Graft versus host disease

* A 36-year-old Hispanic man who had undergone allogeneic bone marrow transplantation, complicated by graft versus host disease, was admitted with acute gastrointestinal symptoms, including severe diarrhea and diffuse abdominal pain. He also had a persistent cough with sputum production. Blood cultures yielded Escherichia coli, and sputum cultures grew Apergilfus species. The patient was treated with antifungal agents and broad-spectrum antibiotics. Despite aggressive medical therapy, the patient died 10 days after admission. Postmortem examination disclosed severe, bilateral confluent bronchopneumonia, with numerous septated branching hyphae consistent with Aspergillus species fungal organisms that involved the pulmonary parenchyma and tracheobronchial tree. Although the small and large bowels were only mildly congested, the entire gastric mucosa was covered with a 1.5-cm-thick pseudomembrane that contained numerous Aspergillus organisms. Our report represents the first description, to our knowledge, of a diffuse inflammatory pseudomembrane in the stomach, a complication that to date has only been associated with small and large bowel involvement.

(Arch Pathol Lab Med 2000;124:619-624)

Development of pseudomembranes in the gastrointestinal tract during acute inflammatory or vascular diseases has been confined to the small and / or large bowel, with rare occurrences in the esophagus. Pseudomembranous enterocolitis is a serious; often fatal disease that usually follows antimicrobial therapy and Clostridium dif fiche infection.1 Other reported risk factors include cancer2 ischemic colitis,3 leukemia,4 severe infection,5 and neonatal necrotizing enterocolitis.6

In this report, we describe our observations in a patient who had undergone allogeneic bone marrow transplantation for chronic myelogenous leukemia complicated by graft versus host disease (GVHD) and who was admitted with severe diarrhea and diffuse abdominal pain. In addition, he had persistent cough with sputum production. He died after a complicated 10-day hospitalization despite aggressive medical therapy.

Postmortem examination revealed an extensive, bilateral bronchopneumonia and pseudomembranous necrotizing bronchial aspergillosis. A striking 1.5-cm-thick pseudomembrane that covered the gastric mucosa from the gastroesophageal junction to the distal end of the stomach was identified. The esophagus, small bowel, and colon had no significant pathologic lesions.

REPORT OF A CASE

A 36-year-old man in acute distress was transferred to Loyola University Medical Center on December 13, 1991. He had a history of chronic myelogenous leukemia that had been diagnosed in Mexico. In March 1991, he underwent bone marrow transplantation in Mexico City; following initial treatment with cyclophosphamide and busulfan, which was unsuccessful. The course was complicated by GVHD in July 1991, diagnosed by skin and colon biopsy specimens. He improved for 2 months but then developed severe diarrhea and severe jaundice. Results of repeated tests for C difficile toxin were negative. A liver biopsy specimen taken in October 1991 yielded diffuse cholestasis and nonspecific inflammation: These findings were described as consistent with recurrent GVHD; however, toxic effects due to drugs could not be completely ruled out. The patient was transferred to Loyola University Medical Center because of persistent productive cough; jaundice, and progressive worsening of his medical condition.

Findings of the physical examination on admission revealed an emaciated; deeply jaundiced man, with orthostatic hypotension and marked dyspnea. Vital signs were as follows: temperature, 40.36(deg)C (104.6(deg)F); blood pressure, 92/40 mm Hg; pulse, 150/min; and respirations, 28/min. There were coarse basilar rates in both lungs. I3eart sounds were muffled, and no murmurs were present: The abdomen was soft, with mild diffuse tenderness and decreased bowel sounds.

Significant laboratory findings on admission included the following values: total bilirubin, 616 (mu)mol/L (36 mg/dL); direct bilirubin; 513 (mu)mol(L (30 mg/dL); and alkaline phosphatase, greater than 2000 U / L.

Blood cultures drawn on admission grew Escherichia toll, and sputum cultures revealed abundant Aspergillus fumigatus.

His medications before admission included methylprednisolone; ciprofloxacin, ranitidine hydrochloride, folate, azathioprine, and trimethoprim-sulfamethoxazole. In addition, he had been taking amphotericin 8 far 2 weeks for a sputum culture that had reportedly grown Aspergillus fungal organisms.

The day after admission the patient went into hypotensive shock and was transferred to the intensive care unit. He received intravenous fluids, gentamycin, and metronidazole, while administration of his preadmission medications was continued. The blood pressure was maintained at 90/60 mm Hg with vasopressar agents. Because of severe dyspnea, he was intubated and given mechanical ventilatory support. His diarrhea continued, and a flat plate of the abdomen revealed pneumatosis intestinalis. The possibility of surgical intervention was entertained, but the risk of the operating mortality was considered to be high and the operation was deferred.

