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Cytomegalovirus infection of the appendix in a patient with the acquired immunodeficiency syndrome
GASTROENTEROLOGY
1991;101:247-249
Cytomegalovirus Infection of the Appendix in a Patient With the Acquired Immunodeficiency Syndrome S. VALERDIZ-CASASOLA Department
of Pathology, University
and F. J. PARDO-MINDAN Clinic, University
Disseminated cytomegalovirus infection occurs predominantly in immunocompromised hosts. Involvement of the gastrointestinal tract in the acquired immunodeficiency syndrome is frequent, but to our knowledge there is only one report of involvement of the appendix. In this study, a patient with a history of the acquired immunodeficiency syndrome who presented with fever and an acute abdomen is described. At surgery, appendicitis was found. In the surgical specimen, appendicitis and cytomegalovirus infection were found. Cytomegalovirus should be considered as a possible cause of appendicitis in the acquired immunodeficiency syndrome.
of Navarra, Pamplona,
Spain
On the seventh hospital day, the patient showed elevation of temperature to 39.3% and tenderness in the right lower quadrant and midline of the abdomen with rebound and guarding. Rectal examination showed tenderness referred to the lower abdomen. The’white blood cell count was 14,000 mm3. The preoperative diagnosis was acute appendicitis, and 16 hours after presentation the patient was taken to the operating room and underwent an appendectomy. On the sixth postoperative day, the patient was discharged following an uncomplicated operative course. Three months after the patient was well, the serology titer for CMV was decreased (21 EIU) and there was no evidence of CMV infection in other parts of the gastrointestinal tract.
Pathological Findings
D
isseminated
cytomegalovirus
(CMV) infection is seen in immunocompromised patients with hematologic malignancies, the acquired immunodeficiency syndrome (AIDS), or renal transplantation, or in those who are receiving corticosteroids or chemotherapy (l-3).The viral infection commonly involves the lungs, gastrointestinal tract, adrenal glands, liver, and spleen (4).The most common localization of CMV in the gastrointestinal tract is colon and esophagus (5). We report a patient with AIDS who presented with CMV appendicitis. To our knowledge this is the second reported case of CMV appendicitis.
Case Report A 31-year-old man with a history of IV drug abuse, presented with an B-month history of chills, malaise, fever, and weight loss. Physical examination on admission showed a temperature of 38°C. The abdomen was normal. Laboratory data on admission were within normal limits except erythrocyte sedimentation rate, 45 mm/h, human immunodeficiency virus (HIV) positive ( enzyme-linked immunosorbent assay ); monocytes and lymphocytes, 671 mm3; OKT4/ OKTB, 0.35 (CD4, 33.5 and CDB, 93.9); and serology titers for CMV, 34 EIU (low positive until 50 EIU). Computed tomographic scans of the abdomen and thorax were normal.
Grossly, the appendix was edematous and showed a fibrinous coating of the serosa. On section, the lumen was not obstructed and the wall had hemorragic punctates. There was no perforation of the appendix. Histologically, there was ulceration of the mucosa and infiltration of neutrophils in the whole wall. Endothelium, smooth muscle, fibroblasts, and histiocytes had numerous intranuclear and intracytoplasmatic viral inclusion (Figure 1). Special stains Gram, Grocott, Ziehl-Neelsen, and methenamine silver were negative. Cultures for bacteria, acid-fast bacilli, and fungi of the appendix were negative. The in situ hybridization with CMV probes (Enzo Biochem, Inc., New York, NY) was positive (Figure 2).
Discussion Disseminated CMV infection is commonly a result of reactivation of latent infection and usually occurs in patients with altered immune status (3,6). The stimulus
for reactivation
may be a suppression
of
Abbreviations used in this paper: AIDS, acquired immunodeficiency syndrome; CMV, cytomegalovirus. o 1991 by the American Gastroenterological Association 0016~5085/91/$3.00
248
VALERDIZ-CASASOLA
AND PARDO-MINDAN
Figure 1. Appendix. Cytomegalovirus inclusion in mesenchymal cell (arrow) in area of acute inflammation (H&E; original magnification x 125).
