The diagnostic work-up for all symptomatic patients suspected to have histoplasmosis should include fungal blood cultures, Histoplasma urine and serum antigen, and serologic testing.134 For pulmonary histoplasmosis, bronchoscopy with culture and antigen testing of bronchoalveolar lavage are useful. Biopsy of other affected sites, including bone marrow, should be considered.134
For treatment of histoplasmosis, the guidelines recommend cessation of immunosuppression.134 Initial antifungal therapy with lipid formulation of amphotericin B is recommended, and this can be switched to itraconazole, once there is satisfactory clinical response and effective microbial control. Itraconazole may be used for milder infections.134 Treatment should be continued for at least 12 months and until clinical findings have resolved, antigenemia has cleared, and antigenuria has declined to <4 ng/mL. Cessation of anti-TNF-α therapy is sometimes associated with worsening of symptoms, despite improvement of fungal infection, and this illness is compatible with immune reconstitution inflammatory syndrome, which may need treatment with corticosteroids.134 Currently, there are no guidelines about resuming anti-TNF-α therapy after the infection has cleared.
Diagnosis is based on the isolation of the yeast or the presence of its soluble antigen in biological fluids. Treatment consists of induction with amphotericin B (or preferably using its lipid formulation) and flucytosine for at least 2 weeks, and this is followed by consolidation therapy with oral fluconazole for 6 to 12 months.137 Currently, there are no guidelines for routine screening and prophylaxis in the IBD population.4 A total of 28 cases of cryptococcosis have been reported in patients receiving TNF-α inhibitors; however, prospective studies are needed to establish screening or prevention guidelines in patients with IBD receiving these drugs.136
Diagnostic methods are special staining of respiratory fluids (toluidine blue O, Gomori-Grocott's methenamine silver nitrate, and methanol, Giemsa), direct antigen detection by immunofluorescence, or nucleic acid amplification by PCR (of sputum or bronchoalveolar lavage).139 Treatment of P. jirovecii pneumonia is primarily with trimethoprim/sulfamethoxazole, and the alternative agents are primaquine/clindamycin, pentamidine, or atovaquone.141 The role of adjunctive corticosteroids is controversial but is generally given for patients with severe hypoxemia.141
The definition for proven aspergillosis requires histopathologic documentation of infection and a positive result of culture of a specimen from a normally sterile site. The definition of probable aspergillosis requires the fulfillment of criteria within 3 categories: host factors, clinical manifestations (symptoms, signs, and radiological features), and microbiological evidence.144 The gold standard for diagnosis is direct examination of tissues and microbial culture.146,147 Additional diagnostic tests include Galactomannan antigen assays (from serum and bronchoalveolar lavage), detection of (1 → 3)-β-D-glucans in serum, and PCR. High-resolution computed tomography aid in detection of angioinvasive fungal disease due to the presence of the “halo sign”—nodular lesions that are surrounded by a ground glass appearance.147
Voriconazole and amphotericin B are licensed in the United States for primary treatment of invasive aspergillosis. Because of better survival and improved responses of initial therapy (compared with amphotericin B), voriconazole is recommended as the first-line treatment per the guidelines of the IDSA.144 The lipid formulations of amphotericin B, itraconazole, and caspofungin are approved for salvage therapy of invasive aspergillosis. Surgical resection is useful in patients with lesions that are contiguous with the great vessels or pericardium, lesions causing hemoptysis from a single focus, and lesions causing erosion into the pleural space or ribs.144 Routine prophylaxis in patients with IBD on immunosuppression is not indicated.
Diagnostic tests include serial examination of stool specimens (considered gold standard), microscopic examination of the duodenal aspirate, duodenal biopsy, culture techniques using Baermann's technique or agar plate method, and serologic assays (crude larval antigen enzyme-linked immunosorbent assay, luciferase immunoprecipitation system assay, etc.).153,155,156 Management in patients with IBD includes withdrawal of immunosuppression and anti-nematode therapy (ivermectin or albendazole).153 ECCO recommends that all patients with IBD from endemic areas with positive serology should receive anti-nematode therapy.4 In Table 4 we provide one approach for tests and vaccinations in patients with IBD.
