The Unturned Stone
http://www.100md.com
《新英格兰医药杂志》
In this Journal feature, information about a real patient is presented in stages (boldface type) to an expert clinician, who responds to the information, sharing his or her reasoning with the reader (regular type). The authors' commentary follows.
A 20-year-old man was transferred to an academic medical center in Salt Lake City for further evaluation of diarrhea, abdominal pain, and fever. Two months before admission, he presented to a community hospital with dull, intermittent pain in the right lower quadrant. A colonoscopy performed at that time showed patchy erythema, edema, and ulcerations from the transverse colon to the cecum. The terminal ileum also appeared inflamed and had linear ulcerations. Pathological examination of specimens revealed nonspecific chronic inflammation.
The patient's symptoms have been present for two months, defining this as a case of chronic diarrhea. Acute diarrhea, most often caused by infectious agents, resolves within four weeks. Among the four major categories of chronic diarrhea — osmotic, secretory, fatty, and inflammatory — the fever and endoscopic and pathological findings point to an inflammatory process. Disorders to consider include Crohn's disease, Beh?et's disease, and chronic infections such as gastrointestinal tuberculosis, histoplasmosis, and amebiasis. Ulcerating viral infections (such as cytomegalovirus and herpes simplex infection) would be important concerns in an immunocompromised patient.
While at the community hospital, the patient tested positive for Clostridium difficile toxin, but did not improve despite treatment with oral metronidazole and, subsequently, oral vancomycin. He was also treated aggressively for presumed Crohn's disease with mesalamine, corticosteroids (prednisone, 60 mg daily), and two infusions of infliximab — with no improvement. Because of increasing pain and abdominal distention, the patient was placed on total parenteral nutrition and transferred to the academic medical center for further management of his condition.
Risk factors for C. difficile infection include advanced age, hospitalization, and antibiotic exposure. Even without prior antibiotic use, the patient may have become colonized during a hospitalization. Most infections with C. difficile respond to vancomycin or metronidazole, and the lack of a response warrants a search for an alternative diagnosis. Furthermore, although rectal sparing has been described, the endoscopic findings are inconsistent with the diagnosis of C. difficile colitis. A flare-up of Crohn's disease is possible; an association between C. difficile infection and exacerbations of inflammatory bowel disease is well recognized. Although most patients with moderate-to-severe Crohn's disease respond to prednisone or infliximab (a chimeric tumor necrosis factor monoclonal antibody), the absence of a response does not rule out the diagnosis. Treatment with corticosteroids and infliximab for presumptive Crohn's disease without convincing histopathological evidence is potentially hazardous, given that chronic infections are well known to mimic Crohn's disease.
The patient was born in Guatemala and adopted at birth. He moved to the western United States at nine years of age with his adoptive family. He said that he had not traveled recently. He had had lifelong diarrhea, with several watery stools daily. The stools were small to moderate in volume, occasionally tinged with blood, but not greasy or notably foul smelling. He had undergone multiple evaluations and lower endoscopies and had been given a diagnosis of nonspecific colitis. Treatment with aminosalicylates and corticosteroids led to minimal improvement. At 12 years of age, he was diagnosed with colonic malacoplakia (yellowish, soft papules or nodules) at another academic medical center after colonic biopsy revealed histiocytes with intracytoplasmic inclusion bodies and intracellular bacilli. Extensive evaluation at that time showed no evidence of inflammatory bowel disease. Bacterial cultures and examination of stool samples for signs of ova and parasites were negative. In addition, acid-fast staining and cultures, including fungal cultures, of colonic-biopsy specimens were negative. He was treated with trimethoprim–sulfamethoxazole with moderate but temporary improvement, and diarrhea soon recurred. Further details of the medical history included a positive tuberculin skin test but a normal chest radiograph; he subsequently received oral isoniazid for six months. The patient reported no use of alcohol, tobacco, or illicit drugs, and he was not sexually active. He had received a blood transfusion during infancy for unknown reasons.
The patient's history of immigration from Central America suggests the possibility of tropical sprue, a syndrome that can occur in persons residing in certain tropical locations, which is presumed to be caused by small-bowel bacterial overgrowth and characterized by chronic diarrhea and malabsorption. However, tropical sprue is rare in Guatemala, and the characteristic pathological findings are limited to the small intestine, rather than the colon. Predisposing conditions for colonic malacoplakia include chronic infections by coliform bacteria and granulomatous processes, such as sarcoidosis and tuberculosis. Colonic tuberculosis usually causes ulcers with associated nodularity, a finding not observed in this patient. The diagnosis is established by culture or histologic examination, both of which were negative. Nonetheless, the yield from cultures and biopsy material may be low, and diagnosing intestinal tuberculosis may be particularly challenging in the absence of extraintestinal manifestations. The history of a blood transfusion during infancy raises the possibility of an underlying infection with the human immunodeficiency virus (HIV).
