Systemic Lupus Erythematosus Complicated by Cytomegalovirus-Induced Hemophagocytic

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1 CASE REPORT Systemic Lupus Erythematosus Complicated by Cytomegalovirus-Induced Hemophagocytic Syndrome and Colitis Osamu Sakamoto, Makoto Ando, Shinichi Yoshimatsu, Hirotsugu Kohrogi, Moritaka Suga and Masayuki Ando Abstract Here, wereport a case of systemic lupus erythematosus (SLE) complicated by cytomegalovirus (CMV)-induced hemophagocytic syndrome (HPS) and colitis. A 44-year-old womanwith SLE was treated with corticosteroid and cyclophosphamide for lupus nephritis. Although her lupus nephritis improved, fever, progressive pancytopenia and intestinal bleeding were observed. A bone marrow aspiration showed an increase in mature histiocytes with hemophagocytosis. In addition, a colonoscopy showed hemorrhagic colitis with ulcer and the biopsy specimen from the colon revealed typical CMVcells with CMVinclusions confirmed by immunohistochemistry. Furthermore, a large number of CMVantigen-positive leukocytes was detected, suggesting an active CMVinfection. CMVinfection is serious in compromised hosts. Therefore clinicians should be aware of the clinical settings in which this infection can arise and the target organs potentially affected in order to initiate the appropriate intervention. (Internal Medicine 41: , 2002) Key words: lupus nephritis, VAHS Introduction immunocompromisedhosts, Cytomegalovirus (CMV)infection is an opportunistic infection that primarily affects patients with acquired immunodeficiency syndrome (AIDS), transplant recipients and patients receiving immunosuppressive therapy (1). Although the primary CMVinfection in immunocompetentindividuals usually leads to acute hepatitis and/or mononucleosis syndrome (1), this infection in immunocompromisedhosts is serious and lifethreatening with substantial mortality (2). Furthermore, this infection manifests itself in the lung, liver, central nervous systern, eyes, and gastrointestinal tract (2). Wereport here a case of fatal CMV-associated hemophagocytic syndrome (HPS) and colitis, which occurred in a systemic lupus erythematosus (SLE) patient receiving immunosuppressive therapy. For editorial comment, see p 77. Case Report A 44-year-old womanwith SLEwas admitted to our hospital in November1 997 because of worsening of lupus nephritis. She had been diagnosed as having SLE at age 23 and was treated with a corticosteroid for 2 1 years. A renal biopsy was performed for lupus nephritis 13 years previously (age 3 1) and the biopsy findings showed diffuse proliferative glomerulonephritis (Type IV by WHOclassification). Although she was treated with prednisolone (15 mg/day) for her SLE, a gradual increase of proteinuria was observed. Onadmission, her body temperature was 36.1 C, height 155 cm, body weight 50 kg, and a body mass index 20.8 kg/m2. On physical examination, her blood pressure was 148/70 mmhgand heart rate 72/min. Other physical examinations werenormal except for slight edemaon both lower legs. Laboratory data on admission are summarized in Table 1. Her blood chemistry showed hypoproteinemia, hypoalbuminemia, and mild liver dysfunction because of chronic active hepatitis C. Urinalysis showed proteinuria and the protein in her urine was 1.9 g/day, however, cast was not observed in the urinary sediment. In addition, creatinine clearance was significantly lowered to 21.1 ml/min. Immunologically, hypogammaglobulinemiawas observed; however, complements and auto-antibodies were within normal limits. Judging from the immunological data, her SLE was considered as inactive. Although the corticosteroid dose was increased to 30 mg/day for her lupus nephritis, the proteinuria did not improve and the protein in the urine gradually increased to >2.0 g/day. Therefore, we administered cyclophosphamide (50 mg/day) in addition to the corticosteroid. The lupus nephritis improved gradu- From the First Department of Internal Medicine, KumamotoUniversity School of Medicine, Kumamoto Received for publication May 25, 2001 ; Accepted for publication September 29, 2001 Reprint requests should be addressed to Dr. OsamuSakamoto, the First Department of Internal Medicine, KumamotoUniversity School of Medicine, Honjo, Kumamoto