He continued with a complicated clinical course and died an hospital day 10 after experiencing cardiorespiratory arrest.

AUTOPSY FINDINGS

Postmortem examination revealed an extensive bilateral confluent bronchopneumonia that involved predominately the lower lobes. The pulmonary parenchyma was hemorrhagic, with multiple areas containing a friable yellow-tan material and similar material found along the mucosal surface of the entire tracheobronchial tree (Figure 1 ). Microscopic sections demonstrated the presence of numerous branching septated fungal hyphae along the tracheobronchial mucosa consistent with pseudomembranous necrotizing bronchial aspergillosis (Figure 2). Diffuse hyaline membranes were also present in the pulmonary parenchyma. The abdominal cavity contained 1000 mL of serosanguinous ascites. The liver and-kidneys were grossly icteric and congested. Microscopic examination of the liver showed diffuse cholestasis; with acute and chronic passive congestion and interlobular bile duct epithelial changes consistent with acute GVHD. No ductopenia was identifled. There were bile casts present in the lumen of the proximal tubules of both kidneys. Gross examination of the gastrointestinal tract showed the esophagus without abnormalities. The small and large bowels were congested; however, there was no evidence of pneumatosis intestinalis. The mucosa of the entire bowel appeared edematous. Microscopic examination of the esophagus and small and large bowels showed only submucosal and mucosal edema and congestion with no evidence of necrosis.

Another pertinent finding was the severe hypocellularity in bane marrow sections from the fourth lumbar vertebra.

The most remarkable findings were seen in the stomach, in sharp contract with the rest of the gastrointestinal tract. The entire gastric mucosa was covered with a 1.5-cm-thick friable pseudomembrane that consisted of friable yellow mucoid material with multiple hemorrhagic foci. The pseudomembrane extended from the gastroesophageal junction to the distal end of the stomach, ending abruptly at the pylorus (Figure 3).

Microscopic examination of the stomach revealed the mucosa to be covered by a thick pseudomembrane that contained fibrin, mucus, neutrophils, and fungal hyphae (Figure 4). The gastric mucosa had distended glands that extended to the pseudomembrane with a volcano-like appearance. There were also multiple areas of hemorrhagic necrosis with transmural extension. The areas of mucosal necrosis contained ghost outlines of gastric glands. Grocott-Gomori methenamine-silver stains of the gastric mucosa highlighted the presence of septated acute angle branching hyphae in the pseudomembrane (Figure 5).5

Postmortem cultures of lung tissue grew A fumigatus, one colony of coagulase-negative staphylococcus species and one colony of group D' enterococcus.

COMMENT

The first description of pseudomembranous lesions in the gastrointestinal tract was by Finney in 1883.1 The patient was a 22-year-old woman who had a tumor resected from the stomach. Postoperatively she developed severe diarrhea and died 2 weeks after surgery. Postmortem examination revealed a "diphteritic membrane" in the small bowel. Since that observation, a small number of cases were recognized annually, mainly in large medical centers, during the preantibiotic era. The introduction of antibiotic therapy in the early 1950s brought about a dramatic increase in the incidence of pseudomembranous enterocolitis. Initially Staphylococcus aureus was identified as the nosocomial agent responsible for the inflammation and pseudomembrane formation.7 In the early 1970s, it was conclusively proven that the cytopathic toxin of C dif ficile was responsible for the inflammation and pathologic findings.8 The pathogenetic mechanism of human colitis produced by C difficle toxin was successfully demonstrated in guinea pigs and hamsters.1 Examination of the colon and small bowel in all cases usually shows multiple elevated yellow plaques up to 2 cm in diameter, with intervening areas of normal or edematous mucosa. Microscopic examination showed the pseudomembranes arising from an area of ulceration, surrounded by acute and chronic inflammation. Typically the glands are disrupted and dilated with neutrophil infiltration capped by a pseudomembrane, which has been described as a "volcanic eruption." The disease can advance to complete necrosis of the bowel mucosa. Clostridium difficile is usually not seen in the pseudomembrane, since the disease is produced by the C difficile toxin.