The patient appeared to be underdeveloped and chronically ill, with diminutive stature and decreased muscle mass. On physical examination, his height was 160 cm and his weight 47.5 kg. His temperature was 39.2°C, his blood pressure 98/40 mm Hg, his heart rate 94 beats per minute, and his respiratory rate 20 breaths per minute. His lungs were clear, and his cardiac examination showed no abnormalities. His abdomen was soft, with mild distention, normal bowel sounds, and no organomegaly. There was diffuse tenderness to palpation that was worse in the right lower quadrant, but without rebound tenderness. A rectal examination revealed no masses; a small amount of brown stool was obtained, which tested positive for occult blood. An examination of the skin revealed no lesions, and a neurologic examination showed no abnormalities.
The patient clearly has chronic diarrhea and resulting nutrient malabsorption, as reflected in his habitus. A complete blood count and measurements of prothrombin time and serum levels of electrolytes, albumin, calcium, phosphate, magnesium, iron, folate, and vitamin B12 should be obtained to screen for malabsorption; blood cultures should also be obtained. Abdominal computed tomography (CT) should be performed, with special attention to the ileocecal region for signs of mural and omental thickening, lymphadenopathy, ascites, or abscess. Fever, right-lower-quadrant pain, and an ileocecal distribution of inflammation may be clues to the presence of Crohn's disease, but they may also suggest a neoplasm or an infection that might include tuberculosis, histoplasmosis, amebiasis, Mycobacterium avium complex, and Yersinia enterocolitica.
The white-cell count was 5500 per cubic millimeter, with 10 percent band forms. The hematocrit was 36 percent, with a mean corpuscular volume of 81 μm3, and the platelet count was 146,000 per cubic millimeter. Other laboratory values were as follows: sodium, 138 mmol per liter; chloride, 101 mmol per liter; potassium, 4.6 mmol per liter; bicarbonate, 33 mmol per liter; blood urea nitrogen, 11 mg per deciliter (3.93 mmol per liter); creatinine, 0.9 mg per deciliter (79.6 mmol per liter); and lipase, 20 U per liter (normal range, 30 to 190). The calcium level was normal. The serum albumin level was 2.9 g per deciliter. The aspartate aminotransferase level was 95 U per liter (normal range, 15 to 59); the alanine aminotransferase level was normal. The prothrombin time was prolonged at 17.8 seconds (international normalized ratio, 1.4) with a normal partial thromboplastin time of 31 seconds. Chest radiography revealed no abnormalities. CT of the abdomen and pelvis showed a thickened cecum and terminal ileum, without signs of fistula, abscess, or free air.
The patient has mild anemia, probably the result of iron deficiency due to either malabsorption or chronic blood loss. Alternatively, an ongoing infection or inflammatory process could result in anemia of chronic disease. His prolonged prothrombin time is likely to reflect a deficiency of vitamin K resulting from malabsorption of fat-soluble vitamins, in which case I would expect it to be corrected with parenteral supplementation. Celiac sprue has been associated with elevated levels of serum aminotransferase that become normal when the patient adopts a gluten-free diet. A high prevalence of amebiasis is seen in the general population in Central America. Although the manifestation of intestinal amebiasis is typically subacute, it may be associated on rare occasions with a chronic nondysenteric infection accompanied by diarrhea, abdominal pain, and weight loss that may be present for years. The diagnosis rests on microscopical evidence of cysts or trophozoites in stool or endoscopic biopsy samples, both of which were negative in this patient. Tuberculosis is also a major health problem in Central America, particularly infection with drug-resistant strains. Exacerbations of intestinal tuberculosis mimicking Crohn's disease have been reported after infliximab treatment similar to that received by this patient. I remain concerned about an undiagnosed intestinal infection.
The patient received intravenous fluids and total parenteral nutrition. His treatment with mesalamine was continued, and the dosage of prednisone was increased to 80 mg daily. Testing for HIV was negative. A repeated colonoscopy revealed normal-appearing mucosa from the distal colon to the proximal transverse colon, where patchy erythema, edema, and linear ulcerations were seen. A narrow stricture was encountered at the hepatic flexure, preventing safe advancement of the endoscope (Figure 1). Multiple biopsy samples were obtained, including tissue for viral and fungal cultures. A biopsy specimen was obtained from a single 4-mm nodule at the rectosigmoid junction. The clinical findings were thought to be consistent with Crohn's disease, and plans were made for surgery.
Figure 1. Stricture at the Hepatic Flexure on Endoscopy with Edema, Erythema, and Linear Ulcerations.
