Review Article | Published:

Inflammatory and infectious manifestations of immunodeficiency in the gastrointestinal tract

Modern Pathologyvolume 31pages844861 (2018) | Download Citation


Immune compromise may result from genetic abnormalities, HIV/AIDS, or consequences of therapy for neoplastic and autoimmune diseases. Many immunocompromised patients develop severe gastrointestinal symptoms, particularly diarrhea, accompanied by non-specific or mild endoscopic abnormalities; mucosal biopsy with pathologic interpretation has a major role in the diagnosis and management of these patients. Immunocompromised individuals are at risk for all the diseases that affect those with a healthy immune system, but they are also prone to other illnesses that rarely affect immunocompetent patients. This review discusses the gastrointestinal manifestations of primary and acquired immunodeficiency, chemotherapy-related injury, and infections that show a predilection for immunocompromised patients. Key histologic features and relevant differential diagnoses are emphasized.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1.

    Conley ME, Notarangelo LD, Etzioni A. Diagnostic criteria for primary immunodeficiencies. Representing PAGID (Pan-American Group for Immunodeficiency) and ESID (European Society for Immunodeficiencies). Clin Immunol. 1999;93:190–7.

  2. 2.

    Bonilla FA, Barlan I, Chapel H, et al. International Consensus Document (ICON): common variable immunodeficiency disorders. J Allergy Clin Immunol Pract. 2016;4:38–59.

  3. 3.

    Patuzzo G, Barbieri A, Tinazzi E, et al. Autoimmunity and infection in common variable immunodeficiency (CVID). Autoimmun Rev. 2016;15:877–82.

  4. 4.

    Mortaz E, Tabarsi P, Mansouri D, et al. Cancers related to immunodeficiencies: update and perspectives. Front Immunol. 2016;7:365.

  5. 5.

    Malamut G, Verkarre V, Suarez F, et al. The enteropathy associated with common variable immunodeficiency: the delineated frontiers with celiac disease. Am J Gastroenterol. 2010;105:2262–75.

  6. 6.

    Molaei M, Kaboli A, Fathi AM, et al. Nodular lymphoid hyperplasia in common variable immunodeficiency syndrome mimicking familial adenomatous polyposis on endoscopy. Indian J Pathol Microbiol. 2009;52:530–3.

  7. 7.

    Biagi F, Bianchi PI, Zilli A, et al. The significance of duodenal mucosal atrophy in patients with common variable immunodeficiency: a clinical and histopathologic study. Am J Clin Pathol. 2012;138:185–9.

  8. 8.

    Daniels JA, Lederman HM, Maitra A, et al. Gastrointestinal tract pathology in patients with common variable immunodeficiency (CVID): a clinicopathologic study and review. Am J Surg Pathol. 2007;31:1800–12.

  9. 9.

    Washington K, Stenzel TT, Buckley RH, et al. Gastrointestinal pathology in patients with common variable immunodeficiency and X-linked agammaglobulinemia. Am J Surg Pathol. 1996;20:1240–52.

  10. 10.

    Aghamohammadi A, Cheraghi T, Gharagozlou M, et al. IgA deficiency: correlation between clinical and immunological phenotypes. J Clin Immunol. 2009;29:130–6.

  11. 11.

    Barton SH, Murray JA. Celiac disease and autoimmunity in the gut and elsewhere. Gastroenterol Clin North Am. 2008;37:411–28. vii

  12. 12.

    Pallav K, Xu H, Leffler DA, et al. Immunoglobulin A deficiency in celiac disease in the United States. J Gastroenterol Hepatol. 2016;31:133–7.

  13. 13.

    Lai KK, Lamps LW. Enterocolitis in immunocompromised patients. Semin Diagn Pathol. 2014;31:176–91.

  14. 14.

    Marciano BE, Rosenzweig SD, Kleiner DE, et al. Gastrointestinal involvement in chronic granulomatous disease. Pediatrics. 2004;114:462–8.

  15. 15.

    Obayashi N, Arai K, Nakano N, et al. Leopard skin-like colonic mucosa: a novel endoscopic finding of chronic granulomatous disease-associated colitis. J Pediatr Gastroenterol Nutr. 2016;62:56–59.

  16. 16.