GASTROENTEROLOGY
Vol. 101. No. 1
immunity, as seen with chemotherapy, AIDS, and malignancy (2). Cytomegalovirus is the most common gastrointestinal infection in patients with AIDS (4). The most common localization of CMV infection in the autopsy of these patients are lungs, adrenal glands, and gastrointestinal tract (7). Alimentary tract involvement has been described frequently due to accessability of the alimentary tract to biopsy (6,8). Cytomegalovirus infection has been found in the esophagus, stomach, duodenum, jejunum, ileum, gallbladder, colon, and rectum (5). Nevertheless, in autopsy as in biopsy, the description of this infection is limited to upper gastrointestinal tract and colon, and there is one reference to involvement of the appendix in the literature (9). Because CMV colitis primarily affects the right colon (6), CMV appendicitis is not an unexpected finding and is probably more frequent than the absence of published reports would suggest. Perhaps many such cases remain asymptomatic or are missed because the appendix is usually not examined at autopsy. Appendicitis is one of the most frequent causes of acute abdomen and it is estimated that 7% of the population will develop this entity in their life time (10). Appendicitis caused by virus is extremely rare: we found reports of only three cases produced by adenovirus (11,12) and one case of appendiceal perforation with positive culture for CMV (13). Cytomegalovirus infection of the gastrointestinal tract is characterized by ulceration (4,6,9). In our case, the mucosa of the appendix was ulcerated, but
’
!
Figure 2. Cytomegalovirus inclusions after incubation with CMV DNA probe (in situ hybridization; original magnification X400).
July 1991
there was no perforation. The pathogenesis of CMVassociated ulcerations is controversial. Some authors claim that the virus is a secondary invader, colonizing previously damaged tissues (14). Other authors, such as Sisson et al. (x5), considered that in many cases of acute appendicitis the virus induced ulceration as the “trigger” followed by bacterial invasion of the wall. In our patient, no other microorganisms were found in culture of the appendix, and the special stains for fungi and bacteria were negative. The serological titer to CMV was scarcely elevated, but in patients with AIDS the immune responses are poor. Most cells infected with CMV are mesenchymal cells (4,6). In our case, the inclusions were in fibroblasts, histiocytes, endothelial cells, and smooth muscle. With the anticipated increase of AIDS-related infections, an increased awareness of unusual presentations of usual infections is necessary. The appendix is an unusual localization for usual infections (CMV) in AIDS. References Wilcox CM, Forksmark ChE, Grendell JH, Darragh TM, Cello JP. Cytomegalovirus-associated acute pancreatic disease in patients with acquired immunodeficiency syndrome. Report of two patients. Gastroenterology 1990;99:263-267. Spiegel JS, Schwabe AD. Disseminated cytomegalovirus infection with gastrointestinal involvement: the role of altered immunity in the elderly. Am J Gastroenterol 1980;73:37-44. Teixidor HS, Honig CL, Norsoph E, Albert S, Mouradian JA, Whalen JP. Cytomegalovirus infection of the alimentary canal: radiologic findings with pathologic correlation. Radiology 1987; 163:317-323. Waisman J, Rotterdam H, Niedt G, Lowin K, Racz P. AIDS: an overview of the pathology. Path01 Res Pratt 1987;182:729-754.