In reviewing all the data, including the poor response to therapy, I remain skeptical of the diagnosis of Crohn's disease. I am still concerned about a chronic infection; this should be ruled out before proceeding to surgery. Gastrointestinal tuberculosis, histoplasmosis, amebiasis, and actinomycosis have all been reported to mimic Crohn's disease. Aeromonas and yersinia, although typically self-limited infections, may last several weeks and would be considerations were this illness the patient's initial presentation. The patient's stool samples should be examined again for Entamoeba histolytica cysts and trophozoites. The cultures and histologic sections obtained from the endoscopic-biopsy specimens should be carefully evaluated for evidence of any of these pathogens.
Before surgery, the biopsy specimens were reviewed. Both the samples from the right-sided biopsies and the sample from the rectosigmoid nodule included numerous macrophages containing organisms compatible with Histoplasma capsulatum (Figure 2 and Figure 3). This was confirmed with Gomori–methenamine silver staining. There was no distortion in colonic crypts to suggest inflammatory bowel disease. A review of the peripheral-blood smear revealed previously undetected organisms in leukocytes, a finding that is consistent with histoplasmosis (Figure 4). The serum was strongly positive for histoplasma antigen, at 30 enzyme immunoassay units.
Figure 2. Low-Power View of Ulcerated Colonic Mucosa with Chronic Inflammatory Infiltrate (Hematoxylin and Eosin).
Figure 3. Numerous H. capsulatum in Macrophages (Hematoxylin and Eosin).
Figure 4. Peripheral-Blood Smear Showing Intracellular Organisms.
The patient has disseminated histoplasmosis, which involves the gastrointestinal tract in up to 70 percent of patients. The usual treatment is itraconazole, although amphotericin B is used in severely immunocompromised patients. This patient tested negative for HIV, but prolonged courses of corticosteroids and a potential underlying immunodeficiency that might have predisposed him to disseminated histoplasmosis support the use of amphotericin B until a clinical response, which may be slow, is observed.
The patient was started on therapy with amphotericin B, and the corticosteroids were slowly decreased. Three days after the new drug was introduced, hypotension and a rigid abdomen developed. Exploratory laparotomy revealed extensive bowel necrosis; a right hemicolectomy and distal ileal resection with ileostomy were performed. Blood cultures grew Streptococcus mitis. The resected bowel showed extensive histoplasmosis. The patient's hospital course was complicated by nosocomial pneumonia and the abdominal compartment syndrome, which required prolonged open decompression of the abdomen. He eventually underwent partial surgical closure of his abdomen with mesh placement. Superficial layers healed subsequently by secondary intention. He was discharged to his home with treatment with oral itraconazole to continue for six months. Sixteen months after hospital discharge, he reported feeling well and had gained 25 kg.
Abdominal perforation is a recognized complication of gastrointestinal histoplasmosis — a complication that might have been avoided with an earlier diagnosis and medical treatment. Despite his complicated course, his improved general health and weight gain at follow-up indicate successful treatment of his infection.
Commentary
A challenge that clinicians face on a daily basis is deciding when they have sufficient information to make a diagnosis. Clinical medicine is filled with scenarios in which ruling out a condition that mimics another disorder is important. One example is the necessity to rule out pulmonary tuberculosis or an anaerobic infection in an elderly patient with a history of smoking who presents with a cavitary lung mass. The current case provides another example: the need to consider infections that may mimic inflammatory bowel disease.
Unfortunately, no single test is perfectly sensitive and specific for Crohn's disease. The diagnosis relies on a consistent historical, endoscopic, radiographic, and histopathological pattern. As was seen with the patient in this case, management with early, aggressive immunosuppression without a definitive diagnosis can lead to catastrophic consequences when a chronic infection goes undiagnosed.
Histoplasmosis, which primarily affects the lungs, is caused by a dimorphic fungus endemic to river valleys in the midwestern and southeastern United States, as well as Central America and South America. The organism is transmitted by inhalation of spores from soil contaminated by bat or bird droppings. Histoplasmosis is not an easy diagnosis to make. Indeed, Goodwin and colleagues noted two decades ago that "the diagnosis of histoplasmosis begins with thinking of it."1
More than 90 percent of infected persons remain asymptomatic and are identified only as a result of abnormal chest radiographs or positive skin testing.2 Fewer than 10 percent of all recognized cases represent disseminated disease. Disseminated disease is uncommon in immunocompetent patients, but it is common when infection occurs in immunocompromised patients.3 Gastrointestinal involvement occurs in 70 to 90 percent of patients with disseminated disease and has been reported primarily in immunocompromised patients.3,4,5,6
Clinical manifestations of gastrointestinal histoplasmosis range from none, in asymptomatic infection, to nausea, vomiting, diarrhea, bleeding, abdominal pain, weight loss, obstruction, and perforation. The most frequently involved sites are the terminal ileum and cecum.4 Endoscopic findings include plaques, small polyps, mucosal edema, ulcerations, strictures, and masses.3,6 Definitive diagnosis is made by histologic examination or culture growth, with subsequent identification of H. capsulatum. Histoplasmosis antigen in serum or urine is specific and sensitive, and organisms may occasionally be detected on a peripheral-blood smear. Serologic testing for antibodies is less reliable, since immunocompromised patients may be anergic.4 Treatment options include intravenous amphotericin B or oral itraconazole; early treatment usually results in good outcomes.
