Here we describe the first case of a biopsyprovenCytomegalovirus ulcero-hemorrhagic colitis,associated with Clostridium Difficile co-infection,occurring during standard induction chemotherapyfor common B cell acute lymphoblastic leukemia.We discuss the case and focalize clinical managementand diagnostic issues arising from it

Ferrari A

IMOVILLI, Annalisa

LUPPI, Mario

MAIORANA, Antonino

Merighi A

Morselli M

POTENZA, Leonardo

RIVA, Giovanni

SAVIOLA, Alessia

TORELLI, Giuseppe

Volzone F

English

Here we describe the first case of a biopsyprovenCytomegalovirus ulcero-hemorrhagic colitis,associated with Clostridium Difficile co-infection,occurring during standard induction chemotherapyfor common B cell acute lymphoblastic leukemia.We discuss the case and focalize clinical managementand diagnostic issues arising from it.Here we describe the first case of a biopsy-proven Cytomegalovirus ulcero-hemorrhagic colitis, associated with Clostridium Difficile co-infection, occurring during standard induction chemotherapy for common B cell acute lymphoblastic leukemia. We discuss the case and focalize clinical management and diagnostic issues arising from it

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haematologica online 2005haematologica/the hematology journal | 2005; 90(online) | 1 |Cytomegalovirus and Clostridium Difficile co-infec-tion in severe ulcero-hemorrhagic colitis duringinduction chemotherapy for acute lymphoblasticleukemiaHere we describe the first case of a biopsy-proven Cytomegalovirus ulcero-hemorrhagic colitis,associated with Clostridium Difficile co-infection,occurring during standard induction chemotherapyfor common B cell acute lymphoblastic leukemia.We discuss the case and focalize clinical manage-ment and diagnostic issues arising from it.Haematologica 2005; 90:(1)e1-e3A previously healthy 39-year-old Caucasian male wasadmitted to the hospital because of the diagnosis of com-mon B-cell acute lymphoblastic leukemia (ALL), associat-ed with t(1;19) chromosomal translocation. He was com-menced on induction chemotherapy with daunorubicin,vincristine and prednisone, according to the LAL-2000protocol for ALL proposed by Italian multicentre groupGIMEMA. On day 14 after the beginning of chemothera-py, owing to the onset of febrile neutropenia, intravenousantibiotic therapy with ceftazidime and vancomycin wasinitiated, obtaining a rapid clinical improvement. On day26, the patient developed abdominal pain and severalepisodes of diarrhea, with bright red blood mixed tosemiformed stool, followed by profuse rectorrhagia. Thepatient was afebrile, neither nausea nor vomiting werereferred, and no signs of peritoneal irritation were found.Stool samples were collected for microbiological analy-ses. Urgent laboratory investigations were as follows:hemoglobin level lowering from 9.5 g/dL to 7.8 g/dL in24-hours; white blood cell count of 3.7×109/L, with a dif-ferential leukocyte count showing severe lymphocytope-nia; platelet count of 133×109/l, with normal coagulationclotting times and unremarkable blood chemistry profile.Packed erythrocytes were transfused; then an urgentcolonsigmoidoscopy permitted to identify three large lin-ear ulcerations, the widest approximatively measuring 4×1 cm, localized at the transition from the discendingcolon to the sigmoid colon, in the transverse colon, andin the coecum, respectively. The lesions were covered byfibrinous-necrotic exudates and fibrin clots, but nopseudomembranes were found (Figure 1A). Microscopic examination of multiple endoscopic biop-sies performed at the borders of the lesions revealed aninflammatory granulation tissue, containing distinct giantcells with prominent intranuclear inclusion bodies.Immunohistochemical staining with anti-Cytomegalovirus (CMV) monoclonal antibody (cloneCCH2; Dako) resulted focally positive (Figure 1B). PCRamplification of DNA extracted from formalin-fixed,paraffin-embebbed bioptic specimens was positive forCMV DNA. All other tissutal searches for herpesviruses,mycotic forms, acid-fast bacilli and for common-B blastcells infiltration yielded negative results. On day 27, bothCMV-pp65 antigenemia (2 positive cells/slide) and quali-tative PCR amplification for CMV DNA on whole bloodresulted positive. At the same time, microbiologicalanalyses of stool samples showed negative results forcommon intestinal pathogenic