It is essential for physicians to rigorously screen all their patients with IBD for infectious risks before the start of immunomodulator therapy. The risk of infection depends on, among other factors, the specific immunomodulator/biologic to be used, age of the patient, risk factors for exposure, nutritional status, and comorbidities.4
Although there have been numerous studies examining infectious complications related to IBD therapy, only a small minority of patients actually develop opportunistic infections. We still do not have a good test to determine the degree of immunosuppression in patients with IBD; thus, future research should focus on biomarkers that can predict which patients are most likely to develop opportunistic infection. Such biomarkers would enable better surveillance and preemptive measures to be taken to obviate that risk. Meanwhile, a detailed history, physical examination, and diagnostic work-up before embarking on immunosuppression are essential. Close follow-up after the start of immunosuppressive therapy is also essential to prevent fatal infectious complications.
1. Afif W, Loftus EV Jr. Safety profile of IBD therapeutics: infectious risks. Med Clin North Am. 2010;94:115–133.
2. Azie N, Neofytos D, Pfaller M, et al.. The PATH (prospective antifungal therapy) alliance(R) registry and invasive fungal infections: update 2012. Diagn Microbiol Infect Dis. 2012;73:293–300.
3. Lichtenstein GR, Feagan BG, Cohen RD, et al.. Serious infection and mortality in patients with Crohn's disease: more than 5 years of follow-up in the TREAT registry. Am J Gastroenterol. 2012;107:1409–1422.
4. Rahier JF, Ben-Horin S, Chowers Y, et al.. European evidence-based consensus on the prevention, diagnosis and management of opportunistic infections in inflammatory bowel disease. J Crohns Colitis. 2009;3:47–91.
5. Toruner M, Loftus EV Jr, Harmsen WS, et al.. Risk factors for opportunistic infections in patients with inflammatory bowel disease. Gastroenterology. 2008;134:929–936.
6. Ainley C, Cason J, Slavin BM, et al.. The influence of zinc status and malnutrition on immunological function in Crohn's disease. Gastroenterology. 1991;100:1616–1625.
7. Park MA, Li JT, Hagan JB, et al.. Common variable immunodeficiency: a new look at an old disease. Lancet. 2008;372:489–502.
8. Hammer SM. Clinical practice. Management of newly diagnosed HIV infection. N Engl J Med. 2005;353:1702–1710.
9. Doran MF, Crowson CS, Pond GR, et al.. Predictors of infection in rheumatoid arthritis. Arthritis Rheum. 2002;46:2294–2300.
10. Cottone M, Kohn A, Daperno M, et al.. Advanced age is an independent risk factor for severe infections and mortality in patients given anti-tumor necrosis factor therapy for inflammatory bowel disease. Clin Gastroenterol Hepatol. 2011;9:30–35.
11. Xu F, Sternberg MR, Kottiri BJ, et al.. Trends in herpes simplex virus type 1 and type 2 seroprevalence in the United States. JAMA. 2006;296:964–973.
12. Schunter MO, Walles T, Fritz P, et al.. Herpes simplex virus colitis complicating ulcerative colitis: a case report and brief review on superinfections. J Crohns Colitis. 2007;1:41–46.
13. Gnann JW Jr, Whitley RJ. Clinical practice. Herpes zoster. N Engl J Med. 2002;347:340–346.
14. Francois-Dufresne A, Garbino J, Ricou B, et al.. ARDS caused by herpes simplex virus pneumonia in a patient with Crohn's disease: a case report. Intensive Care Med. 1997;23:345–347.
15. Sevilla J, Fernandez-Plaza S, Gonzalez-Vicent M, et al.. Fatal hepatic failure secondary to acute herpes simplex virus infection. J Pediatr Hematol Oncol. 2004;26:686–688.
16. Zuckerman R, Wald A; Practice ASTIDCo. Herpes simplex virus infections in solid organ transplant recipients. Am J Transplant. 2009;9(suppl 4):S104–S107.
17. Buss DH, Scharyj M. Herpesvirus infection of the esophagus and other visceral organs in adults. Incidence and clinical significance. Am J Med. 1979;66:457–462.
18. Ali T, Yun L, Shapiro D, et al.. Viral infections in patients with inflammatory bowel disease on immunosuppressants. Am J Med Sci. 2012;343:227–232.
19. Kennedy PG. Varicella-zoster virus latency in human ganglia. Rev Med Virol. 2002;12:327–334.
20. Gershon AA. Varicella-zoster virus infections. Pediatr Rev. 2008;29:5–10; quiz 11.
21. Ansari F, Baker RD, Patel R, et al.. Varicella immunity in inflammatory bowel disease. J Pediatr Gastroenterol Nutr. 2011;53:386–388.