    Marks DJ, Miyagi K, Rahman FZ, et al. Inflammatory bowel disease in CGD reproduces the clinicopathological features of Crohn’s disease. Am J Gastroenterol. 2009;104:117–24.

  17. 17.

    Alimchandani M, Lai JP, Aung PP, et al. Gastrointestinal histopathology in chronic granulomatous disease: a study of 87 patients. Am J Surg Pathol. 2013;37:1365–72.

  18. 18.

    Lederman HM, Winkelstein JA. X-linked agammaglobulinemia: an analysis of 96 patients. Med (Baltim). 1985;64:145–56.

  19. 19.

    Chandrakasan S, Venkateswaran S, Kugathasan S. Nonclassic inflammatory bowel disease in young infants: immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome, and other disorders. Pediatr Clin North Am. 2017;64:139–60.

  20. 20.

    Krones E, Hogenauer C. Diarrhea in the immunocompromised patient. Gastroenterol Clin North Am. 2012;41:677–701.

  21. 21.

    Heimall J, Puck J, Buckley R, et al. Current knowledge and priorities for future research in late effects after hematopoietic stem cell transplantation (HCT) for severe combined immunodeficiency patients: a consensus statement from the second pediatric blood and marrow transplant consortium international conference on late effects after pediatric HCT. Biol Blood Marrow Transplant. 2017;23:379–87.

  22. 22.

    Lee SJ, Flowers ME. Recognizing and managing chronic graft-versus-host disease. Hematology Am Soc Hematol Educ Program. 2008;1:134–141.

  23. 23.

    Holtan SG, Pasquini M, Weisdorf DJ. Acute graft-versus-host disease: a bench-to-bedside update. Blood. 2014;124:363–73.

  24. 24.

    Ross WA, Couriel D. Colonic graft-versus-host disease. Curr Opin Gastroenterol. 2005;21:64–69.

  25. 25.

    Lampert IA, Thorpe P, van Noorden S, et al. Selective sparing of enterochromaffin cells in graft versus host disease affecting the colonic mucosa. Histopathology. 1985;9:875–86.

  26. 26.

    Levine JE, Huber E, Hammer ST, et al. Low Paneth cell numbers at onset of gastrointestinal graft-versus-host disease identify patients at high risk for nonrelapse mortality. Blood. 2013;122:1505–9.

  27. 27.

    Kreft A, Mottok A, Mesteri I, et al. Consensus diagnostic histopathological criteria for acute gastrointestinal graft versus host disease improve interobserver reproducibility. Virchows Arch. 2015;467:255–63.

  28. 28.

    Shulman HM, Cardona DM, Greenson JK, et al. NIH Consensus development project on criteria for clinical trials in chronic graft-versus-host disease: II. The 2014 Pathology Working Group Report. Biol Blood Marrow Transplant. 2015;21:589–603.

  29. 29.

    Yeh SP, Liao YM, Hsu CH, et al. Gastric bleeding due to graft-vs-host disease: discrepancy between endoscopic and histologic assessment. Am J Clin Pathol. 2004;122:919–25.

  30. 30.

    Cruz-Correa M, Poonawala A, Abraham SC, et al. Endoscopic findings predict the histologic diagnosis in gastrointestinal graft-versus-host disease. Endoscopy. 2002;34:808–13.

  31. 31.

    Abraham J, Janin A, Gornet JM, et al. Clinical severity scores in gastrointestinal graft-versus-host disease. Transplantation. 2014;97:965–71.

  32. 32.

    Narkhede M, Rybicki L, Abounader D, et al. The association of histologic grade with acute graft-versus-host disease response and outcomes. Am J Hematol. 2017;92:683–8.

  33. 33.

    Lerner KG, Kao GF, Storb R, et al. Histopathology of graft-vs.-host reaction (GvHR) in human recipients of marrow from HL-A-matched sibling donors. Transplant Proc. 1974;6:367–71.

  34. 34.

    Myerson D, Steinbach G, Gooley TA, et al. Graft-versus-host disease of the gut: a histologic activity grading system and validation. Biol Blood Marrow Transplant. 2017;23:1573–9.

  35. 35.