Certainly, this patient's diarrhea, right-lower-quadrant pain, and endoscopic findings of ileocecal inflammation and stricture could have been consistent with Crohn's disease. Several clues, however, raised the suspicion of a chronic infection that mimicked Crohn's disease, including the patient's childhood in Central America and the substantial mononuclear cell inflammation on colonic-biopsy specimens, in the absence of the distortion of crypt architecture or granulomas typical of Crohn's disease.
An important additional clue that the diagnosis was incorrect was the poor clinical response to aggressive treatment for Crohn's disease. Corticosteroid therapy typically results in short-term response rates of 80 to 90 percent among patients with moderate-to-severe Crohn's disease.7 Patients with Crohn's disease that is refractory to aminosalicylates and corticosteroids have short-term responses to infliximab 50 to 80 percent of the time.8 Rather than improving while receiving these agents, this patient's condition worsened. In retrospect, the infliximab may have led to his decompensation.
Infliximab, along with etanercept, exerts biologic effects through antagonism of tumor necrosis factor . Several reports have documented disseminated histoplasmosis in patients treated with infliximab or etanercept for rheumatoid arthritis or Crohn's disease.9,10,11 Cell cultures infected with H. capsulatum and treated with infliximab show proliferation of the organism and decreased lymphocyte proliferation.9 Tuberculosis has also been reported in patients treated with infliximab, and tuberculin skin testing is routinely performed before the initiation of infliximab therapy.12 Although routine testing for histoplasmosis is not recommended before infliximab therapy is initiated, a test for histoplasmosis antigen in urine or serum could have been helpful in this case, especially since the diagnosis was uncertain.
The lack of a pathognomonic test for Crohn's disease makes this condition one that is frequently misdiagnosed.13 The identification of chronic infections may be particularly challenging, since their diagnosis may require multiple biopsies, large amounts of sample tissue, special culture media, and prolonged culture times. This case demonstrates that infections precipitated by antagonists to tumor necrosis factor may mimic Crohn's disease. Diligence — leaving no stone unturned — will facilitate the appropriate diagnosis and treatment of these challenging conditions.
Dr. Saint is the recipient of a Career Development Award from the Health Services Research and Development Program of the Department of Veterans Affairs; his work is supported by a Patient Safety Developmental Center Grant (P20-HS11540) from the Agency for Healthcare Research and Quality.
Dr. Moseley reports having received consulting fees from Pfizer for serving as an expert witness.
Source Information
From the Department of Internal Medicine, University of Utah, Salt Lake City (C.J.G., C.T., I.S.S.); and the Medical Service, Ann Arbor Department of Veterans Affairs Medical Center (R.H.M., S.S.); the Ann Arbor Veterans Affairs Health Services Research and Development Center of Excellence (S.S.); and the Department of Internal Medicine, University of Michigan Health System (R.H.M., S.S.) — all in Ann Arbor, Mich.
Address reprint requests to Dr. Goulet at the Division of Gastroenterology, University of Utah, Rm. 4R118, 30 North Medical, Salt Lake City, UT 84132, or at chrisgoulet_98@yahoo.com.
References
Goodwin RA, Loyd JE, Des Prez RM. Histoplasmosis in normal hosts. Medicine (Baltimore) 1981;60:231-266.
Deepe GS Jr. Histoplasmosis capsulatum. In: Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas, and Bennett's principles and practice of infectious disease. 5th ed. Philadelphia: Churchill Livingstone, 2000:2718-33.
Lamps LW, Molina CP, West AB, Haggitt RC, Scott MA. The pathologic spectrum of gastrointestinal and hepatic histoplasmosis. Am J Clin Pathol 2000;113:64-72.
Cappell MS, Mandell W, Grimes MM, Neu HC. Gastrointestinal histoplasmosis. Dig Dis Sci 1988;33:353-360.
Mullick SS, Mody DR, Schwartz MR. Cytology of gastrointestinal histoplasmosis: a report of two cases with differential diagnosis and diagnostic pitfalls. Acta Cytol 1996;40:989-994.
Hertan H, Nair S, Arguello P. Progressive gastrointestinal histoplasmosis leading to colonic obstruction two years after initial presentation. Am J Gastroenterol 2001;96:221-222.