22. American Academy of Pediatrics Committee on Infectious Diseases. Prevention of varicella: recommendations for use of varicella vaccines in children, including a recommendation for a routine 2-dose varicella immunization schedule. Pediatrics. 2007;120:221–231.
23. Sands BE, Cuffari C, Katz J, et al.. Guidelines for immunizations in patients with inflammatory bowel disease. Inflamm Bowel Dis. 2004;10:677–692.
24. Marin M, Guris D, Chaves SS, et al.. Prevention of varicella: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2007;56:1–40.
25. Lu Y, Bousvaros A. Varicella vaccination in children with inflammatory bowel disease receiving immunosuppressive therapy. J Pediatr Gastroenterol Nutr. 2010;50:562–565.
26. Harpaz R, Ortega-Sanchez IR, Seward JF, et al.. Prevention of herpes zoster: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2008;57:1–30; quiz CE32–CE34.
27. Zhang J, Delzell E, Xie F, et al.. The use, safety, and effectiveness of herpes zoster vaccination in individuals with inflammatory and autoimmune diseases: a longitudinal observational study. Arthritis Res Ther. 2011;13:R174.
28. Cullen G, Baden RP, Cheifetz AS. Varicella zoster virus infection in inflammatory bowel disease. Inflamm Bowel Dis. 2012;18:2392–2403.
29. Strangfeld A, Listing J, Herzer P, et al.. Risk of herpes zoster in patients with rheumatoid arthritis treated with anti-TNF-alpha agents. JAMA. 2009;301:737–744.
30. Smitten AL, Choi HK, Hochberg MC, et al.. The risk of herpes zoster in patients with rheumatoid arthritis in the United States and the United Kingdom. Arthritis Rheum. 2007;57:1431–1438.
31. Oxman MN, Levin MJ, Johnson GR, et al.. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med. 2005;352:2271–2284.
32. Kroger AT, Atkinson WL, Marcuse EK, et al.. General recommendations on immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2006;55:1–48.
33. Zhang J, Xie F, Delzell E, et al.. Association between vaccination for herpes zoster and risk of herpes zoster infection among older patients with selected immune-mediated diseases. JAMA. 2012;308:43–49.
34. Hommes DW, Sterringa G, van Deventer SJ, et al.. The pathogenicity of cytomegalovirus in inflammatory bowel disease: a systematic review and evidence-based recommendations for future research. Inflamm Bowel Dis. 2004;10:245–250.
35. Papadakis KA, Tung JK, Binder SW, et al.. Outcome of cytomegalovirus infections in patients with inflammatory bowel disease. Am J Gastroenterol. 2001;96:2137–2142.
36. Matsuoka K, Iwao Y, Mori T, et al.. Cytomegalovirus is frequently reactivated and disappears without antiviral agents in ulcerative colitis patients. Am J Gastroenterol. 2007;102:331–337.
37. Domenech E, Vega R, Ojanguren I, et al.. Cytomegalovirus infection in ulcerative colitis: a prospective, comparative study on prevalence and diagnostic strategy. Inflamm Bowel Dis. 2008;14:1373–1379.
38. Kambham N, Vij R, Cartwright CA, et al.. Cytomegalovirus infection in steroid-refractory ulcerative colitis: a case-control study. Am J Surg Pathol. 2004;28:365–373.
39. Cohen JI. Epstein-Barr virus infection. N Engl J Med. 2000;343:481–492.
40. Straus SE, Cohen JI, Tosato G, et al.. NIH conference. Epstein-Barr virus infections: biology, pathogenesis, and management. Ann Intern Med. 1993;118:45–58.
41. Posthuma EF, Westendorp RG, van der Sluys Veer A, et al.. Fatal infectious mononucleosis: a severe complication in the treatment of Crohn's disease with azathioprine. Gut. 1995;36:311–313.
42. Beaugerie L, Brousse N, Bouvier AM, et al.. Lymphoproliferative disorders in patients receiving thiopurines for inflammatory bowel disease: a prospective observational cohort study. Lancet. 2009;374:1617–1625.
43. Imashuku S. Clinical features and treatment strategies of Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis. Crit Rev Oncol Hematol. 2002;44:259–272.
44. N'Guyen Y, Andreoletti L, Patey M, et al.. Fatal Epstein-Barr virus primo infection in a 25-year-old man treated with azathioprine for Crohn's disease. J Clin Microbiol. 2009;47:1252–1254.
