- Email: [email protected]
Opportunistic infections and anti-tumor necrosis factor antagonists in patients with IBD: prevention and diagnosis
Crohn’s Disease: Achieving Patients’ Benefits / Digestive and Liver Disease Supplements 2 (2008) 3–26
23
Opportunistic infections and anti-tumor necrosis factor antagonists in patients with IBD: prevention and diagnosis J.F. Rahier 1 , J.F. Colombel 2 1 Department 2 Department
of Hepatogastroenterology, Cliniques Universitaires de Mont Godinne Belgique of Hepatogastroenterology, Hôpital Claude Huriez, Centre Hospitalier Universitaire de Lille, Lille, France
In this new era of increasing use of immunosuppressors and biologics occurrence of opportunistic infections has emerged as a key safety issue in patients with inflammatory bowel disease (IBD). The introduction of biologic agents, especially inhibitors of tumor necrosis factor alpha (TNF-α) (infliximab, adalimimab, certolizumab) initiated a new therapeutic era and their use has continuously grown since their introduction. These agents suppress the activity of tumor necrosis factor (TNF), a proinflammatory cytokine that is important in the human immune response to infection. Opportunistic infections are infections caused by an organism that does not ordinarily cause disease but that under certain circumstances becomes pathogenic, or infection of unusual severity with an organism that normally causes only mild disease. Not surprisingly, a variety of infections have been reported in association with the use of anti-TNF agents. Infections with opportunistic pathogens such as Coccidiodes immitis (which causes coccidioidomycosis), Listeria spp., Histoplasma capsulatum (which causes histoplasmosis), Aspergillus spp., Nocardia spp., and mycobacteria, as well as with routine bacterial pathogens such as streptococci have been reported. With TNF antagonists, the risk of reactivation of granulomatous diseases and infections where host defenses are macrophage-dependent is of particular concern. Of serious concern is the development of active tubercular disease in some patients receiving anti-TNF therapy. As with HIV-positive individuals who develop tubercular disease, these cases frequently present in atypical fashion with extrapulmonary manifestations, or as disseminated disease. TNF antagonists should be used with caution in any person who has risk factors for tuberculosis. Screening for latent tubercular infection (LTBI) should be undertaken and, if present, treatment of LTBI should be started before anti-TNF therapy is initiated. Specific guidance has recently been published, to assist clinicians in screening for and preventing tuberculosis and other opportunistic infections when using these agents. Although there are no universal recommendations in the management of opportunistic infections while using
immunosuppressors and/or TNF antagonists, prevention of opportunistic infections relies on a thorough clinical and laboratory work-up, vaccinations, chemoprophylaxis and, when indicated, appropriate control of underlying chronic viral infections. Prevalence and awareness regarding specific infections may vary country by country as for instance for Histoplasmosis in endemic or non endemic regions. However, unlike screening for tuberculosis, there are no guidelines on screening for other opportunistic infections before initiation of TNF blockade. Histoplasma capsulatum is a dimorphic fungus that is endemic to North America and also found in South America, Asia, and parts of Africa; this organism is the second most commonly reported pathogen to be associated with TNF blockade. Like tuberculosis, histoplasmosis can be latent or progress very slowly, and can be reactivated and progress to active disease, particularly during immunosuppression. The presence of a granuloma on a chest radiograph might raise suspicion for a history of such infection; however, chest radiography findings are not specific for this or any granulomatous disease. Evidence of previous infection could be obtained before anti-TNF treatment starts by serologic tests, or histoplasmin skin tests; however, it is unclear how useful these tests are, and whether positive results indicate a need for antifungal prophylaxis or even contraindicate TNF blockade. Currently, neither skin nor serologic testing for histoplasmosis are recommended in HIV-infected persons. Given the small number of histoplasmosis cases that have been reported in association with TNF blockade, and the large number of people who have theoretically been exposed to H. capsulatum while taking anti-TNF agents, routine screening and antifungal prophylaxis is probably not warranted. Coccidioides immitis is another dimorphic fungus, and is endemic in the southwestern US, Central and South America. In humans, initial exposure can result in persistent, latent or subclinical infection, which can later progress to disease in immunosuppressed individuals. In areas where the fungus is endemic, patients could potentially undergo serologic screening before initiation of TNF blockade. A
24
Crohn’s Disease: Achieving Patients’ Benefits / Digestive and Liver Disease Supplements 2 (2008), 3–26