CYTOMEGALOVIRUS INFECTION OF APPENDIX
249
5. Rotterdam H, Sommers HC. Alimentary tract biopsy lesions in the acquired immune deficiency syndrome. Pathology 1985;17: 181-192. 6. Hinnant KL, Rotterdam H, Bell ET, Tapper ML. Cytomegalovirus infection of the alimentary tract: a clinicopathological correlation, Am J Gastroenterol1986;81:944-950. 7. Reichert CM, O’Leary TJ, Levens OL, Simrell ChR, Macher AM. Autopsy pathology in the acquired immune deficiency syndrome. Am J Path01 1983;112:357-382. 8. Gertler SL, Pressman J, Price P, Brozinsky S, Miyai K. Gastrointestinal cytomegalovirus infection in a homosexual man with severe acquired immunodeficiency syndrome. Gastroenterology 1983;85:1403-1406. 9. Rotterdam H. The pathology of the gastrointestinal tract in AIDS. Dig Dis Path01 2:21-38. In: Watanabe S, Wolff M, Sommers SC. New York; Field & Wood, 1989. 10. Roza AM, Perloff LJ, Nafi A, Jorkasky D, Grossman RA, Tomazewski JE, Barker CF. Acute appendicitis in the renal allograft recipient. Transplantation 1987;44:715-716. 11. Reif RM. Viral appendicitis. Hum Path01 1981;12:193-196. 12. Yunis EJ, Hashida Y. Electron microscopic demonstration of adenovirus in appendix vermiformis in case of ileocecal intussusception. Pediatrics 1973;51:566-568, 13. Peterson PK, Balfour HH, Marker SC, Fryd DS, Howard RT, Simmons RL. Cytomegalovirus disease in renal allograft recipients. Medicine 1980;59:283-300. 14. Cooper HS, Raffensperger EC, Jonas L, Fitts WT. Cytomegalovirus inclusions in patients with ulcerative colitis and toxic dilation requiring colonic resection. Gastroenterology 1977;72: 1253-1256. 15. Sisson RG, Ahlvin RC, Harlow MC. Superficial mucosal ulceration and pathogenesis of acute appendicitis in childhood. Am J Surg 1971;122:378-380.
Received September 13,199O. Accepted February 8, 1991. Address requests for reprints to: S. Valerdiz-Casasola, M.D., Department of Pathology, Clinica Universitaria, Universidad de Navarra, Apartado 192, Pamplona, Spain,
1991;101:247-249
Cytomegalovirus Infection of the Appendix in a Patient With the Acquired Immunodeficiency Syndrome S. VALERDIZ-CASASOLA Department
of Pathology, University
and F. J. PARDO-MINDAN Clinic, University
Disseminated cytomegalovirus infection occurs predominantly in immunocompromised hosts. Involvement of the gastrointestinal tract in the acquired immunodeficiency syndrome is frequent, but to our knowledge there is only one report of involvement of the appendix. In this study, a patient with a history of the acquired immunodeficiency syndrome who presented with fever and an acute abdomen is described. At surgery, appendicitis was found. In the surgical specimen, appendicitis and cytomegalovirus infection were found. Cytomegalovirus should be considered as a possible cause of appendicitis in the acquired immunodeficiency syndrome.
of Navarra, Pamplona,
Spain
On the seventh hospital day, the patient showed elevation of temperature to 39.3% and tenderness in the right lower quadrant and midline of the abdomen with rebound and guarding. Rectal examination showed tenderness referred to the lower abdomen. The’white blood cell count was 14,000 mm3. The preoperative diagnosis was acute appendicitis, and 16 hours after presentation the patient was taken to the operating room and underwent an appendectomy. On the sixth postoperative day, the patient was discharged following an uncomplicated operative course. Three months after the patient was well, the serology titer for CMV was decreased (21 EIU) and there was no evidence of CMV infection in other parts of the gastrointestinal tract.
Pathological Findings
D
isseminated
cytomegalovirus
(CMV) infection is seen in immunocompromised patients with hematologic malignancies, the acquired immunodeficiency syndrome (AIDS), or renal transplantation, or in those who are receiving corticosteroids or chemotherapy (l-3).The viral infection commonly involves the lungs, gastrointestinal tract, adrenal glands, liver, and spleen (4).The most common localization of CMV in the gastrointestinal tract is colon and esophagus (5). We report a patient with AIDS who presented with CMV appendicitis. To our knowledge this is the second reported case of CMV appendicitis.