45. Salado CT, Gallego AG, Carnerero EL, et al.. Hemophagocytic lymphohistiocytosis in Crohn's disease associated with primary infection by Epstein-Barr virus. Inflamm Bowel Dis. 2011;17:E143–E144.
46. Weinstock DM. Epstein-Barr virus, lymphoma risk and the potential role of HIV infection in IBD patients undergoing immunosuppression. Dig Dis. 2010;28:519–524.
47. Larvol L, Soule JC, Le Tourneau A. Reversible lymphoma in the setting of azathioprine therapy for Crohn's disease. N Engl J Med. 1994;331:883–884.
48. Losco A, Gianelli U, Cassani B, et al.. Epstein-Barr virus-associated lymphoma in Crohn's disease. Inflamm Bowel Dis. 2004;10:425–429.
49. Dayharsh GA, Loftus EV Jr, Sandborn WJ, et al.. Epstein-Barr virus-positive lymphoma in patients with inflammatory bowel disease treated with azathioprine or 6-mercaptopurine. Gastroenterology. 2002;122:72–77.
50. Weinstock DM, Ambrossi GG, Brennan C, et al.. Preemptive diagnosis and treatment of Epstein-Barr virus-associated post transplant lymphoproliferative disorder after hematopoietic stem cell transplant: an approach in development. Bone Marrow Transplant. 2006;37:539–546.
51. Roset Bahmanyar E, Paavonen J, Naud P, et al.. Prevalence and risk factors for cervical HPV infection and abnormalities in young adult women at enrolment in the multinational PATRICIA trial. Gynecol Oncol. 2012;127:440–450.
52. Walboomers JM, Jacobs MV, Manos MM, et al.. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol. 1999;189:12–19.
53. de Sanjose S, Quint WG, Alemany L, et al.. Human papillomavirus genotype attribution in invasive cervical cancer: a retrospective cross-sectional worldwide study. Lancet Oncol. 2010;11:1048–1056.
54. Bouvard V, Baan R, Straif K, et al.. A review of human carcinogens—part B: biological agents. Lancet Oncol. 2009;10:321–322.
55. ACOG Practice Bulletin Number 131: Screening for cervical cancer. Obstet Gynecol. 2012;120:1222–1238.
56. Kane S, Khatibi B, Reddy D. Higher incidence of abnormal pap smears in women with inflammatory bowel disease. Am J Gastroenterol. 2008;103:631–636.
57. Bhatia J, Bratcher J, Korelitz B, et al.. Abnormalities of uterine cervix in women with inflammatory bowel disease. World J Gastroenterol. 2006;12:6167–6171.
58. Lees CW, Critchley J, Chee N, et al.. Lack of association between cervical dysplasia and IBD: a large case-control study. Inflamm Bowel Dis. 2009;15:1621–1629.
59. Seksik P, Cosnes J, Sokol H, et al.. Incidence of benign upper respiratory tract infections, HSV and HPV cutaneous infections in inflammatory bowel disease patients treated with azathioprine. Aliment Pharmacol Ther. 2009;29:1106–1113.
60. Kane S. Abnormal Pap smears in inflammatory bowel disease. Inflamm Bowel Dis. 2008;14:1158–1160.
61. Fiore AE, Uyeki TM, Broder K, et al.. Prevention and control of influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2010;59:1–62.
62. Harper SA, Bradley JS, Englund JA, et al.. Seasonal influenza in adults and children–diagnosis, treatment, chemoprophylaxis, and institutional outbreak management: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis. 2009;48:1003–1032.
63. Landry ML. Diagnostic tests for influenza infection. Curr Opin Pediatr. 2011;23:91–97.
64. Fiore AE, Fry A, Shay D, et al.. Antiviral agents for the treatment and chemoprophylaxis of influenza—recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2011;60:1–24.
65. deBruyn JC, Hilsden R, Fonseca K, et al.. Immunogenicity and safety of influenza vaccination in children with inflammatory bowel disease. Inflamm Bowel Dis. 2012;18:25–33.
66. Chartrand C, Leeflang MM, Minion J, et al.. Accuracy of rapid influenza diagnostic tests: a meta-analysis. Ann Intern Med. 2012;156:500–511.
67. Andrisani G, Frasca D, Romero M, et al.. Immune response to influenza A/H1N1 vaccine in inflammatory bowel disease patients treated with anti TNF-alpha agents: effects of combined therapy with immunosuppressants. J Crohns Colitis. 2013;7:301–307.
