after hepatitis B vaccination. In individuals with a poor response to the usual vaccine doses (ie, 10–100 IU/ml HBs antibodies) an additional booster dose can be proposed. 64 Note, however, that this does not necessarily apply to all vaccines. For example, in patients on TNF blockers, low rates of seroconver- sion after pneumococcal vaccination were not confirmed in recent studies. 65 A satisfactory response to influenza vaccine has been reported in rheumatoid arthritis patients receiving immu- nosuppressive agents. 66 Patients with IBD are very likely to need immunosuppressive therapy in the course of their disease. Given the advisability of performing immunisation before starting treatment with immunosuppressive agents, we believe that the best time for immunisation is at diagnosis, unless significant protein-caloric malnutrition is observed. Chemoprophylaxis In patients with suspected latent or active tuber- culosis, anti-TNFa therapy should be postponed Recent advances in clinical practice 552 Gut 2008;57:549–558. doi:10.1136/gut.2006.114660 on 11 August 2008 gut.bmj.comDownloaded from and antituberculosis treatment given, according to local guidelines. 38–44 Data on P jiroveci prophylaxis are scarce. In our opinion, based on data from other diseases, it should be considered for two categories of patients: (1) those on chronic treatment with multiple immunosuppressants (at least two agents, including steroids) 14 67 and (2) those with lympho- penia (lymphocyte count of ,600/ml), and low CD4+ T lymphocyte counts (,300/ml). 25 68 However, further studies are needed to identify precisely those patients at risk for P jiroveci in whom prophylaxis should be considered. When prophylaxis is considered, trimethoprim-sulpha- methoxazole (TMP-SMZ) is the prophylactic agent of choice, with a single one-strength tablet daily (80–400 mg), half a double-strength tablet daily (160–800 mg) or a double-strength tablet three times a week. 14 If TMP-SMZ is not tolerated, alternative prophylactic regimens include dapsone, aerosolised pentamidine, and atovaquone. 69 70 Patients who have frequent and/or severe recurrences (.4) of HSV disease can be given daily suppressive therapy with oral acyclovir or valaci- clovir. Severe strongyloidiasis is a preventable life- threatening disease (59% mortality has been reported in case series) which may occur in patients who have lived or travelled in endemic countries during the 30 years before onset. 71 These patients should be screened for hypereosinophilia (which may be absent or minimal in 50% of cases), and serological testing for Strongyloides species and stool examination should be prescribed. Patients with positive screening tests and/or unexplained hypereosinophilia, as well as a history of travel or residence indicative of exposure to Strongyloides stercoralis, should be empirically treated, preferably with ivermectin 72 73 before starting immunosup- pressive therapy. Treatment of underlying chronic viral infections Although cases of fulminant hepatitis and hepatitis B reactivation are rare, they have been reported in patients with chronic hepatitis B infection (ie, the presence of HBs antigens (HBsAgs), with or with- out detectable viraemia) after starting treatment with anti-TNF drugs, 74 75 corticosteroids, AZA, MTX or cyclophosphamide. 76 77 In untreated HBsAg-positive patients, several authors have recommended starting lamivudine at least 3 weeks before immunosuppressive therapy. 75 78 Other anti- HBV nucleosides (ie, entecavir) or nucleotides (ie, adefovir), alone or combined with lamivudine, should in future be considered, because today lamivudine monotherapy is no longer standard care for chronic hepatitis B patients. Immunosuppressive agents, especially TNF antagonists, have traditionally been contraindicated for HIV-infected patients. Thanks to the use of highly active antiretroviral therapy (HAART), viral replication can now be controlled, and immune reconstitution induced. Immuno-suppressive agents and TNF antagonists in particular could be used for treated HIV-infected patients with high CD4+ T lymphocyte cell counts (.500/ml) who have been stabilised by antiretroviral therapy (ART). 79–81 In untreated patients who need immunosuppressive agents, earlier initiation of ART may be considered if the CD4 cell count is lower than 500/ml. DIAGNOSIS Listing the specific symptoms of each opportunis- tic infection is outside the scope of this article. The purpose of this section is to help doctors to manage specific clinical situations frequently encountered in IBD patients on immunomodulatory agents and/or TNF antagonists. In immunocompromised patients, fever is the principal and sometimes the only manifestation of serious infection, 82 and has long been recognised to constitute an urgent clinical problem, especially in patients with severe neutropenia (ie, an absolute neutrophil count ,500/mm 3 ) and/or lymphocyto- penia and low CD4 cell counts. The management Table 2 Vaccines and recommendations for their