large transplant center in Arizona has reported their experience with pretransplant and post-transplant serologic monitoring, coupled with fluconazole treatment, in an effort to prevent coccidioidomycosis in organ recipients. Most coccidioidomycosis that has been reported in association with TNF blockade has, however, involved cases of acute infection and not reactivation. The usefulness of pretreatment serologic screening for coccidioidomycosis is, therefore, unclear. Furthermore, HIV-infected individuals who live in endemic areas are not routinely screened for coccidioidomycosis, and given the paucity of cases reported in association with TNF blockade, it is unclear whether there exists a need to screen for this pathogen before initiation of such therapy. Listeria monocytogenes is an intracellular pathogen acquired via the ingestion of contaminated meats and dairy products. Newly acquired (and fatal) cases of listeriosis have occurred in patients who were taking anti-TNF agents. Patient education on the avoidance of potentially infected food products is essential in the prevention of listeriosis. Physicians should advise patients who are being treated with anti-TNF agents to avoid unpasteurized milk products, undercooked meat, and ready-to-eat delicatessen foods. With the increasing use of immunosuppressive agents and more and more aggressive therapies, patients with IBD and their physicians should increase their level of knowledge and awareness about opportunistic infections. The challenge to the medical practitioner relies not only in
managing inflammatory disease but also in recognizing common and uncommon infections. The risk/benefit profile of a particular agent or therapeutic strategy should be considered for each group of patients. In the absence of national and international recommendations, we believe that the organisation of a consensus conference on this topic would help to standardize and optimize patients’ care. Essential references [1] Winthrop KL. Risk and Prevention of Tuberculosis and Other Serious Opportunistic Infections Associated with the Inhibition of Tumor Necrosis Factor. Nat Clin Pract Rheumatol 2006;2:602–10. [2] Furst DE, Breedveld FC, Kalden JR, Smolen JS, Burmester GR, Bijlsma JW, et al. Updated consensus statement on biological agents, specifically tumour necrosis factor-α (TNF-α) blocking agents and interleukin-1 receptor antagonist (IL-1ra), for the treatment of rheumatic diseases. Ann Rheum Dis 2005;64 (Suppl 4): iv2–iv14. [3] Keane J Gershon S, Wise RP, Mirabile-Levens E, Kasznica J, Schwieterman WD. Tuberculosis associated with infliximab, a tumor necrosis factor-α neutralizing agent. N Engl J Med 2001;345:1098–104. [4] British Thoracic Society Standards of Care Committee BTS recommendations for assessing risk and for managing Mycobacterium tuberculosis infection and disease in patients due to start anti-TNFalpha treatment. Thorax 2005;60:800–5. [5] Kaplan JE et al. Infectious Disease Society of America. Guidelines for preventing opportunisitic infections among HIV-infected persons – 2002. Recommendations of the US Public Health Service and the Infectious Diseases Society of America. MMWR Recomm Rep 2002;51(RR-8):1–52.
23
Opportunistic infections and anti-tumor necrosis factor antagonists in patients with IBD: prevention and diagnosis J.F. Rahier 1 , J.F. Colombel 2 1 Department 2 Department
of Hepatogastroenterology, Cliniques Universitaires de Mont Godinne Belgique of Hepatogastroenterology, Hôpital Claude Huriez, Centre Hospitalier Universitaire de Lille, Lille, France
In this new era of increasing use of immunosuppressors and biologics occurrence of opportunistic infections has emerged as a key safety issue in patients with inflammatory bowel disease (IBD). The introduction of biologic agents, especially inhibitors of tumor necrosis factor alpha (TNF-α) (infliximab, adalimimab, certolizumab) initiated a new therapeutic era and their use has continuously grown since their introduction. These agents suppress the activity of tumor necrosis factor (TNF), a proinflammatory cytokine that is important in the human immune response to infection. Opportunistic infections are infections caused by an organism that does not ordinarily cause disease but that under certain circumstances becomes pathogenic, or infection of unusual severity with an organism that normally causes only mild disease. Not surprisingly, a variety of infections have been reported in association with the use of anti-TNF agents. Infections with opportunistic pathogens such as Coccidiodes immitis (which causes coccidioidomycosis), Listeria spp., Histoplasma capsulatum (which causes histoplasmosis), Aspergillus spp., Nocardia spp., and mycobacteria, as well as with routine bacterial pathogens such as streptococci have been reported. With TNF antagonists, the risk of reactivation of granulomatous diseases and infections where host defenses are macrophage-dependent is of particular concern. Of serious concern is the development of active tubercular disease in some patients receiving anti-TNF therapy. As with HIV-positive individuals who develop tubercular disease, these cases frequently present in atypical fashion with extrapulmonary manifestations, or as disseminated disease. TNF antagonists should be used with caution in any person who has risk factors for tuberculosis. Screening for latent tubercular infection (LTBI) should be undertaken and, if present, treatment of LTBI should be started before anti-TNF therapy is initiated. Specific guidance has recently been published, to assist clinicians in screening for and preventing tuberculosis and other opportunistic infections when using these agents. Although there are no universal recommendations in the management of opportunistic infections while using