    Epstein RJ, McDonald GB, Sale GE, et al. The diagnostic accuracy of the rectal biopsy in acute graft-versus-host disease: a prospective study of thirteen patients. Gastroenterology. 1980;78:764–71.

  36. 36.

    Kamar N, Faure P, Dupuis E, et al. Villous atrophy induced by mycophenolate mofetil in renal-transplant patients. Transpl Int. 2004;17:463–7.

  37. 37.

    Star KV, Ho VT, Wang HH, et al. Histologic features in colon biopsies can discriminate mycophenolate from GVHD-induced colitis. Am J Surg Pathol. 2013;37:1319–28.

  38. 38.

    Welch DC, Wirth PS, Goldenring JR, et al. Gastric graft-versus-host disease revisited: does proton pump inhibitor therapy affect endoscopic gastric biopsy interpretation? Am J Surg Pathol. 2006;30:444–9.

  39. 39.

    Herrera AF, Soriano G, Bellizzi AM, et al. Cord colitis syndrome in cord-blood stem-cell transplantation. N Engl J Med. 2011;365:815–24.

  40. 40.

    Shimoji S, Kato K, Eriguchi Y, et al. Evaluating the association between histological manifestations of cord colitis syndrome with GVHD. Bone Marrow Transplant. 2013;48:1249–52.

  41. 41.

    Bhatt AS, Freeman SS, Herrera AF, et al. Sequence-based discovery of Bradyrhizobium enterica in cord colitis syndrome. N Engl J Med. 2013;369:517–28.

  42. 42.

    Gorkiewicz G, Trajanoski S, Hogenauer C. Bradyrhizobium enterica in cord colitis syndrome. N Engl J Med. 2013;369:1866–7.

  43. 43.

    Machado NO. Neutropenic enterocolitis: a continuing medical and surgical challenge. N Am J Med Sci. 2010;2:293–300.

  44. 44.

    Sachak T, Arnold MA, Naini BV, et al. Neutropenic enterocolitis: new insights into a deadly entity. Am J Surg Pathol. 2015;39:1635–42.

  45. 45.

    Hermsen JL, Schurr MJ, Kudsk KA, et al. Phenotyping Clostridium septicum infection: a surgeon’s infectious disease. J Surg Res. 2008;148:67–76.

  46. 46.

    Batman PA, Kapembwa MS, Belmonte L, et al. HIV enteropathy: HAART reduces HIV-induced stem cell hyperproliferation and crypt hypertrophy to normal in jejunal mucosa. J Clin Pathol. 2014;67:14–18.

  47. 47.

    Batman PA, Miller AR, Forster SM, et al. Jejunal enteropathy associated with human immunodeficiency virus infection: quantitative histology. J Clin Pathol. 1989;42:275–81.

  48. 48.

    Cello JP, Day LW. Idiopathic AIDS enteropathy and treatment of gastrointestinal opportunistic pathogens. Gastroenterology. 2009;136:1952–65.

  49. 49.

    Cannon MJ, Schmid DS, Hyde TB. Review of cytomegalovirus seroprevalence and demographic characteristics associated with infection. Rev Med Virol. 2010;20:202–13.

  50. 50.

    Chetty R, Roskell DE. Cytomegalovirus infection in the gastrointestinal tract. J Clin Pathol. 1994;47:968–72.

  51. 51.

    Keates J, Lagahee S, Crilley P, et al. CMV enteritis causing segmental ischemia and massive intestinal hemorrhage. Gastrointest Endosc. 2001;53:355–9.

  52. 52.

    Chen YM, Hung YP, Huang CF, et al. Cytomegalovirus disease in nonimmunocompromised, human immunodeficiency virus-negative adults with chronic kidney disease. J Microbiol Immunol Infect. 2014;47:345–9.

  53. 53.

    Shah R, Vaidya G, Kalakonda A, et al. Cytomegalovirus colitis mimicking rectal carcinoma in a young immunocompetent patient. ACG Case Rep J. 2015;2:165–7.

  54. 54.

    Juric-Sekhar G, Upton MP, Swanson PE, et al. Cytomegalovirus (CMV) in gastrointestinal mucosal biopsies: should a pathologist perform CMV immunohistochemistry if the clinician requests it? Hum Pathol. 2017;60:11–15.

  55. 55.