Case Report A 31-year-old man with a history of IV drug abuse, presented with an B-month history of chills, malaise, fever, and weight loss. Physical examination on admission showed a temperature of 38°C. The abdomen was normal. Laboratory data on admission were within normal limits except erythrocyte sedimentation rate, 45 mm/h, human immunodeficiency virus (HIV) positive ( enzyme-linked immunosorbent assay ); monocytes and lymphocytes, 671 mm3; OKT4/ OKTB, 0.35 (CD4, 33.5 and CDB, 93.9); and serology titers for CMV, 34 EIU (low positive until 50 EIU). Computed tomographic scans of the abdomen and thorax were normal.
Grossly, the appendix was edematous and showed a fibrinous coating of the serosa. On section, the lumen was not obstructed and the wall had hemorragic punctates. There was no perforation of the appendix. Histologically, there was ulceration of the mucosa and infiltration of neutrophils in the whole wall. Endothelium, smooth muscle, fibroblasts, and histiocytes had numerous intranuclear and intracytoplasmatic viral inclusion (Figure 1). Special stains Gram, Grocott, Ziehl-Neelsen, and methenamine silver were negative. Cultures for bacteria, acid-fast bacilli, and fungi of the appendix were negative. The in situ hybridization with CMV probes (Enzo Biochem, Inc., New York, NY) was positive (Figure 2).
Discussion Disseminated CMV infection is commonly a result of reactivation of latent infection and usually occurs in patients with altered immune status (3,6). The stimulus
for reactivation
may be a suppression
of
Abbreviations used in this paper: AIDS, acquired immunodeficiency syndrome; CMV, cytomegalovirus. o 1991 by the American Gastroenterological Association 0016~5085/91/$3.00
248
VALERDIZ-CASASOLA
AND PARDO-MINDAN
Figure 1. Appendix. Cytomegalovirus inclusion in mesenchymal cell (arrow) in area of acute inflammation (H&E; original magnification x 125).
GASTROENTEROLOGY
Vol. 101. No. 1
immunity, as seen with chemotherapy, AIDS, and malignancy (2). Cytomegalovirus is the most common gastrointestinal infection in patients with AIDS (4). The most common localization of CMV infection in the autopsy of these patients are lungs, adrenal glands, and gastrointestinal tract (7). Alimentary tract involvement has been described frequently due to accessability of the alimentary tract to biopsy (6,8). Cytomegalovirus infection has been found in the esophagus, stomach, duodenum, jejunum, ileum, gallbladder, colon, and rectum (5). Nevertheless, in autopsy as in biopsy, the description of this infection is limited to upper gastrointestinal tract and colon, and there is one reference to involvement of the appendix in the literature (9). Because CMV colitis primarily affects the right colon (6), CMV appendicitis is not an unexpected finding and is probably more frequent than the absence of published reports would suggest. Perhaps many such cases remain asymptomatic or are missed because the appendix is usually not examined at autopsy. Appendicitis is one of the most frequent causes of acute abdomen and it is estimated that 7% of the population will develop this entity in their life time (10). Appendicitis caused by virus is extremely rare: we found reports of only three cases produced by adenovirus (11,12) and one case of appendiceal perforation with positive culture for CMV (13). Cytomegalovirus infection of the gastrointestinal tract is characterized by ulceration (4,6,9). In our case, the mucosa of the appendix was ulcerated, but
’
!
Figure 2. Cytomegalovirus inclusions after incubation with CMV DNA probe (in situ hybridization; original magnification X400).