68. Rahier JF, Papay P, Salleron J, et al.. H1N1 vaccines in a large observational cohort of patients with inflammatory bowel disease treated with immunomodulators and biological therapy. Gut. 2011;60:456–462.
69. Maginnis MS, Atwood WJ. JC virus: an oncogenic virus in animals and humans? Semin Cancer Biol. 2009;19:261–269.
70. Knowles WA, Pipkin P, Andrews N, et al.. Population-based study of antibody to the human polyomaviruses BKV and JCV and the simian polyomavirus SV40. J Med Virol. 2003;71:115–123.
71. Bloomgren G, Richman S, Hotermans C, et al.. Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med. 2012;366:1870–1880.
72. Van Assche G, Van Ranst M, Sciot R, et al.. Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn's disease. N Engl J Med. 2005;353:362–368.
73. Yousry TA, Major EO, Ryschkewitsch C, et al.. Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy. N Engl J Med. 2006;354:924–933.
74. Van Assche G, Lewis JD, Lichtenstein GR, et al.. The London position statement of the World Congress of Gastroenterology on biological therapy for IBD with the European crohn's and colitis organisation: safety. Am J Gastroenterol. 2011;106:1594–1602; quiz 1593–1603.
75. Bellizzi A, Barucca V, Fioriti D, et al.. Early years of biological agents therapy in Crohn's disease and risk of the human polyomavirus JC reactivation. J Cell Physiol. 2010;224:316–326.
76. Tan CS, Koralnik IJ. Progressive multifocal leukoencephalopathy and other disorders caused by JC virus: clinical features and pathogenesis. Lancet Neurol. 2010;9:425–437.
77. Millet JP, Moreno A, Fina L, et al.. Factors that influence current tuberculosis epidemiology. Eur Spine J. 2013;22(suppl 4):539–548.
78. Gomez-Reino JJ, Carmona L, Valverde VR, et al.. Treatment of rheumatoid arthritis with tumor necrosis factor inhibitors may predispose to significant increase in tuberculosis risk: a multicenter active-surveillance report. Arthritis Rheum. 2003;48:2122–2127.
79. Qumseya BJ, Ananthakrishnan AN, Skaros S, et al.. QuantiFERON TB gold testing for tuberculosis screening in an inflammatory bowel disease cohort in the United States. Inflamm Bowel Dis. 2011;17:77–83.
80. Raval A, Akhavan-Toyserkani G, Brinker A, et al.. Brief communication: characteristics of spontaneous cases of tuberculosis associated with infliximab. Ann Intern Med. 2007;147:699–702.
81. Vaughn BP, Doherty GA, Gautam S, et al.. Screening for tuberculosis and hepatitis B prior to the initiation of anti-tumor necrosis therapy. Inflamm Bowel Dis. 2012;18:1057–1063.
82. Lichtenstein GR, Abreu MT, Cohen R, et al.. American Gastroenterological Association Institute technical review on corticosteroids, immunomodulators, and infliximab in inflammatory bowel disease. Gastroenterology. 2006;130:940–987.
83. Kornbluth A, Sachar DB; Practice Parameters Committee of the American College of G. Ulcerative colitis practice guidelines in adults: American College Of Gastroenterology, Practice Parameters Committee. Am J Gastroenterol. 2010;105:501–523; quiz 524.
84. Theis VS, Rhodes JM. Review article: minimizing tuberculosis during anti-tumour necrosis factor-alpha treatment of inflammatory bowel disease. Aliment Pharmacol Ther. 2008;27:19–30.
85. Zabana Y, Domenech E, San Roman AL, et al.. Tuberculous chemoprophylaxis requirements and safety in inflammatory bowel disease patients prior to anti-TNF therapy. Inflamm Bowel Dis. 2008;14:1387–1391.
86. Sichletidis L, Settas L, Spyratos D, et al.. Tuberculosis in patients receiving anti-TNF agents despite chemoprophylaxis. Int J Tuberc Lung Dis. 2006;10:1127–1132.
87. Stack WA, Richardson PD, Logan RP, et al.. Nocardia asteroides lung abscess in acute ulcerative colitis treated with cyclosporine. Am J Gastroenterol. 2001;96:2255–2256.
88. Wilson JW. Nocardiosis: updates and clinical overview. Mayo Clin Proc. 2012;87:403–407.
89. Nakahara T, Kan H, Nakahara H, et al.. [A case of liver nocardiosis associated with Crohn's disease while treating infliximab]. Nihon Shokakibyo Gakkai Zasshi. 2011;108:619–626.