bacteria, virus, ova andparasites, except for detection of Clostridium Difficile(CD) A and B toxins by enzyme-linked immunoassay(EIA). The patient was promptly started on a three-weekcourse of antiviral therapy with Foscarnet (180mg/kg/die), preferred to ganciclovir because of thereported minor hematotoxicity; moreover, intravenousvancomycin and ceftazidime were withdrawn, and oralmetronidazole (1g/die) was started. The patient returnedto his normal bowel habits in ten days, with stool sam-ples negative for CD toxins and with persistently nega-tive CMV-pp65 antigenemia. The patient completed thestandard course of induction chemotherapy withoutother relevant complications, obtaining hematologicaland molecular complete remission of leukemia. After dis-charge, control colonoscopy revealed healing ulcerationsand immunohistochemical assay for CMV antigen testedinvariably negative in all biopsy specimens. On day 70 from the beginning of induction chemother-apy, the patient developed fever and interstitial pneumo-nia with highly positive bronchoalveolar lavage fluid forCMV-pp65 antigenemia, for which he was successfullytreated with ganciclovir (5 mg/kg twice a day, for threeweeks). At that time, he was not receiving chemotherapyand his blood cell count was normal, except for mild lym-phocytopenia. Then he underwent consolidationchemotherapy and autologous bone marrow transplanta-tion, without further complications, and with a persist-ently negative CMV antigenemia, during the whole post-transplant period. The patient is still in hematologic andmolecular remission, 20 months after the diagnosis.Discussion CMV colitis is a well recognized complication inacquired immunodeficiency syndrome (AIDS) as well asin solid organ and bone marrow transplant (BMT) set-tings. In other subsets of immunocompromised (IC)patients, CMV colitis is a rare but equally serious disease.To the best of our knowledge, only few cases havedescribed the occurrence of CMV colitis during anti-neo-plastic treatment for solid tumors and hematologic malig-nancies.1-5 In all of these cases, the diagnosis of CMV dis-ease was obtained by an endoscopic biopsy of coloniclesions, allowing tissutal identification of the virus. In oneof these cases, the diagnosis was also supported by thepositivization of high-level CMV antigenemia and, aftertreatment of CMV colitis, the patient also developedCMV-negative CD-associated pseudomembranous coli-tis.4 Here we report the first case of biopsy-proven CMVcolitis occurring in the course of standard inductionchemotherapy for B-cell ALL. Our diagnosis, according tothe definition of CMV gastrointestinal disease,6 wasbased on the identification of clinical and endoscopic fea-tures associated with bioptical demonstration of CMVinfection by immunohistochemical analysis, also sup-ported by the positivization of CMV antigenemia.Nevertheless, a simultaneous CD infection was disclosedby the isolation of both fecal CD toxins with highly spe-cific enzyme immunoassay (EIA) test. It is known that aproblematic issue in the diagnostic process of CMV end-organ disease arises when other pathogens are identifiedtogether with CMV infection.7 Concerning the gastroin-testinal disease, there are no clear indications for specificand reliable evaluation of CMV and CD co-infection.Indeed, in the case reported here, while CMV seems tobe strongly involved in the genesis of the colitis, leavingno doubt about the occurence of an inflammatory diseaseof the colonic mucosa driven by the virus, it appearsmuch more difficult to assess the pathogenic contributionand clinical relevance of CD infection. In favour of acausative role of CD is the evidence that CD is a commoncause of nosocomial diarrhea in IC patients. Consistentwith this, in a large retrospective study, 7% of hemato-logic patients treated with myelosuppressive chemother-apy showed clinical symptoms with EIA positivity forCD-toxins.8 Moreover, our patient presented major riskfactors for CD colitis, such as prolonged treatment withthird generation cephalosporine, long-term hospitaladmission and recent receipt of antineoplasticchemotherapy.8,9 Against a major role of CD is the lackingof endoscopic evidence of typical psudomembranouscolitis, which is commonly associated with the severeclinical presentation of CD infection with frank hema-tochezia.10 Moreover, other case series reported CD-tox-ins