Sands B. Crohn's disease. In: Feldman M, Friedman LS, Sleisenger MH, eds. Sleisenger and Fordtran's gastrointestinal and liver disease. 7th ed. Philadelphia: Saunders, 2002:2005-38.
Targan SR, Hanauer SB, van Deventer SJ, et al. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor for Crohn's disease. N Engl J Med 1997;337:1029-1035.
Wood KL, Hage CA, Knox KS, et al. Histoplasmosis after treatment with anti-tumor necrosis factor- therapy. Am J Respir Crit Care Med 2003;167:1279-1282.
Lee JH, Slifman NR, Gershon SK, et al. Life-threatening histoplasmosis complicating immunotherapy with tumor necrosis factor antagonists infliximab and etanercept. Arthritis Rheum 2002;46:2565-2570.
Colombel JF, Loftus EV Jr, Tremaine WJ, et al. The safety profile of infliximab in patients with Crohn's disease: the Mayo Clinic experience in 500 patients. Gastroenterology 2004;126:19-31.
Keane J, Gershon S, Wise RP, et al. Tuberculosis associated with infliximab, a tumor necrosis factor -neutralizing agent. N Engl J Med 2001;345:1098-1104.
Lavy A, Militianu D, Eidelman S. Diseases of the intestine mimicking Crohn's disease. J Clin Gastroenterol 1992;15:17-23.(Christopher J. Goulet, M.)
A 20-year-old man was transferred to an academic medical center in Salt Lake City for further evaluation of diarrhea, abdominal pain, and fever. Two months before admission, he presented to a community hospital with dull, intermittent pain in the right lower quadrant. A colonoscopy performed at that time showed patchy erythema, edema, and ulcerations from the transverse colon to the cecum. The terminal ileum also appeared inflamed and had linear ulcerations. Pathological examination of specimens revealed nonspecific chronic inflammation.
The patient's symptoms have been present for two months, defining this as a case of chronic diarrhea. Acute diarrhea, most often caused by infectious agents, resolves within four weeks. Among the four major categories of chronic diarrhea — osmotic, secretory, fatty, and inflammatory — the fever and endoscopic and pathological findings point to an inflammatory process. Disorders to consider include Crohn's disease, Beh?et's disease, and chronic infections such as gastrointestinal tuberculosis, histoplasmosis, and amebiasis. Ulcerating viral infections (such as cytomegalovirus and herpes simplex infection) would be important concerns in an immunocompromised patient.
While at the community hospital, the patient tested positive for Clostridium difficile toxin, but did not improve despite treatment with oral metronidazole and, subsequently, oral vancomycin. He was also treated aggressively for presumed Crohn's disease with mesalamine, corticosteroids (prednisone, 60 mg daily), and two infusions of infliximab — with no improvement. Because of increasing pain and abdominal distention, the patient was placed on total parenteral nutrition and transferred to the academic medical center for further management of his condition.
Risk factors for C. difficile infection include advanced age, hospitalization, and antibiotic exposure. Even without prior antibiotic use, the patient may have become colonized during a hospitalization. Most infections with C. difficile respond to vancomycin or metronidazole, and the lack of a response warrants a search for an alternative diagnosis. Furthermore, although rectal sparing has been described, the endoscopic findings are inconsistent with the diagnosis of C. difficile colitis. A flare-up of Crohn's disease is possible; an association between C. difficile infection and exacerbations of inflammatory bowel disease is well recognized. Although most patients with moderate-to-severe Crohn's disease respond to prednisone or infliximab (a chimeric tumor necrosis factor monoclonal antibody), the absence of a response does not rule out the diagnosis. Treatment with corticosteroids and infliximab for presumptive Crohn's disease without convincing histopathological evidence is potentially hazardous, given that chronic infections are well known to mimic Crohn's disease.
The patient was born in Guatemala and adopted at birth. He moved to the western United States at nine years of age with his adoptive family. He said that he had not traveled recently. He had had lifelong diarrhea, with several watery stools daily. The stools were small to moderate in volume, occasionally tinged with blood, but not greasy or notably foul smelling. He had undergone multiple evaluations and lower endoscopies and had been given a diagnosis of nonspecific colitis. Treatment with aminosalicylates and corticosteroids led to minimal improvement. At 12 years of age, he was diagnosed with colonic malacoplakia (yellowish, soft papules or nodules) at another academic medical center after colonic biopsy revealed histiocytes with intracytoplasmic inclusion bodies and intracellular bacilli. Extensive evaluation at that time showed no evidence of inflammatory bowel disease. Bacterial cultures and examination of stool samples for signs of ova and parasites were negative. In addition, acid-fast staining and cultures, including fungal cultures, of colonic-biopsy specimens were negative. He was treated with trimethoprim–sulfamethoxazole with moderate but temporary improvement, and diarrhea soon recurred. Further details of the medical history included a positive tuberculin skin test but a normal chest radiograph; he subsequently received oral isoniazid for six months. The patient reported no use of alcohol, tobacco, or illicit drugs, and he was not sexually active. He had received a blood transfusion during infancy for unknown reasons.