90. Singh SM, Rau NV, Cohen LB, et al.. Cutaneous nocardiosis complicating management of Crohn's disease with infliximab and prednisone. CMAJ. 2004;171:1063–1064.
91. Vohra P, Burroughs MH, Hodes DS, et al.. Disseminated nocardiosis complicating medical therapy in Crohn's disease. J Pediatr Gastroenterol Nutr. 1997;25:233–235.
92. Brown-Elliott BA, Brown JM, Conville PS, et al.. Clinical and laboratory features of the Nocardia spp. based on current molecular taxonomy. Clin Microbiol Rev. 2006;19:259–282.
93. Kyne L, Warny M, Qamar A, et al.. Asymptomatic carriage of Clostridium difficile and serum levels of IgG antibody against toxin A. N Engl J Med. 2000;342:390–397.
94. Elixhauser A, Jhung MA. Clostridium Difficile-Associated Disease in U.S. Hospitals, 1993–2005. HCUP Statistical Brief #50. April 2008. Rockville, MD: Agency for Healthcare Research and Quality. Available at: http://www.hcup-us.ahrq.gov/reports/statbriefs/sb50.pdf
. Accessed September 4, 2013.
95. Rodemann JF, Dubberke ER, Reske KA, et al.. Incidence of Clostridium difficile infection in inflammatory bowel disease. Clin Gastroenterol Hepatol. 2007;5:339–344.
96. Ananthakrishnan AN. Detecting and treating Clostridium difficile infections in patients with inflammatory bowel disease. Gastroenterol Clin North Am. 2012;41:339–353.
97. Ananthakrishnan AN, McGinley EL, Binion DG. Excess hospitalisation burden associated with Clostridium difficile in patients with inflammatory bowel disease. Gut. 2008;57:205–210.
98. McDonald LC, Killgore GE, Thompson A, et al.. An epidemic, toxin gene-variant strain of Clostridium difficile. N Engl J Med. 2005;353:2433–2441.
99. Kariv R, Navaneethan U, Venkatesh PG, et al.. Impact of Clostridium difficile infection in patients with ulcerative colitis. J Crohns Colitis. 2011;5:34–40.
100. Sinh P, Barrett TA, Yun L, et al.. Clostridium difficile infection and inflammatory bowel disease: a review. Gastroenterol Res Pract. 2011;2011:136064.
101. Ananthakrishnan AN, Guzman-Perez R, Gainer V, et al.. Predictors of severe outcomes associated with Clostridium difficile infection in patients with inflammatory bowel disease. Aliment Pharmacol Ther. 2012;35:789–795.
102. Cohen SH, Gerding DN, Johnson S, et al.. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the society for healthcare epidemiology of America (SHEA) and the infectious diseases society of America (IDSA). Infect Control Hosp Epidemiol. 2010;31:431–455.
103. Crook DW, Walker AS, Kean Y, et al.. Fidaxomicin versus vancomycin for Clostridium difficile infection: meta-analysis of pivotal randomized controlled trials. Clin Infect Dis. 2012;55(suppl 2):S93–S103.
104. Louie TJ, Miller MA, Mullane KM, et al.. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med. 2011;364:422–431.
105. van Nood E, Vrieze A, Nieuwdorp M, et al.. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med. 2013;368:407–415.
106. Mattila E, Uusitalo-Seppala R, Wuorela M, et al.. Fecal transplantation, through colonoscopy, is effective therapy for recurrent Clostridium difficile infection. Gastroenterology. 2012;142:490–496.
107. Hamilton MJ, Weingarden AR, Sadowsky MJ, et al.. Standardized frozen preparation for transplantation of fecal microbiota for recurrent Clostridium difficile infection. Am J Gastroenterol. 2012;107:761–767.
108. Centers for Disease Control and Prevention. Prevention of pneumococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 1997:1–24.
109. Lynch JP III, Zhanel GG. Streptococcus pneumoniae: epidemiology, risk factors, and strategies for prevention. Semin Respir Crit Care Med. 2009;30:189–209.
110. Dezfoli S, Melmed GY. Vaccination issues in patients with inflammatory bowel disease receiving immunosuppression. Gastroenterol Hepatol (N Y). 2012;8:504–512.