It is now well established that most cases of C difficile diarrhea are due to antibiotic therapy (cg, clindamycin, ampicillin, or cephalosporin).9,10 Other antibiotics may cause diarrhea but are not necessarily associated with C difficile toxin or the development of pseudomembranous colitis: The list includes cefixime, cefoperazone, and amoxicillin among others.1

Pseudomembranous colitis has been reported in cases not associated with antibiotic therapy.11 The risk factors identified include intestinal obstruction, colon cancer, leukemia, severe burns, hemolytic-uremic syndrome, ischemic cardiovascular disease, ischemic colitis, neonatal necrotizing enterocolitis, Crohn disease, and Hirschsprung disease. Pseudomembranous colitis also been reported in individuals without identifiable risk factors.

In a case of acquired immunodeficiency syndrome, the stomach was reported to be diffusely thickened and the gastric mucosa raised by an underlying yellow-white infiltrate. Microscopically there was marked edema of the submucosal layer; vascular thromboses, fibrin, cocci, and neutrophils. Because of the diffuse inflammation of the gastric wall, the changes were reported as phlegmonous gastritis; however, mucosa was not covered by any pseudomembrane; and the mucosa was illustrated as intact. In our case, there were similar inflammatory changes; however, the mucosa-changed pseudomembranes were significant histopathologic features.12

The "volcano-like lesions ` responsible for pseudomembrane formation have been reported in the stomach in chronic erosions of the stomach ("diffuse varioliform gastritis").13 The authors described a group of 300 patients with hyperchlorhydria and chronic gastric erosions: Biopsy specimens of the erosions showed volcano-like lesions covered by pseudomembranes. The authors concluded that ischemia and increased gastric secretion were responsible for the lesions, To fur knowledge, there are no other reports in the literature that confirm the presence of pseudomembranes in chronic gastric erosions; however, other reports describe diffuse varioliform gastritis and its association with lymphocytic gastritis,14,15 defined endoscopically as involving the whole stomach with thick folds, aphthoid ulcers, and nodules at the top of the folds spreading in a stringlike manner and crossed by serpiginoes erosions.15 Lymphocytic gastritis was associated with this endoscopic appearance in 96% of cases in a prospective study.15

In our case, the ischemic and inflammatory changes were associated with an A figiigattus infection. Aspergillosis of the stomach has been reported in cases of acute GVHD following bone marrow transplantation.16 Acute GVF-iD usually occurs 3 to 8 weeks after marrow transplantation that involves the esophagus, stomach, small and large bowels, and liver and skin: Histologically there is varying acute inflammation, ulceration, glandular epithelial injury, and drop out in the gastrointestinal tract, and the patients experience nausea, vomiting; abdominal pain, and diarrhea.17-20 In the liver, there is progressive destruction of bile ducts, causing jaundice with high levels of serum bilirubin and alkaline phosphatase. Our patient had the classic symptoms of acute GVHD, with gastrointestinal and hepatic involvement. The severe immunodeficiency accompanying his GVHD, with an absolute neutrophil count of 50, became a fertile ground for disseminated aspergillosis that involved the bronchopulmonary tree and the gastric mucosa. The small and large bowel mucosa was not significantly involved, displaying only mild edema of the wall. Thus, the chronic diarrhea in our patient was at least in part due to pseudomembranous gastritis caused by Aspergillus infection. Interestingly, pseudomembranes with Aspergillus fungal organisms were also identified within necrotizing pseudomembranes of the tracheobronchial mucosa. The term pseudomembranous Aspergillus tracheobronchitis has been used for bronchial mucosa that contains Aspergillus species organisms with a membranous dough and extensive involvement of the tracheobronchial tree. It has been seen in a variety of clinical settings, including acquired immunodeficiency syndrome; lung transplants, leukemia, and even in an immunocompetent patient with chronic pulmonary disease.21,22

There are few reports of Aspergillus infection of the stomach. The pathologic findings in these cases include ischemic necrosis and vascular thrombosis with ulcerations.16 One of the cases was that of a patient with malabsorption associated with chronic lymphocytic leukemia. The fungal infection caused multiple tumorlike masses ("aspergillomas").23 The masses contained neutrophils and Aspergillus hyphae, which invaded the gastric muscular layer and blood vessels, causing thrombosis. The malabsorption syndrome; secondary to chronic diarrhea, was explained as a result of aspergillosis of the stomach. No pseudomembranes in the bowel were present.

In conclusion, we describe a patient with a severe immunocompromised state due to GVHD after bone marrow transplantation who presented with severe diarrhea and wasting. The gastrointestinal symptoms were due at least in part to the pseudomembranous gastritis caused by Aspergilius infection. To the best of our knowledge, this case is the first report of pseudomembranous gastritis.