use in immune compromised inflammatory bowel disease patients* 53 Illness Type of vaccine Recommendation in immune- compromised patients Diphteria{ Purified anatoxin Recommended Tetanus{ Purified anatoxin Recommended Poliomyelitis{ Oral route: live attenuated Contraindicated Injectable: inactivated Recommended Pertussis{ Acellular antigen Authorised Hepatitis B Recombinant peptide Recommended Pneumococcal disease 23-valent purified capsular antigen Recommended 7-valent conjugated capsular antigen Authorised (indicated for children only) Influenza Inactivated virus Recommended Human papillomavirus infection1 Recombinant L1 protein Authorised Measles, mumps and rubella Live attenuated Contraindicated Chickenpox" Live attenuated Contraindicated Hepatitis A** Inactivated virus Authorised Yellow fever** Live attenuated Contraindicated Cholera** Oral killed Use with caution Oral live Contraindicated Meningococcal disease** Conjugate polysaccharide C Authorised Polysaccharide combined A+C Authorised Polysaccharide combined A+C+W+Y Authorised Typhoid** Vi capsular polysaccharide Authorised Rabies** Cell culture-derived vaccine Authorised Japanese encephalitis** Inactivated virus Authorised Tick-borne encephalitis** Inactivated virus Use with caution Haemophilus influenzae B disease Conjugated capsular polyosidique antigen Authorised *Immune-compromised patients are defined as: (1) treatment with glucocorticoids: prednisone >20 mg/day equivalent for 2 weeks or more, and within 3 months of stopping; (2) treatment with methotrexate; (3) treatment with 6-mercaptopurine/azathioprine; treatment with infliximab or other tumour necrosis factor-blocking agent; (4) significant protein-caloric malnutrition. {Adult patients with inflammatory bowel diseaseshould undergo combined vaccination against tetanus, diphtheria and poliomyelitis every 10 years. {A booster dose could be administered at least once in adults, following each country’s recommendation on pertussis vaccination, in combination with vaccination against tetanus, poliomyelitis and diphtheria. 54 1In young women with inflammatory bowel disease, human papilloma virus vaccination could be proposed; the same schedule as that recommended for the general population should be used. 55 "Should be performed before starting treatment with immunosuppressive agents, the best time for immunisation being at diagnosis. **To prevent travel-related illnesses. Recent advances in clinical practice Gut 2008;57:549–558. doi:10.1136/gut.2006.114660 553 on 11 August 2008 gut.bmj.comDownloaded from of febrile patients must include a thorough exploration of their history, and physical examina- tion of the oral cavity, lungs, gastrointestinal tract, nervous system, skin, soft tissues and indwelling catheter sites. It is important to ascertain whether there are any symptoms or signs that can help to pinpoint the site of infection, although this may often not be found. Repeated blood cultures should be performed before starting empirical antibiother- apy. In patients with a central venous catheter, blood cultures, together with a quantitative assay, may be performed on samples from this catheter. 83 Chest radiography and urine tests should also be systematically performed. Measurement of C- reactive protein (CRP) can be useful for differentia- tion between infection and inflammatory symp- toms due to IBD. Although CRP increases during IBD flares, 84 85 it is usually higher in cases of infection, especially bacterial infections. 86 In stu- dies conducted in patients with connective tissue diseases and rheumatic or autoimmune disorders, serum procalcitonin (PCT) has exhibited good sensitivity and specificity for early diagnosis of systemic bacterial infections. 87–91 PCT has not been formally tested in IBD patients with suspected infections, and cannot be recommended in routine practice. Nevertheless, given the promising interest in this marker in other inflammatory diseases, its use should be also explored in IBD patients. Fever with mild respiratory tract symptoms In febrile patients with shortness of breath, cough, production of sputum, pleuritic chest pain and/or focal chest signs, chest x ray should be performed immediately and oxygen saturation determined. For patients with normal chest x ray but abnormal oxygen saturation rates, CT is needed. If the chest x ray and/or CT indicate a diagnosis of pneumonia, sputum and blood cultures should be performed, as well as tests for atypical pathogens, including Mycoplasma pneumoniae, Chlamydia sp., Coxiella burnetii and Legionella sp., and more especially for the Legionella urinary antigen. The possible pre- sence of Tubercle bacillus should be explored in gastric aspirates collected on three consecutive days. Pneumococcal urinary antigen may be pre- sent in patients with severe pneumonia. In severely immunosuppressed patients, or after failure of a first-line empirical antibiotic therapy, fibreoptic bronchoscopia with bronchoalveolar lavage must be envisaged, together with a search for specific uncommon bacterial agents (i.e. mycobacteria and nocardia), fungal agents (i.e. histoplasmosis, cryp- tocococcosis and aspergillosis), and parasitic agents (i.e. P jiroveci) (figs 1 and 2). Fever with digestive symptoms In IBD patients on immunosuppressive therapy, the persistence or relapses of gastrointestinal tract symptoms, especially diarrhoea, may be due to exacerbation of the underlying IBD or enteric infections. 