2 Table 1. Laboratory Sakamotoet al Data on Admission ANA, Anti ds-dnaaband Anti Sm Ab were measured by enzyme-linked immunosorbent assay (ELISA) and normal range of the autoantibodies were <12.0, <12.0, and <5.0, respectively. /XI, 97' /I, 98' III /ffl /IV 15 mg Pulse (M-PSL 1 g/day) Pulse PSLW^////^^^ 3Qmg/da-^^^ ill 50 mg/day y-globulin M I I I I CPA å å å å å å å å å å å 1 Lwx F0Y< > <» GCV -^ > PAPM/BP MEPM IPM/CS Melena TAE Panperitonitis MOF CRP (mg/dl) LDH (U//) ,155 3,165 CMV-Ag Ferritin (ng/ml) 2, ,262 4,652 8,254 SIL-2R (U/ml) 3,600 1, WBC(Ad) 20'00 ] >^ ^ /\ J jv-nxiov/a) Figure 1. Clinical course. PSL: prednisolone, M-PSL: methyl-prednisolone, CPA: cyclophosphamide, FOY: gabexate mesilate, LVFX: levofloxacin, GCV: ganciclovir, PAPM/BP: panipenem/betamipron, MEPM:meropenem trihydrate, IPM/CS : imipenem/ cilastatin sodium, TAE: transcatheter arterial embolization, MOF:multiple organ failure, CMV-Ag:cytomegalovirus antigenemia, SIL-2R: soluble interleukin-2 receptor. 152 Internal Medicine Vol. 41, No. 2 (February 2002)

3 SLE with CMVInduced HPS and Colitis ally and the protein in the urine decreased to about 1.0 g/day; however, a low grade fever appeared and progressive pancytopenia was observed (Fig. 1). A bone marrowaspiration showed benign-appearing histiocytes scattered throughout the marrow, indicating phagocytosis of erythrocytes, erythroblasts, leukocytes, and platelets (Fig. 2). In addition, CMVantigenpositive leukocytes in the peripheral blood were 412 per slide and serum ferritin was 2,590 ng/ml. Weconsidered this case to be virus-associated hemophagocytic syndrome (VAHS)caused by CMVinfection. The total lymphocytes in peripheral blood prednisolone 1 g/day for three days). Furthermore, we admin- istered corticosteroid (prednisolone 60 mg/day) and ganciclovir. The patient's general condition improved, her fever was alleviated, and the pancytopenia also improved. However, melena with abdominal pain appeared suddenly. Emergent colonoscopic examination revealed a hemorrhagic ulcer in the diverticulum of the sigmoid colon (Fig. 3). A biopsy specimen obtained from the ulcer clearly showed CMVinclusions in the colon mucosa, which were confirmed by specific immunohis- had fallen to 252/mm3 at the onset ofvahs. Since her IgG was significantly lowered to 389 mg/dl, we administered CMV immuneglobulin and initiated steroid pulse therapy (methyl- Figure 2. Bonemarrow smear showing ingested erythrocytes, erythroblasts, and platelets in mature histiocytes (Wright-Giemsa stain, Figure 3. Colonoscopic photograph of diverticulum colon showing hemorrhagic ulcer with colitis. of sigmoid xl,000). Figure 4. (A) Biopsy specimen from an ulcerative lesion of the sigmoid colon showing CMVcells with CMVinclusions in the colon mucosa (arrow, HE stain, x400). (B) Immunohistochemical staining using an anti-cmv monoclonal antibody showing CMVcells in the colon mucosa (x400). 153

4 Sakamotoet al tochemistry (Fig. 4A, B). An endoscopical clipping and transcatheter arterial embolization were performed for the hemorrhagic ulcer; however, intestinal bleeding continued and resulted in panperitonitis following perforation of the diverticulum of the sigmoid colon. Although intensive care was provided following the operation, the patient died of multiple organ failure. Autopsy findings confirmed the infiltration of hemophagocytic histiocytes into the bone marrow, spleen, lymph nodes, lung, liver, kidney, pancreas and colon. In addition, CMVcells with CMVinclusions were detected in the liver and pancreas. Although lupus nephritis and pancreatitis were observed, angitis wasnot observed. Discussion CMVis a memberof the herpes virus family. Primary CMV infection in immunocompetenthosts is usually asymptomatic or associated with nonspecific symptomssimilar to acute viral infections (1). However, in immunosuppressed hosts, this infection can cause retinitis, gastroenteritis, colitis, pneumonitis, and encephalitis and may be responsible for significant morbidity and mortality (2). In addition, CMVis an etiological agent of virus-associated