July 1991
there was no perforation. The pathogenesis of CMVassociated ulcerations is controversial. Some authors claim that the virus is a secondary invader, colonizing previously damaged tissues (14). Other authors, such as Sisson et al. (x5), considered that in many cases of acute appendicitis the virus induced ulceration as the “trigger” followed by bacterial invasion of the wall. In our patient, no other microorganisms were found in culture of the appendix, and the special stains for fungi and bacteria were negative. The serological titer to CMV was scarcely elevated, but in patients with AIDS the immune responses are poor. Most cells infected with CMV are mesenchymal cells (4,6). In our case, the inclusions were in fibroblasts, histiocytes, endothelial cells, and smooth muscle. With the anticipated increase of AIDS-related infections, an increased awareness of unusual presentations of usual infections is necessary. The appendix is an unusual localization for usual infections (CMV) in AIDS. References Wilcox CM, Forksmark ChE, Grendell JH, Darragh TM, Cello JP. Cytomegalovirus-associated acute pancreatic disease in patients with acquired immunodeficiency syndrome. Report of two patients. Gastroenterology 1990;99:263-267. Spiegel JS, Schwabe AD. Disseminated cytomegalovirus infection with gastrointestinal involvement: the role of altered immunity in the elderly. Am J Gastroenterol 1980;73:37-44. Teixidor HS, Honig CL, Norsoph E, Albert S, Mouradian JA, Whalen JP. Cytomegalovirus infection of the alimentary canal: radiologic findings with pathologic correlation. Radiology 1987; 163:317-323. Waisman J, Rotterdam H, Niedt G, Lowin K, Racz P. AIDS: an overview of the pathology. Path01 Res Pratt 1987;182:729-754.
CYTOMEGALOVIRUS INFECTION OF APPENDIX
249
5. Rotterdam H, Sommers HC. Alimentary tract biopsy lesions in the acquired immune deficiency syndrome. Pathology 1985;17: 181-192. 6. Hinnant KL, Rotterdam H, Bell ET, Tapper ML. Cytomegalovirus infection of the alimentary tract: a clinicopathological correlation, Am J Gastroenterol1986;81:944-950. 7. Reichert CM, O’Leary TJ, Levens OL, Simrell ChR, Macher AM. Autopsy pathology in the acquired immune deficiency syndrome. Am J Path01 1983;112:357-382. 8. Gertler SL, Pressman J, Price P, Brozinsky S, Miyai K. Gastrointestinal cytomegalovirus infection in a homosexual man with severe acquired immunodeficiency syndrome. Gastroenterology 1983;85:1403-1406. 9. Rotterdam H. The pathology of the gastrointestinal tract in AIDS. Dig Dis Path01 2:21-38. In: Watanabe S, Wolff M, Sommers SC. New York; Field & Wood, 1989. 10. Roza AM, Perloff LJ, Nafi A, Jorkasky D, Grossman RA, Tomazewski JE, Barker CF. Acute appendicitis in the renal allograft recipient. Transplantation 1987;44:715-716. 11. Reif RM. Viral appendicitis. Hum Path01 1981;12:193-196. 12. Yunis EJ, Hashida Y. Electron microscopic demonstration of adenovirus in appendix vermiformis in case of ileocecal intussusception. Pediatrics 1973;51:566-568, 13. Peterson PK, Balfour HH, Marker SC, Fryd DS, Howard RT, Simmons RL. Cytomegalovirus disease in renal allograft recipients. Medicine 1980;59:283-300. 14. Cooper HS, Raffensperger EC, Jonas L, Fitts WT. Cytomegalovirus inclusions in patients with ulcerative colitis and toxic dilation requiring colonic resection. Gastroenterology 1977;72: 1253-1256. 15. Sisson RG, Ahlvin RC, Harlow MC. Superficial mucosal ulceration and pathogenesis of acute appendicitis in childhood. Am J Surg 1971;122:378-380.
Received September 13,199O. Accepted February 8, 1991. Address requests for reprints to: S. Valerdiz-Casasola, M.D., Department of Pathology, Clinica Universitaria, Universidad de Navarra, Apartado 192, Pamplona, Spain,