111. Farah R, Lisitsin S, Shay M. Bacterial meningitis associated with infliximab. Pharm World Sci. 2006;28:123–125.
112. Muller AF, Toghill PJ. Hyposplenism in gastrointestinal disease. Gut. 1995;36:165–167.
113. William BM, Corazza GR. Hyposplenism: a comprehensive review. Part I: basic concepts and causes. Hematology. 2007;12:1–13.
114. Shah A, Lettieri CJ. Fulminant meningococcal sepsis in a woman with previously unknown hyposplenism. Medscape J Med. 2008;10:36.
115. Centers for Disease Control and Prevention. Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine for adults with immunocompromising conditions: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep. 2012;61:816–819.
116. Fiorino G, Peyrin-Biroulet L, Naccarato P, et al.. Effects of immunosuppression on immune response to pneumococcal vaccine in inflammatory bowel disease: a prospective study. Inflamm Bowel Dis. 2012;18:1042–1047.
117. Kapetanovic MC, Saxne T, Sjoholm A, et al.. Influence of methotrexate, TNF blockers and prednisolone on antibody responses to pneumococcal polysaccharide vaccine in patients with rheumatoid arthritis. Rheumatology (Oxford). 2006;45:106–111.
118. Mandell LA, Wunderink RG, Anzueto A, et al.. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis. 2007;44(suppl 2):S27–S72.
119. Hameed N, Tunkel AR. Treatment of Drug-resistant Pneumococcal Meningitis. Curr Infect Dis Rep. 2010;12:274–281.
120. Diederen BM. Legionella spp. and Legionnaires' disease. J Infect. 2008;56:1–12.
121. Beigel F, Jurgens M, Filik L, et al.. Severe Legionella pneumophila pneumonia following infliximab therapy in a patient with Crohn's disease. Inflamm Bowel Dis. 2009;15:1240–1244.
122. Marston BJ, Lipman HB, Breiman RF. Surveillance for Legionnaires' disease. Risk factors for morbidity and mortality. Arch Intern Med. 1994;154:2417–2422.
123. Miyara T, Tokashiki K, Shimoji T, et al.. Rapidly expanding lung abscess caused by Legionella pneumophila in immunocompromised patients: a report of two cases. Intern Med. 2002;41:133–137.
124. Hawn TR, Berrington WR, Smith IA, et al.. Altered inflammatory responses in TLR5-deficient mice infected with Legionella pneumophila. J Immunol. 2007;179:6981–6987.
125. Chuang MH, Singh J, Ashouri N, et al.. Listeria meningitis after infliximab treatment of ulcerative colitis. J Pediatr Gastroenterol Nutr. 2010;50:337–339.
126. Centers for Disease Control and Prevention. Vital signs: listeria illnesses, deaths, and outbreaks—United States, 2009-2011. MMWR Morb Mortal Wkly Rep. 2013;62:448–452.
127. Slifman NR, Gershon SK, Lee JH, et al.. Listeria monocytogenes infection as a complication of treatment with tumor necrosis factor alpha-neutralizing agents. Arthritis Rheum. 2003;48:319–324.
128. Hohmann EL, Kim J. Case records of the Massachusetts General Hospital. Case 8-2012. A 53-year-old man with Crohn's disease, diarrhea, fever, and bacteremia. N Engl J Med. 2012;366:1039–1045.
129. Dotson JL, Crandall W, Mousa H, et al.. Presentation and outcome of histoplasmosis in pediatric inflammatory bowel disease patients treated with antitumor necrosis factor alpha therapy: a case series. Inflamm Bowel Dis. 2011;17:56–61.
130. Tsiodras S, Samonis G, Boumpas DT, et al.. Fungal infections complicating tumor necrosis factor alpha blockade therapy. Mayo Clin Proc. 2008;83:181–194.
131. Baddley JW, Winthrop KL, Patkar NM, et al.. Geographic distribution of endemic fungal infections among older persons, United States. Emerg Infect Dis. 2011;17:1664–1669.
132. Ledtke C, Tomford JW, Jain A, et al.. Clinical presentation and management of histoplasmosis in older adults. J Am Geriatr Soc. 2012;60:265–270.
133. Wallis RS, Broder MS, Wong JY, et al.. Granulomatous infectious diseases associated with tumor necrosis factor antagonists. Clin Infect Dis. 2004;38:1261–1265.
134. Hage CA, Bowyer S, Tarvin SE, et al.. Recognition, diagnosis, and treatment of histoplasmosis complicating tumor necrosis factor blocker therapy. Clin Infect Dis. 2010;50:85–92.