EIA positivity in 57% of patients with asymptomaticCD infection,11 suggesting that, in the presence of colitiswith tissutal CMV isolation, CD-toxins EIA positivitycould be a non-diagnostic finding. On the basis of theseconsiderations, CD colitis was categorized as a possibledisease in our patient, and we decided to start combinedantiviral and antimicrobial therapy. Abdominal infectious diseases are common in patientswith acute leukemia receiving standard chemotherapy,and bacterial and fungal enterocolitis are much more fre-quent than viral colitis.8,12 However, a proven diagnosis ofviral colitis is difficult to obtain. Relevant to this, CMVgastrointestinal disease can be only defined by the histo-logic demonstration of CMV on biopsy materialsobtained by endoscopy..6 The importance of searching forthe viral involvment in hematological patients withsevere colitis, even in the presence of other pathogens,has been underlined by the case, described by Kottaridiset al.,13 of an autologous BMT recipient who developedlife-threatening diarrhea associated with fecal CD toxinsand bowel pseudomembranes but unresponsive to initialoral metronidazole. Because of the worsening of the clin-ical conditions of the patient, a second colonoscopy withrectal biopsy was performed, allowing the definitive diag-nosis of CMV colitis, for which the patient was success-fully treated with antivirals. Similarly, in our patient,urgent endoscopic biopsy evidenced CMV colitis that,otherwise, could have been diagnosed with delay, as aconsequence of the misleading detection of CD toxins. While allogeneic bone marrow recipients and evenautologous recipients of selected CD34 positive cellsshould be treated with anti-virals at any level of antigen-emia,14 information about the clinical relevance of low-level antigenemia in patients receiving standardchemotherapy is scarce. The detection of 2 positivecells/slide in our case of biopsy proven CMV colitis sug-gests that low-level antigenemia should not be over-looked but considered as a possible indicator of CMV dis-ease in patients with severe hemorrhagic diarrhea duringstandard chemotherapy for hematologic malignancies.Therefore, we think that even a low-level positivizationof CMV antigenemia could be decisive to perform urgentendoscopy with biopsy and, whenever invasive diagnos-tic tools are not promptly feasible, this could become ahint for evaluation of empirical antiviral treatment inpatients in whom no other pathogens have been identi-fied or previous specific antimicrobial therapy has failed.Of interest, Mori et al.15 reported that all the examined 19allogeneic hematopoieitic stem cell transplant patientswith the CMV gastrointestinal disease developed positiveCMV antigenemia tests during their clinical course, withthe values remaining at a low-level in 9 patients (47%).However, only 4 of these 19 patients (21%) developed apositive CMV antigenemia test before developing theCMV gastrointestinal diseases, suggesting that CMV anti-genemia testing has limited value in prediction or earlydiagnosis of the CMV gastrointestinal disease after BMT.Real-time PCR could have a more diagnostic significancein this setting, being this test positive in 50% of thepatients, before the developing of CMV gastrointestinaldisease.15 In conclusion, our case shows that not onlyBMT recipients or AIDS patients, but also acute leukemicpatients can develop severe CMV colitis while receivingthe first standard induction chemotherapy. A direct impli-cation of our observation is that IC patients affected withsevere hemorrhagic diarrhea should be considered forendoscopic bowel examination and tissutal search forCMV, even if fecal CD toxins are positive, in order toobtain a reliable diagnosis and start proper treatments assoon as possible. The successful clinical outcome in ourpatient suggests that, despite the occurence of a severeCMV ulcero-hemorrhagic colitis followed by a CMVpneumonia during and immediately after the inductionchemotherapy course, autologous BM/PBSC transplantprocedures can be safely performed in leukemic patients.Giovanni Riva, Mario Luppi, Leonardo Potenza, Monica Morselli,Angela Ferrari, Alessia Saviola, Francesco Volzone, AnnalisaImovilli, °Alberto Merighi, *Antonio Maiorana, Giuseppe Torelli.Department of Oncology and Hematology. ° Gastrointestinal Unit,G. Riva et al.