    Nikkels AF, Delvenne P, Sadzot-Delvaux C, et al. Distribution of varicella zoster virus and herpes simplex virus in disseminated fatal infections. J Clin Pathol. 1996;49:243–8.

  56. 56.

    Weidner AS, Panarelli NC, Rennert H, et al. Immunohistochemistry improves the detection of adenovirus in gastrointestinal biopsy specimens from hematopoietic stem cell transplant recipients. Am J Clin Pathol. 2016;146:627–31.

  57. 57.

    Solomon IH, Hornick JL, Laga AC. Immunohistochemistry is rarely justified for the diagnosis of viral infections. Am J Clin Pathol. 2017;147:96–104.

  58. 58.

    McCurdy JD, Enders FT, Jones A, et al. Detection of cytomegalovirus in patients with inflammatory bowel disease: where to biopsy and how many biopsies? Inflamm Bowel Dis. 2015;21:2833–8.

  59. 59.

    Yan Z, Wang L, Dennis J, et al. Clinical significance of isolated cytomegalovirus-infected gastrointestinal cells. Int J Surg Pathol. 2014;22:492–8.

  60. 60.

    Solomon IH, Hornick JL, Laga AC. Immunohistochemistry is rarely justified for the diagnosis of viral infections. Am J Clin Pathol. 2016;147:96–104.

  61. 61.

    McCoy MH, Post K, Sen JD, et al. qPCR increases sensitivity to detect cytomegalovirus in formalin-fixed, paraffin-embedded tissue of gastrointestinal biopsies. Hum Pathol. 2014;45:48–53.

  62. 62.

    Mills AM, Guo FP, Copland AP, et al. A comparison of CMV detection in gastrointestinal mucosal biopsies using immunohistochemistry and PCR performed on formalin-fixed, paraffin-embedded tissue. Am J Surg Pathol. 2013;37:995–1000.

  63. 63.

    Leen AM, Rooney CM. Adenovirus as an emerging pathogen in immunocompromised patients. Br J Haematol. 2005;128:135–44.

  64. 64.

    Fox JP, Brandt CD, Wassermann FE, et al. The virus watch program: a continuing surveillance of viral infections in metropolitan New York families. VI. Observations of adenovirus infections: virus excretion patterns, antibody response, efficiency of surveillance, patterns of infections, and relation to illness. Am J Epidemiol. 1969;89:25–50.

  65. 65.

    Runde V, Ross S, Trenschel R, et al. Adenoviral infection after allogeneic stem cell transplantation (SCT): report on 130 patients from a single SCT unit involved in a prospective multi center surveillance study. Bone Marrow Transplant. 2001;28:51–57.

  66. 66.

    Workowski KA, Berman S, Centers for Disease C. et al. Sexually transmitted diseases treatment guidelines, 2010. MMWR Recomm Rep. 2010;59:1–110.

  67. 67.

    Goodell SE, Quinn TC, Mkrtichian E, et al. Herpes simplex virus proctitis in homosexual men. Clinical, sigmoidoscopic, and histopathological features. N Engl J Med. 1983;308:868–71.

  68. 68.

    Singh SP, Odze RD. Multinucleated epithelial giant cell changes in esophagitis: a clinicopathologic study of 14 cases. Am J Surg Pathol. 1998;22:93–99.

  69. 69.

    Donoghue HD, Holton J. Intestinal tuberculosis. Curr Opin Infect Dis. 2009;22:490–6.

  70. 70.

    Kirsch R, Pentecost M, Hall Pde M, et al. Role of colonoscopic biopsy in distinguishing between Crohn’s disease and intestinal tuberculosis. J Clin Pathol. 2006;59:840–4.

  71. 71.

    Almadi MA, Ghosh S, Aljebreen AM. Differentiating intestinal tuberculosis from Crohn’s disease: a diagnostic challenge. Am J Gastroenterol. 2009;104:1003–12.

  72. 72.

    Woods GL, Walker DH. Detection of infection or infectious agents by use of cytologic and histologic stains. Clin Microbiol Rev. 1996;9:382–404.

  73. 73.

    Mustafa T, Wiker HG, Mfinanga SG, et al. Immunohistochemistry using a Mycobacterium tuberculosis complex specific antibody for improved diagnosis of tuberculous lymphadenitis. Mod Pathol. 2006;19:1606–14.