The patient's history of immigration from Central America suggests the possibility of tropical sprue, a syndrome that can occur in persons residing in certain tropical locations, which is presumed to be caused by small-bowel bacterial overgrowth and characterized by chronic diarrhea and malabsorption. However, tropical sprue is rare in Guatemala, and the characteristic pathological findings are limited to the small intestine, rather than the colon. Predisposing conditions for colonic malacoplakia include chronic infections by coliform bacteria and granulomatous processes, such as sarcoidosis and tuberculosis. Colonic tuberculosis usually causes ulcers with associated nodularity, a finding not observed in this patient. The diagnosis is established by culture or histologic examination, both of which were negative. Nonetheless, the yield from cultures and biopsy material may be low, and diagnosing intestinal tuberculosis may be particularly challenging in the absence of extraintestinal manifestations. The history of a blood transfusion during infancy raises the possibility of an underlying infection with the human immunodeficiency virus (HIV).
The patient appeared to be underdeveloped and chronically ill, with diminutive stature and decreased muscle mass. On physical examination, his height was 160 cm and his weight 47.5 kg. His temperature was 39.2°C, his blood pressure 98/40 mm Hg, his heart rate 94 beats per minute, and his respiratory rate 20 breaths per minute. His lungs were clear, and his cardiac examination showed no abnormalities. His abdomen was soft, with mild distention, normal bowel sounds, and no organomegaly. There was diffuse tenderness to palpation that was worse in the right lower quadrant, but without rebound tenderness. A rectal examination revealed no masses; a small amount of brown stool was obtained, which tested positive for occult blood. An examination of the skin revealed no lesions, and a neurologic examination showed no abnormalities.
The patient clearly has chronic diarrhea and resulting nutrient malabsorption, as reflected in his habitus. A complete blood count and measurements of prothrombin time and serum levels of electrolytes, albumin, calcium, phosphate, magnesium, iron, folate, and vitamin B12 should be obtained to screen for malabsorption; blood cultures should also be obtained. Abdominal computed tomography (CT) should be performed, with special attention to the ileocecal region for signs of mural and omental thickening, lymphadenopathy, ascites, or abscess. Fever, right-lower-quadrant pain, and an ileocecal distribution of inflammation may be clues to the presence of Crohn's disease, but they may also suggest a neoplasm or an infection that might include tuberculosis, histoplasmosis, amebiasis, Mycobacterium avium complex, and Yersinia enterocolitica.
The white-cell count was 5500 per cubic millimeter, with 10 percent band forms. The hematocrit was 36 percent, with a mean corpuscular volume of 81 μm3, and the platelet count was 146,000 per cubic millimeter. Other laboratory values were as follows: sodium, 138 mmol per liter; chloride, 101 mmol per liter; potassium, 4.6 mmol per liter; bicarbonate, 33 mmol per liter; blood urea nitrogen, 11 mg per deciliter (3.93 mmol per liter); creatinine, 0.9 mg per deciliter (79.6 mmol per liter); and lipase, 20 U per liter (normal range, 30 to 190). The calcium level was normal. The serum albumin level was 2.9 g per deciliter. The aspartate aminotransferase level was 95 U per liter (normal range, 15 to 59); the alanine aminotransferase level was normal. The prothrombin time was prolonged at 17.8 seconds (international normalized ratio, 1.4) with a normal partial thromboplastin time of 31 seconds. Chest radiography revealed no abnormalities. CT of the abdomen and pelvis showed a thickened cecum and terminal ileum, without signs of fistula, abscess, or free air.
The patient has mild anemia, probably the result of iron deficiency due to either malabsorption or chronic blood loss. Alternatively, an ongoing infection or inflammatory process could result in anemia of chronic disease. His prolonged prothrombin time is likely to reflect a deficiency of vitamin K resulting from malabsorption of fat-soluble vitamins, in which case I would expect it to be corrected with parenteral supplementation. Celiac sprue has been associated with elevated levels of serum aminotransferase that become normal when the patient adopts a gluten-free diet. A high prevalence of amebiasis is seen in the general population in Central America. Although the manifestation of intestinal amebiasis is typically subacute, it may be associated on rare occasions with a chronic nondysenteric infection accompanied by diarrhea, abdominal pain, and weight loss that may be present for years. The diagnosis rests on microscopical evidence of cysts or trophozoites in stool or endoscopic biopsy samples, both of which were negative in this patient. Tuberculosis is also a major health problem in Central America, particularly infection with drug-resistant strains. Exacerbations of intestinal tuberculosis mimicking Crohn's disease have been reported after infliximab treatment similar to that received by this patient. I remain concerned about an undiagnosed intestinal infection.