| 2 | haematologica/the hematology journal | 2005; 90(online)Figure 1. A. Endoscopic presentation of the severe colitis.Transverse colon: large ulceration with raised edges and irregularborders, indicated by arrows. B. Immunostaining of colonic biopsy.Cluster of giant cells with large intranuclear CMV inclusions (orig-inal magnification, x40; counterstaining with Giemsa). Inset: typi-cal owl eyes aspect of a CMV infected cell (original magnification,x100; counterstaining with Giemsa).and *Department of Pathology, University of Modena and ReggioEmilia. Modena, Italy. Correspondence: Mario Luppi, M.D., Ph.D.Department of Oncology and Haematology.University of Modena and Reggio Emilia, Modena, ItalyTel: 39 059 4224641 - Fax: 39 059 4224549E-mail: mluppi@unimore.it Key words: CMV, CD, colitis, leukemia, chemotherapy.Acknowledgments: the authors disclose neither conflicts of interestnor financial support related to this studyReferences1. Carpiuc I, Antoun S, Delabarthe A, Driss B, Vantelon JM,Griscelli F, et al. Segmental coecal cytomegalovirus colitis dur-ing fludarabine, cytarabine and mitoxantrone inductionchemotherapy for myelodysplastic syndrome. LeukLymphoma 2002; 43:1701-3.2. Matthes T, Kaiser L, Weber D, Kurt AM, Dietrich PY.Cytomegalovirus colitis--a severe complication after standardchemotherapy. Acta Oncol. 2002;41:704-6.3. Van den Brande J, Schrijvers D, Colpaert C, Vermorken JB.Cytomegalovirus colitis after administration of docetaxel-5-fluorouracil-cisplatin chemotherapy for locally advancedhypopharyngeal cancer. Ann Oncol 1999;10:1369-72.4. Oshima Y, Nishida K, Kawazoye S, Noda T, Arima F,Miyahara M, et al. Successful treatment of cytomegaloviruscolitis with ganciclovir in a patient with adult T cell leukemialymphoma: case report. J Chemother 1999;11:215-9.5. Baker JL, Gosland MP, Herrington JD, Record KE.Cytomegalovirus colitis after 5-fluorouracil and interferon-alpha therapy. Pharmacotherapy 1994;14:246-9.6. Buckner FS, Pomeroy C. Cytomegalovirus disease of the gas-trointestinal tract in patients without AIDS. Clin Infect Dis1993;17:644-56.7. Ljungman P, Griffiths P, Paya C. Definitions ofCytomegalovirus infection and disease in transplant recipi-ents. Clin Infect Dis 2002;34:1094-7. 8. Gorschlüter M, Glasmacher A, Hahn C, Schakowski F, ZiskeC, Molitor E, et al. Clostridium difficile infection in patientswith neutropenia. Clin Infect Dis 2001;33:786-91.9. Bartlett JG. Antibiotic-associated diarrhea. N Engl J Med2002;346:334-9.10. Kelly CP, Pothoulakis C, LaMont JT. Clostridium difficile coli-tis. N Engl J Med 1994;330:257-62.11. McFarland LV, Elmer GW, Stamm WE, Mulligan ME.Correlation of immunoblot type, enterotoxin production, andcytotoxin production with clinical manifestations ofClostridium difficile infection in a cohort of hospitalizedpatients. Infect Immun 1991; 59:2456-62.12. Gorschlüter M, Marklein G, Höfling K, Clarenbach R,Baumgartner S, Hahn C, et al. Abdominal infections inpatients with acute leukemia: a prospective study applyingultrasonography and microbiology. Br J Haematol 2002; 117:351-8.13. Kottaridis PD, Peggs K, Devereux S, Goldstone AH,Mackinnon S. Simultaneous occurrence of Clostridium diffi-cile and Cytomegalovirus colitis in a recipient of autologousstem cell transplantation. Haematologica 2000; 85:1116-7.14. Centers for Disease Control and Prevention. Guidelines forpreventing opportunistic infections among hematopoieticstem cell transplant recipients: recommendations of CDC, theInfectious Disease Society of America, and the AmericanSociety of Blood and Marrow Transplantation. MMWR MorbMortal Wkly Rep 2000; 49(RR-10):1 128.15. Mori T, Mori S, Kanda Y, Yakushiji K, Mineishi S, Takue Y, etal. Clinical significance of cytomegalovirus (CMV) antigene-mia in the prediction and diagnosis of CMV gastrointestinaldisease after allogeneic stem cell transplantation. BoneMarrow Transplantation 2004; 33: 431-4.haematologica online 2005haematologica/the hematology journal | 2005; 90(online) | 3 |

Cytomegalovirus and ClostridiumDifficile co-infection in severe ulcero-hemorrhagic colitis during inductionchemotherapy for acute lymphoblastic leukemia

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Cytomegalovirus and ClostridiumDifficile co-infection in severe ulcero-hemorrhagic colitis during inductionchemotherapy for acute lymphoblastic leukemia

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