immunosuppressors and/or TNF antagonists, prevention of opportunistic infections relies on a thorough clinical and laboratory work-up, vaccinations, chemoprophylaxis and, when indicated, appropriate control of underlying chronic viral infections. Prevalence and awareness regarding specific infections may vary country by country as for instance for Histoplasmosis in endemic or non endemic regions. However, unlike screening for tuberculosis, there are no guidelines on screening for other opportunistic infections before initiation of TNF blockade. Histoplasma capsulatum is a dimorphic fungus that is endemic to North America and also found in South America, Asia, and parts of Africa; this organism is the second most commonly reported pathogen to be associated with TNF blockade. Like tuberculosis, histoplasmosis can be latent or progress very slowly, and can be reactivated and progress to active disease, particularly during immunosuppression. The presence of a granuloma on a chest radiograph might raise suspicion for a history of such infection; however, chest radiography findings are not specific for this or any granulomatous disease. Evidence of previous infection could be obtained before anti-TNF treatment starts by serologic tests, or histoplasmin skin tests; however, it is unclear how useful these tests are, and whether positive results indicate a need for antifungal prophylaxis or even contraindicate TNF blockade. Currently, neither skin nor serologic testing for histoplasmosis are recommended in HIV-infected persons. Given the small number of histoplasmosis cases that have been reported in association with TNF blockade, and the large number of people who have theoretically been exposed to H. capsulatum while taking anti-TNF agents, routine screening and antifungal prophylaxis is probably not warranted. Coccidioides immitis is another dimorphic fungus, and is endemic in the southwestern US, Central and South America. In humans, initial exposure can result in persistent, latent or subclinical infection, which can later progress to disease in immunosuppressed individuals. In areas where the fungus is endemic, patients could potentially undergo serologic screening before initiation of TNF blockade. A
24
Crohn’s Disease: Achieving Patients’ Benefits / Digestive and Liver Disease Supplements 2 (2008), 3–26
large transplant center in Arizona has reported their experience with pretransplant and post-transplant serologic monitoring, coupled with fluconazole treatment, in an effort to prevent coccidioidomycosis in organ recipients. Most coccidioidomycosis that has been reported in association with TNF blockade has, however, involved cases of acute infection and not reactivation. The usefulness of pretreatment serologic screening for coccidioidomycosis is, therefore, unclear. Furthermore, HIV-infected individuals who live in endemic areas are not routinely screened for coccidioidomycosis, and given the paucity of cases reported in association with TNF blockade, it is unclear whether there exists a need to screen for this pathogen before initiation of such therapy. Listeria monocytogenes is an intracellular pathogen acquired via the ingestion of contaminated meats and dairy products. Newly acquired (and fatal) cases of listeriosis have occurred in patients who were taking anti-TNF agents. Patient education on the avoidance of potentially infected food products is essential in the prevention of listeriosis. Physicians should advise patients who are being treated with anti-TNF agents to avoid unpasteurized milk products, undercooked meat, and ready-to-eat delicatessen foods. With the increasing use of immunosuppressive agents and more and more aggressive therapies, patients with IBD and their physicians should increase their level of knowledge and awareness about opportunistic infections. The challenge to the medical practitioner relies not only in
managing inflammatory disease but also in recognizing common and uncommon infections. The risk/benefit profile of a particular agent or therapeutic strategy should be considered for each group of patients. In the absence of national and international recommendations, we believe that the organisation of a consensus conference on this topic would help to standardize and optimize patients’ care. Essential references [1] Winthrop KL. Risk and Prevention of Tuberculosis and Other Serious Opportunistic Infections Associated with the Inhibition of Tumor Necrosis Factor. Nat Clin Pract Rheumatol 2006;2:602–10. [2] Furst DE, Breedveld FC, Kalden JR, Smolen JS, Burmester GR, Bijlsma JW, et al. Updated consensus statement on biological agents, specifically tumour necrosis factor-α (TNF-α) blocking agents and interleukin-1 receptor antagonist (IL-1ra), for the treatment of rheumatic diseases. Ann Rheum Dis 2005;64 (Suppl 4): iv2–iv14. [3] Keane J Gershon S, Wise RP, Mirabile-Levens E, Kasznica J, Schwieterman WD. Tuberculosis associated with infliximab, a tumor necrosis factor-α neutralizing agent. N Engl J Med 2001;345:1098–104. [4] British Thoracic Society Standards of Care Committee BTS recommendations for assessing risk and for managing Mycobacterium tuberculosis infection and disease in patients due to start anti-TNFalpha treatment. Thorax 2005;60:800–5. [5] Kaplan JE et al. Infectious Disease Society of America. Guidelines for preventing opportunisitic infections among HIV-infected persons – 2002. Recommendations of the US Public Health Service and the Infectious Diseases Society of America. MMWR Recomm Rep 2002;51(RR-8):1–52.