The patient received intravenous fluids and total parenteral nutrition. His treatment with mesalamine was continued, and the dosage of prednisone was increased to 80 mg daily. Testing for HIV was negative. A repeated colonoscopy revealed normal-appearing mucosa from the distal colon to the proximal transverse colon, where patchy erythema, edema, and linear ulcerations were seen. A narrow stricture was encountered at the hepatic flexure, preventing safe advancement of the endoscope (Figure 1). Multiple biopsy samples were obtained, including tissue for viral and fungal cultures. A biopsy specimen was obtained from a single 4-mm nodule at the rectosigmoid junction. The clinical findings were thought to be consistent with Crohn's disease, and plans were made for surgery.
Figure 1. Stricture at the Hepatic Flexure on Endoscopy with Edema, Erythema, and Linear Ulcerations.
In reviewing all the data, including the poor response to therapy, I remain skeptical of the diagnosis of Crohn's disease. I am still concerned about a chronic infection; this should be ruled out before proceeding to surgery. Gastrointestinal tuberculosis, histoplasmosis, amebiasis, and actinomycosis have all been reported to mimic Crohn's disease. Aeromonas and yersinia, although typically self-limited infections, may last several weeks and would be considerations were this illness the patient's initial presentation. The patient's stool samples should be examined again for Entamoeba histolytica cysts and trophozoites. The cultures and histologic sections obtained from the endoscopic-biopsy specimens should be carefully evaluated for evidence of any of these pathogens.
Before surgery, the biopsy specimens were reviewed. Both the samples from the right-sided biopsies and the sample from the rectosigmoid nodule included numerous macrophages containing organisms compatible with Histoplasma capsulatum (Figure 2 and Figure 3). This was confirmed with Gomori–methenamine silver staining. There was no distortion in colonic crypts to suggest inflammatory bowel disease. A review of the peripheral-blood smear revealed previously undetected organisms in leukocytes, a finding that is consistent with histoplasmosis (Figure 4). The serum was strongly positive for histoplasma antigen, at 30 enzyme immunoassay units.
Figure 2. Low-Power View of Ulcerated Colonic Mucosa with Chronic Inflammatory Infiltrate (Hematoxylin and Eosin).
Figure 3. Numerous H. capsulatum in Macrophages (Hematoxylin and Eosin).
Figure 4. Peripheral-Blood Smear Showing Intracellular Organisms.
The patient has disseminated histoplasmosis, which involves the gastrointestinal tract in up to 70 percent of patients. The usual treatment is itraconazole, although amphotericin B is used in severely immunocompromised patients. This patient tested negative for HIV, but prolonged courses of corticosteroids and a potential underlying immunodeficiency that might have predisposed him to disseminated histoplasmosis support the use of amphotericin B until a clinical response, which may be slow, is observed.
The patient was started on therapy with amphotericin B, and the corticosteroids were slowly decreased. Three days after the new drug was introduced, hypotension and a rigid abdomen developed. Exploratory laparotomy revealed extensive bowel necrosis; a right hemicolectomy and distal ileal resection with ileostomy were performed. Blood cultures grew Streptococcus mitis. The resected bowel showed extensive histoplasmosis. The patient's hospital course was complicated by nosocomial pneumonia and the abdominal compartment syndrome, which required prolonged open decompression of the abdomen. He eventually underwent partial surgical closure of his abdomen with mesh placement. Superficial layers healed subsequently by secondary intention. He was discharged to his home with treatment with oral itraconazole to continue for six months. Sixteen months after hospital discharge, he reported feeling well and had gained 25 kg.
Abdominal perforation is a recognized complication of gastrointestinal histoplasmosis — a complication that might have been avoided with an earlier diagnosis and medical treatment. Despite his complicated course, his improved general health and weight gain at follow-up indicate successful treatment of his infection.
Commentary
A challenge that clinicians face on a daily basis is deciding when they have sufficient information to make a diagnosis. Clinical medicine is filled with scenarios in which ruling out a condition that mimics another disorder is important. One example is the necessity to rule out pulmonary tuberculosis or an anaerobic infection in an elderly patient with a history of smoking who presents with a cavitary lung mass. The current case provides another example: the need to consider infections that may mimic inflammatory bowel disease.
Unfortunately, no single test is perfectly sensitive and specific for Crohn's disease. The diagnosis relies on a consistent historical, endoscopic, radiographic, and histopathological pattern. As was seen with the patient in this case, management with early, aggressive immunosuppression without a definitive diagnosis can lead to catastrophic consequences when a chronic infection goes undiagnosed.