References

1. Bartlett JG. Pseudomembranous enter)(: oliW and antilnotic.-associated colitis. tn: Sleisenger Mbi, Fordtran IS, eds. Ciastrointestinal and Liver Disease. 62h ed. Philadelphia, Pa: W& Sanrders Co; 79r38,

2. Dosik GM, L.una M. Valdivieso M, Mi(Cre(lie KB. Nec( rotizing colitis in patients with cancer. flm / A4e'rf. 19'9;67:646-654.

3. Morris Ill. Ke-examination of the Spectrum of lsc(hemit Bowel Disease in P,tthnlogy of the Colon, Sm,rl! lJ Antistin

4. ('n711a )C., Kirnec IB. The gastrointestinal lesions and complications of the leukemias. Ann Intern Me 1964;67:1084-109?.

5. Kelber Ament NME. Shigella dysenteri.a-a forgotten cause of pseudomernbranous colitis. / Pediat. 1976;89:=>95-598.

6. Cashore WI, Peter G, Lavenna nn V1, et al. Clostridia colonization and clostridia) toxin in neonatal net rotizing enterocolitis. ( Pedi.rtr: 1981;98:30-38.

'. tiardaway EtM, Micf

8. Barriello SRP. Pathogenesis of clostridium difficile infection of the gut. ( Mec! l. 1990;33:207-21.>.

9. Andriejak Ml Schmit IL, Tondriaux A. The clinical significance of antihioticassociated pseudomemkrranous colitis in the 1990's. )ruo Sat. 1991;6:339-349. 10. laimes EC. Lini(ocinamides and the incidence of anii6iotic-associated colitis. (-[in Titer. 1991 3:2711-280.

11. Wald A, Mendelow ii, Bartlett jCi. Nonantihiotic-associated pseudomembranous colitis due to toxin-producing clostridia. Ann Intern AMed. 1980:92:798804.

12. Mittlcman RE, Suarez RV. Phlegmonous gastritis associated with the acquired immunodeficiency sydrome/pre-acquired imnadeficiency syndrome. ASic`h Pathol l.ab Med. 198 5;109:76 >-76i.

I a. Franzi*i (,., Manfrini G, Rodella S, Fratton A. Chronic erosions of the stomach: a clinical, enioscopic and histological evaluation. Endoscopy. 1984;6:1-S. 14. Hot I, Berger F, Andre C, rMc'wlinicer 8, Mainguet P, Lambert R. Lvmpha

evtic gastritis versus varioliform gastritis. a historical series revisited. f !'athol. 1989; 158:19-22.

1 t. t-la I, loure! ,A, Willette y1, Goussu in A, Main;;uet P. Lymphocytic gastritis-prospective study of its relationship with varioliform gastritis. Gut. 1990;31: 282-285.

16. Lewin Kh Ridden RH, Weinstein WM. Stomach anology wand Its Clinical Implications. New York, NY: Igaku-Shoin; 1992:540.

17. Snover D, tveistiorf SA, Vercell)tti GKI, Rauk B, Hutton 5, vlcGlove P. A histopathologic study of gastric and sail intestinal graft-versus-host disease forlowing allcioeii( ic bone marrow Transplantation. Nom Paihol. 1981:16:387-392.

78. Spencer GD, S[hulman HM, tvtyefson D, Donnall Thomas F, McDonald C;B. Diffuse intestine( ulceratian after marrow transplantation: a clinicopathologic study of 13 patients. I turn Pium Yathol. 1986;17:627-633.

19. Thorning D; Howard ID. Epithelial denudement in the gastrointestinal tract of two bone marrow transpt recipients. Plum Retha/. 1986:17:560-566.

20. Snover DC . Graft versus host disease of the gastrointestinal tract. Am /Surg l''rthol. 1990;14 (suppli: I 11-108.

21. Donning Commentary: unusual manifestation of aspergillosis. Thorax. 1995;:0:812-813.

22. Nicholson AG, Sim KM, Keogh BF, (-orrin B. Pseudamembranous necrorising bronchial aspergillosis complicating chronic airways limitation. Thorax. 1995: 50:807-808.

23. t'rosc)ott RL, Flaboubi Nl', Burton IE. Gastrointestinal tract aspergilloma: possible (aura of n,alabsorption Clin F.afhol. 1994;47:170-171.

Accepted for publication September 23, 1999,

from the Department of Pathology, Loyola Medical Center, Maywood, III (Drs Yong and Chejfec! and Department of Pathology, Spectrum-Health, Grand Rapids, Mich (Dr Attal).

Reprints: Gregorio Chejfec, MD, Department of Pathology, Loyola Medical Center, EMS Bldg, Room 2244, 2160 S First Ave, Maywood, IL 60153.

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