  74. 74.

    Lamps LW, Madhusudhan KT, Greenson JK, et al. The role of Yersinia enterocolitica and Yersinia pseudotuberculosis in granulomatous appendicitis: a histologic and molecular study. Am J Surg Pathol. 2001;25:508–15.

  75. 75.

    Amarapurkar DN, Patel ND, Amarapurkar AD, et al. Tissue polymerase chain reaction in diagnosis of intestinal tuberculosis and Crohn’s disease. J Assoc Physicians India. 2004;52:863–7.

  76. 76.

    Kisacik B, Pamuk ON, Onat AM, et al. Characteristics predicting tuberculosis risk under tumor necrosis factor-alpha inhibitors: report from a large multicenter cohort with high background prevalence. J Rheumatol. 2016;43:524–9.

  77. 77.

    Horsburgh CR Jr. Mycobacterium avium complex infection in the acquired immunodeficiency syndrome. N Engl J Med. 1991;324:1332–8.

  78. 78.

    Sun HY, Chen MY, Wu MS, et al. Endoscopic appearance of GI mycobacteriosis caused by the Mycobacterium avium complex in a patient with AIDS: case report and review. Gastrointest Endosc. 2005;61:775–9.

  79. 79.

    Klatt EC, Jensen DF, Meyer PR. Pathology of Mycobacterium avium-intracellulare infection in acquired immunodeficiency syndrome. Hum Pathol. 1987;18:709–14.

  80. 80.

    Dolmans RA, Boel CH, Lacle MM, et al. Clinical manifestations, treatment, and diagnosis of tropheryma whipplei infections. Clin Microbiol Rev. 2017;30:529–55.

  81. 81.

    Yan L, Yang C, Tang J. Disruption of the intestinal mucosal barrier in Candida albicans infections. Microbiol Res. 2013;168:389–95.

  82. 82.

    Lamps LW, Lai KK, Milner DA Jr.. Fungal infections of the gastrointestinal tract in the immunocompromised host: an update. Adv Anat Pathol. 2014;21:217–27.

  83. 83.

    Patterson TF, Kirkpatrick WR, White M, et al. Invasive aspergillosis. Disease spectrum, treatment practices, and outcomes. I3 Aspergillus Study Group. Med (Baltim). 2000;79:250–60.

  84. 84.

    Kazan E, Maertens J, Herbrecht R, et al. A retrospective series of gut aspergillosis in haematology patients. Clin Microbiol Infect. 2011;17:588–94.

  85. 85.

    Petrikkos G, Skiada A, Lortholary O, et al. Epidemiology and clinical manifestations of mucormycosis. Clin Infect Dis. 2012;54:S23–34.

  86. 86.

    Colombo AL, Tobon A, Restrepo A, et al. Epidemiology of endemic systemic fungal infections in Latin America. Med Mycol. 2011;49:785–98.

  87. 87.

    Horwath MC, Fecher RA, Deepe GS Jr.. Histoplasma capsulatum, lung infection and immunity. Future Microbiol. 2015;10:967–75.

  88. 88.

    Assi MA, Sandid MS, Baddour LM, et al. Systemic histoplasmosis: a 15-year retrospective institutional review of 111 patients. Med (Baltim). 2007;86:162–9.

  89. 89.

    Deng Z, Ribas JL, Gibson DW, et al. Infections caused by Penicillium marneffei in China and Southeast Asia: review of eighteen published cases and report of four more Chinese cases. Rev Infect Dis. 1988;10:640–52.

  90. 90.

    Ko CI, Hung CC, Chen MY, et al. Endoscopic diagnosis of intestinal penicilliosis marneffei: report of three cases and review of the literature. Gastrointest Endosc. 1999;50:111–4.

  91. 91.

    Deng ZL, Connor DH. Progressive disseminated penicilliosis caused by Penicillium marneffei. Report of eight cases and differentiation of the causative organism from Histoplasma capsulatum. Am J Clin Pathol. 1985;84:323–7.

  92. 92.

    Girardin M, Greloz V, Hadengue A. Cryptococcal gastroduodenitis: a rare location of the disease. Clin Gastroenterol Hepatol. 2010;8:e28–29.