136. Fraison JB, Guilpain P, Schiffmann A, et al.. Pulmonary cryptococcosis in a patient with Crohn's disease treated with prednisone, azathioprine and adalimumab: exposure to chicken manure as a source of contamination. J Crohns Colitis. 2013;7:e11–e14.
137. Perfect JR, Dismukes WE, Dromer F, et al.. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the infectious diseases society of America. Clin Infect Dis. 2010;50:291–322.
138. Lee JC, Bell DC, Guinness RM, et al.. Pneumocystis jiroveci pneumonia and pneumomediastinum in an anti-TNFalpha naive patient with ulcerative colitis. World J Gastroenterol. 2009;15:1897–1900.
139. Reid AB, Chen SC, Worth LJ. Pneumocystis jirovecii pneumonia in non-HIV-infected patients: new risks and diagnostic tools. Curr Opin Infect Dis. 2011;24:534–544.
140. Mori S, Sugimoto M. Pneumocystis jirovecii infection: an emerging threat to patients with rheumatoid arthritis. Rheumatology (Oxford). 2012;51:2120–2130.
141. McKinnell JA, Cannella AP, Kunz DF, et al.. Pneumocystis pneumonia in hospitalized patients: a detailed examination of symptoms, management, and outcomes in human immunodeficiency virus (HIV)-infected and HIV-uninfected persons. Transpl Infect Dis. 2012;14:510–518.
142. Poppers DM, Scherl EJ. Prophylaxis against Pneumocystis pneumonia in patients with inflammatory bowel disease: toward a standard of care. Inflamm Bowel Dis. 2008;14:106–113.
143. Segal BH. Aspergillosis. N Engl J Med. 2009;360:1870–1884.
144. Walsh TJ, Anaissie EJ, Denning DW, et al.. Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis. 2008;46:327–360.
145. Alderson JW, Van Dinter TG Jr, Opatowsky MJ, et al.. Disseminated aspergillosis following infliximab therapy in an immunosuppressed patient with Crohn's disease and chronic hepatitis C: a case study and review of the literature. MedGenMed. 2005;7:7.
146. Buess M, Cathomas G, Halter J, et al.. Aspergillus-PCR in bronchoalveolar lavage for detection of invasive pulmonary aspergillosis in immunocompromised patients. BMC Infect Dis. 2012;12:237.
147. Beirao F, Araujo R. State of the art diagnostic of mold diseases: a practical guide for clinicians. Eur J Clin Microbiol Infect Dis. 2013;32:3–9.
148. Ahmad S, Khan Z. Invasive candidiasis: a review of nonculture-based laboratory diagnostic methods. Indian J Med Microbiol. 2012;30:264–269.
149. Clancy CJ, Nguyen MH. The end of an era in defining the optimal treatment of invasive candidiasis. Clin Infect Dis. 2012;54:1123–1125.
150. Andes DR, Safdar N, Baddley JW, et al.. Impact of treatment strategy on outcomes in patients with candidemia and other forms of invasive candidiasis: a patient-level quantitative review of randomized trials. Clin Infect Dis. 2012;54:1110–1122.
151. Kett DH, Shorr AF, Reboli AC, et al.. Anidulafungin compared with fluconazole in severely ill patients with candidemia and other forms of invasive candidiasis: support for the 2009 IDSA treatment guidelines for candidiasis. Crit Care. 2011;15:R253.
152. Moghadam KG, Khashayar P, Hashemi M. Gastrointestinal strongyloidiasis in immunocompromised patients: a case report. Acta Med Indones. 2011;43:191–194.
153. Qu Z, Kundu UR, Abadeer RA, et al.. Strongyloides colitis is a lethal mimic of ulcerative colitis: the key morphologic differential diagnosis. Hum Pathol. 2009;40:572–577.
154. Segarra-Newnham M. Manifestations, diagnosis, and treatment of Strongyloides stercoralis infection. Ann Pharmacother. 2007;41:1992–2001.
155. Mylonaki M, Langmead L, Pantes A, et al.. Enteric infection in relapse of inflammatory bowel disease: importance of microbiological examination of stool. Eur J Gastroenterol Hepatol. 2004;16:775–778.
156. Krolewiecki AJ, Ramanathan R, Fink V, et al.. Improved diagnosis of Strongyloides stercoralis using recombinant antigen-based serologies in a community-wide study in northern Argentina. Clin Vaccine Immunol. 2010;17:1624–1630.