92 93 In general, doctors should first exclude a potential enteric infection before con- sidering an exacerbation of the underlying IBD. In this regard, stool cultures with examination for parasites, and testing for Clostridium difficile toxin 92– 94 are necessary. Urgent colonoscopy with biopsies may be considered, especially when stool micro- biological analyses are negative. Herpesviridae infections, HSV and more especially CMV 95 (fig 3), may be responsible for acute IBD attacks. HSV can be diagnosed, either by isolating the virus in a culture of the affected tissue, or by histo- pathological examination of the affected tissue showing nucleated ground-glass herpes inclusions in the cells. For CMV, the best diagnostic method is to confirm its presence by histological analy- sis. 96 97 Biopsies should be performed on the ulcer interface with the intact mucosa. Histopathological examination based on standard Figure 1 Chest x ray. Pneumocystis jiroveci pneumonia following initiation of infliximab and azathioprine therapy in a patient with Crohn’s disease. Note the opacity of the lower right lobe. (From Seddik et al 67 with permission.) Figure 2 Thoracic CT. Pneumocystis jiroveci pneumonia following initiation of infliximab and azathioprine therapy in a patient with Crohn’s disease. Note the bilateral alveolar opacities in the two inferior and the middle lobes. (From Seddik et al 67 with permission.) Recent advances in clinical practice 554 Gut 2008;57:549–558. doi:10.1136/gut.2006.114660 on 11 August 2008 gut.bmj.comDownloaded from staining reveals cytomegalic cells that often con- tain an intranuclear inclusion, usually eccentrically placed, surrounded by a clear halo. This, however, represents late-stage infected cells. Histopathological examination based on immu- nostaining using monoclonal antibodies has been shown to be more sensitive, 95 98 99 but may lead to overestimation of the prevalence of CMV colitis. 96 The PCR for the detection of CMV in tissues is also a highly sensitive technique, but it is not specific for active CMV diagnosis. Serum CMV PCR and PP65 antigenaemia, which quantifies the number of blood leucocytes infected with CMV, are good indicators of CMV dissemination. In particular, they may be useful for monitoring the response to antiviral therapy. 100 Serological tests are not usually of much interest for the diagnosis of HSV or CMV, because most adults are seropositive for IgG antibodies. 101 Fever with nervous system symptoms In patients on immunosuppressive agents, the diagnosis of central nervous system (CNS) infec- tions depends on clinical manifestations, the acuteness or subacuteness of the clinical presenta- tion, and an analysis of the type of immune defect undermining the patient’s host defences. Patients may be classified according to the following manifestations: meningeal signs, mass lesions, encephalopathy, seizures or a stroke-like presenta- tion. 102 CNS infections by Aspergillus are charac- terised either by mass lesions (eg, brain abscess) or by cerebral infarcts, but rarely by meningitis. In contrast, Cryptococcus neoformans usually presents as subacute meningitis with fever and headache, but not neck stiffness. Mass lesions tend to have a subacute or chronic presentation, and meningitis and encephalitis a more acute presentation. In immunocompromised patients, agents that weaken B lymphocyte function are liable to cause meningitis with encapsulated bacterial pathogens. In contrast, when T lymphocyte or macrophage function is impaired, patients are liable to develop infections caused by intracellular pathogens, including fungi, particularly Aspergillus, Nocardia, viruses such as HSV, JC virus, CMV or human herpesvirus-6 (HHV-6), and parasites, particularly Toxoplasma gondii. The involvement of other sites may also be helpful for diagnosing opportunistic infections. For example, combined lung and brain mass involvement may be suggestive of nocardia infection. In patients with meningeal signs and/or ence- phalopathy, a lumbar puncture should be per- formed, with strain culture or serology of cerebral spinal fluid (CSF). CSF cultures are especially important for the detection of encapsulated bacterial pathogens such as Streptococcus pneumo- niae or Listeria monocytogenes, and for mycobacteria detection. Special CSF staining for cryptococcosis diagnosis should be performed, and PCRs of CSF are necessary for CMV, HSV, VZV, T gondii and JC virus detection. MRI should be performed for patients with encephalopathy, and may be of great value for diagnosing progressive multifocal leu- coencephalopathy due to JC virus, as reported for patients treated with natalizumab. 