  93. 93.

    Washington K, Gottfried MR, Wilson ML. Gastrointestinal cryptococcosis. Mod Pathol. 1991;4:707–11.

  94. 94.

    Harris JR, Lockhart SR, Debess E, et al. Cryptococcus gattii in the United States: clinical aspects of infection with an emerging pathogen. Clin Infect Dis. 2011;53:1188–95.

  95. 95.

    Cama VA, Mathison BA. Infections by intestinal Coccidia and Giardia duodenalis. Clin Lab Med. 2015;35:423–44.

  96. 96.

    Agarwal S, Mayer L. Pathogenesis and treatment of gastrointestinal disease in antibody deficiency syndromes. J Allergy Clin Immunol. 2009;124:658–64.

  97. 97.

    Oberhuber G, Mesteri I, Kopf W, et al. Demonstration of Trophozoites of G. Lamblia inileal mucosal biopsy specimens may reveal giardiasis in patients with significantly inflamed parasite-free duodenal mucosa. Am J Surg Pathol. 2016;40:1280–5.

  98. 98.

    Oberhuber G, Kastner N, Stolte M. Giardiasis: a histologic analysis of 567 cases. Scand J Gastroenterol. 1997;32:48–51.

  99. 99.

    Robertson S, Arnold C, Montgomery E, et al. Duodenal giardiasis: lessons from a large tertiary hospital. Mod Pathol. 2015;28:187A.

  100. 100.

    Panarelli NC, Gobara N, Hoda RS, et al. Cytology preparations of formalin fixative aid detection of giardia in duodenal biopsy samples. Am J Surg Pathol. 2017;41:570–4.

  101. 101.

    Field AS, Milner DA Jr.. Intestinal microsporidiosis. Clin Lab Med. 2015;35:445–59.

  102. 102.

    Ryan U, Paparini A, Monis P, et al. It’s official - Cryptosporidium is a gregarine: what are the implications for the water industry? Water Res. 2016;105:305–13.

  103. 103.

    Lai KK, Goyne HE, Hernandez-Gonzalo D, et al. Cystoisospora belli infection of the gallbladder in immunocompetent patients: a clinicopathologic review of 18 cases. Am J Surg Pathol. 2016;40:1070–4.

  104. 104.

    Gupta S, Narang S, Nunavath V, et al. Chronic diarrhoea in HIV patients: prevalence of coccidian parasites. Indian J Med Microbiol. 2008;26:172–5.

  105. 105.

    Milder JE, Walzer PD, Kilgore G, et al. Clinical features of strongyloides stercoralis infection in an endemic area of the United States. Gastroenterology. 1981;80:1481–8.

  106. 106.

    Genta RM. Dysregulation of strongyloidiasis: a new hypothesis. Clin Microbiol Rev. 1992;5:345–55.

  107. 107.

    Kishimoto K, Hokama A, Hirata T, et al. Endoscopic and histopathological study on the duodenum of Strongyloides stercoralis hyperinfection. World J Gastroenterol. 2008;14:1768–73.

  108. 108.

    Minematsu H, Hokama A, Makishi T, et al. Colonoscopic findings and pathologic characteristics of Strongyloides colitis: a case series. Digestion. 2011;83:210–4.

  109. 109.

    Levenhagen MA, Costa-Cruz JM. Update on immunologic and molecular diagnosis of human strongyloidiasis. Acta Trop. 2014;135:33–43.

  110. 110.

    Thompson BF, Fry LC, Wells CD, et al. The spectrum of GI strongyloidiasis: an endoscopic-pathologic study. Gastrointest Endosc. 2004;59:906–10.

Download references


We thank Laura W. Lamps, MD for her critical review of this manuscript.

Author information


  1. Albert Einstein College of Medicine, Bronx, NY, USA

    • Nicole C. Panarelli
  2. Weill Cornell Medicine, New York, NY, USA

    • Rhonda K. Yantiss


  1. Search for Nicole C. Panarelli in:

  2. Search for Rhonda K. Yantiss in:

Conflict of interest

The authors declare that they have no conflict of interest.

Corresponding author

Correspondence to Rhonda K. Yantiss.

About this article

Publication history