Histoplasmosis, which primarily affects the lungs, is caused by a dimorphic fungus endemic to river valleys in the midwestern and southeastern United States, as well as Central America and South America. The organism is transmitted by inhalation of spores from soil contaminated by bat or bird droppings. Histoplasmosis is not an easy diagnosis to make. Indeed, Goodwin and colleagues noted two decades ago that "the diagnosis of histoplasmosis begins with thinking of it."1
More than 90 percent of infected persons remain asymptomatic and are identified only as a result of abnormal chest radiographs or positive skin testing.2 Fewer than 10 percent of all recognized cases represent disseminated disease. Disseminated disease is uncommon in immunocompetent patients, but it is common when infection occurs in immunocompromised patients.3 Gastrointestinal involvement occurs in 70 to 90 percent of patients with disseminated disease and has been reported primarily in immunocompromised patients.3,4,5,6
Clinical manifestations of gastrointestinal histoplasmosis range from none, in asymptomatic infection, to nausea, vomiting, diarrhea, bleeding, abdominal pain, weight loss, obstruction, and perforation. The most frequently involved sites are the terminal ileum and cecum.4 Endoscopic findings include plaques, small polyps, mucosal edema, ulcerations, strictures, and masses.3,6 Definitive diagnosis is made by histologic examination or culture growth, with subsequent identification of H. capsulatum. Histoplasmosis antigen in serum or urine is specific and sensitive, and organisms may occasionally be detected on a peripheral-blood smear. Serologic testing for antibodies is less reliable, since immunocompromised patients may be anergic.4 Treatment options include intravenous amphotericin B or oral itraconazole; early treatment usually results in good outcomes.
Certainly, this patient's diarrhea, right-lower-quadrant pain, and endoscopic findings of ileocecal inflammation and stricture could have been consistent with Crohn's disease. Several clues, however, raised the suspicion of a chronic infection that mimicked Crohn's disease, including the patient's childhood in Central America and the substantial mononuclear cell inflammation on colonic-biopsy specimens, in the absence of the distortion of crypt architecture or granulomas typical of Crohn's disease.
An important additional clue that the diagnosis was incorrect was the poor clinical response to aggressive treatment for Crohn's disease. Corticosteroid therapy typically results in short-term response rates of 80 to 90 percent among patients with moderate-to-severe Crohn's disease.7 Patients with Crohn's disease that is refractory to aminosalicylates and corticosteroids have short-term responses to infliximab 50 to 80 percent of the time.8 Rather than improving while receiving these agents, this patient's condition worsened. In retrospect, the infliximab may have led to his decompensation.
Infliximab, along with etanercept, exerts biologic effects through antagonism of tumor necrosis factor . Several reports have documented disseminated histoplasmosis in patients treated with infliximab or etanercept for rheumatoid arthritis or Crohn's disease.9,10,11 Cell cultures infected with H. capsulatum and treated with infliximab show proliferation of the organism and decreased lymphocyte proliferation.9 Tuberculosis has also been reported in patients treated with infliximab, and tuberculin skin testing is routinely performed before the initiation of infliximab therapy.12 Although routine testing for histoplasmosis is not recommended before infliximab therapy is initiated, a test for histoplasmosis antigen in urine or serum could have been helpful in this case, especially since the diagnosis was uncertain.
The lack of a pathognomonic test for Crohn's disease makes this condition one that is frequently misdiagnosed.13 The identification of chronic infections may be particularly challenging, since their diagnosis may require multiple biopsies, large amounts of sample tissue, special culture media, and prolonged culture times. This case demonstrates that infections precipitated by antagonists to tumor necrosis factor may mimic Crohn's disease. Diligence — leaving no stone unturned — will facilitate the appropriate diagnosis and treatment of these challenging conditions.
Dr. Saint is the recipient of a Career Development Award from the Health Services Research and Development Program of the Department of Veterans Affairs; his work is supported by a Patient Safety Developmental Center Grant (P20-HS11540) from the Agency for Healthcare Research and Quality.
Dr. Moseley reports having received consulting fees from Pfizer for serving as an expert witness.
Source Information
From the Department of Internal Medicine, University of Utah, Salt Lake City (C.J.G., C.T., I.S.S.); and the Medical Service, Ann Arbor Department of Veterans Affairs Medical Center (R.H.M., S.S.); the Ann Arbor Veterans Affairs Health Services Research and Development Center of Excellence (S.S.); and the Department of Internal Medicine, University of Michigan Health System (R.H.M., S.S.) — all in Ann Arbor, Mich.
Address reprint requests to Dr. Goulet at the Division of Gastroenterology, University of Utah, Rm. 4R118, 30 North Medical, Salt Lake City, UT 84132, or at chrisgoulet_98@yahoo.com.
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