103 For patients with mass CNS lesions, MRI should also be performed and tissue biopsy may be considered. In such cases the diagnosis should distinguish between tuberculosis, lymphoma and toxoplasmo- sis. When possible, lumbar puncture is desirable in these patients. For example, a positive EBV-PCR in the CSF may suggest CNS lymphoma. 104 105 However, because treatment response for toxo- plasmosis occurs early, in patients with compatible MRI of the brain empirical treatment against this disease should be initiated. Early response to treatment usually confirms toxoplasmosis diagno- sis. Fever with dermatological signs In the case of febrile dermatological conditions, bacterial infections, fungal infections, viral infec- tions and non-infectious syndromes such as eczemas, toxidermias and vasculitis can be sug- gested. 106 Bacterial infections are attributable to streptococci and staphylococci. They may be benign, like folliculitis, or more severe, like Figure 3 Endoscopic picture of severe colitis in the sigmoid colon in a patient with Crohn’s disease. Biopsies from this area revealed cytomegalovirus. Prevention: practice points c IBD patients have an increased risk of opportunistic infections (OIs). c Immunosuppressors (IS) taken alone or in combination increase the risk of OI occurrence. c History of OIs should be reviewed before considering IS therapy. c A thorough clinical work-up with an evaluation of dental status and gynaecological exam are necessary before starting IS. c A lymphocyte count ,600/mm 3 with a CD4 count ,300 mm 3 are predictive of infection. c Hepatitis C virus, hepatitis B virus and HIV serologies are required before starting IS. c In patients in whom IS and/or a TNF antagonist are planned to be started, local guidelines for managing the risk of tuberculosis should be strictly followed. c Education of patients is essential for the prevention of OIs. c Vaccination status should be checked and recommended vaccines administered before starting IS. Recent advances in clinical practice Gut 2008;57:549–558. doi:10.1136/gut.2006.114660 555 on 11 August 2008 gut.bmj.comDownloaded from erysipelas and cellulitis. Life-threatening infections such as necrotising fasciitis have also been described, especially in patients on TNF antago- nists. 106–108 The diagnosis of these infections is mainly based on clinical manifestations. However, blood tests for local bacteria, and blood cultures, are necessary before starting any empiri- cal antibiotic therapy. Fungal infections are rarely febrile, except for local cutaneous candidaemia. Viral infections are caused by herpesviridae, espe- cially HSV and VZV. The diagnosis of these conditions is usually based solely on clinical manifestations (fig 4). However, in the case of atypical lesions, virological analysis can be per- formed directly on a recent lesion by PCR and/or immunofluorescence and/or viral culture. Use of immunosuppressors and/or TNF antagonists in patients with a history of opportunistic infection In the absence of prospective data for patients whose infections have been diagnosed, immuno- suppressive therapy should be withdrawn and steroids discontinued as quickly as possible. When immunosuppressive therapy is considered to have major clinical value, it should be resumed, but exactly when is not clear. This probably depends on the nature and severity of the infec- tion, and in any case resumption can only be considered once the infection is under control. Multidisciplinary deliberations involving the gas- troenterologist, infectious disease specialist and specialist of the affected organ are probably necessary to decide when to resume immunosup- pressive therapy, on a case by case basis. CONCLUSION In view of the increasing use of immunosuppres- sive agents and of more and more aggressive therapies, patients with IBD and their doctors should acquire far more knowledge and greater awareness of opportunistic infections. The chal- lenge to the medical practitioner rests not only on the maximally efficient management of inflamma- tory disease, but also on the ability to recognise common and uncommon infections. The risk/ benefit profile of a particular drug or therapeutic strategy should be considered for each category of patients. In the absence of national and interna- tional recommendations, we believe that the organisation of a consensus conference on this topic would help to standardise and optimise care. Competing interests: None. REFERENCES 1. Lemann M, Mary JY, Duclos B, et al. Infliximab plus azathioprine for steroid-dependent Crohn’s disease patients: a randomized placebo-controlled trial. Gastroenterology 2006;130:1054–61. 2. 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J, Niom-Lamurier I, et al. Incidence of benign infections in inflammatory bowel disease patients treated with azathioprine. Gastroenterology 2006;130:A-72. Figure 4 Varicella in an immune-compromised