hemophagocytic syndrome (VAHS) (3, 4). Thus, CMVinfection is critical in immunocompromised hosts. Hemophagocytic syndrome (HPS) is a clinicopathological entity characterized by high fever, pancytopenia, liver dysfunction and increased hemophagocytic histiocytes in the bone marrow, lymph nodes, liver and spleen (5, 6). HPSis classified into three groups; familial hemophagocytic lymphohistiocytosis, reactive/secondary HPS (RHS), and histiocytic medullary reticulosis/malignant histiocytosis. RHSis further classified into three groups according to cause; infection-associated HPS (IAHS), disease-associated HPS, and drug-associated HPS (6). VAHSwas established by Risdall et al as a disorder characterized by a proliferation of benign hemophagocytic histiocytes associated with a systemic viral infection, and is included in IAHS (3). Causal viruses include CMV, herpes simplex virus, Epstein-Barr virus, varicella-zoster virus, influenza virus, and human parvovirus B-19 (3, 4, 7, 8). In this report, we present a case of SLE complicated by HPS. Although HPSis associated with autoimmune diseases such as SLE (6), our case was considered to be induced by CMV infection because a large numberof CMVantigen-positive leukocytes were detected in the peripheral blood and the patient suffered from CMVcolitis. SLEis often accompanied by pancytopenia whenthe disease is active. Moreover, cyclophosphamide, which is frequently used for the treatment of SLE, causes pancytopenia as a side effect. Therefore, it is important to identify the cause of pancytopenia seen in SLE. Based on the outcome of our case, when progressive pancytopenia is observed during cyclophosphamide treatment for SLE, a bone marrow aspiration should be performed at an early stage to identify the cause of pancytopenia. The occurrence of CMVdisease in the gastrointestinal tract has been recently noted in immunocompromisedhosts (9), such as AIDS patients (10, 1 1), transplant recipients and patients receiving immunosuppressive therapy ( 1 2). In addition, inflammatory bowel diseases, such as ulcerative colitis and Crohn's disease, are frequently complicated by this disease (1 3). CMV can affect any part of the gastrointestinal tract, and typically causes mucosal ulceration that can result in pain, bleeding, diarrhea, and perforation (1 1). Moreover, Goodman et al showed that CMVinclusions are found only in areas of ulceration or perforation, never in undamagedmucosa (14). These results suggest that the penetrating ulcer of the sigmoid colon of the present case was induced by CMVinfection. Our patient developed CMVcolitis after immunosuppressive therapy that included a corticosteroid and cyclophosphamide. Her colitis could have been the result of impaired cellular immunity because total lymphocytes in the peripheral blood were significantly lowered at the onset of colitis. Page et al reported that the overall mortality of CMVenteritis in immunocompetent and immunosuppressed patients is 45 percent (15). Unexpectedly, the mortality in immunocompetent patients was found to be higher, which was attributed to a low index of suspicion and relatively late initiation of therapy. In addition, Page et al (15) showedthat there is a significant association between early initiation of therapy and improved survival, regardless of the underlying condition or type of treatment. Thus, when intractable enteritis is observed, particularly in immunosuppressed patients and in patients with inflammatory bowel diseases, CMVenteritis should be suspected and the appropriate diagnosis should be made at an early stage. In conclusion, the prognosis of CMVinfection especially in immunocompromised patients is poor. Therefore, it is necessary to recognize diseases caused by this infection in immunocompromisedhosts and to attempt to prevent and treat those diseases using agents such as CMVimmuneglobulin, ganciclovir, and foscarnet. References 1) Ho M. Epidemiology of cytomegalovirus infections. Rev Infect Dis 12 Suppl 7: S , ) Cytomegalovirus infections: epidemiology, diagnosis and treatment strategies. Proceedings of a symposium. Cambridge, Massachusetts November Rev Infect Dis 12 Suppl 7: S , ) Risdall RJ, McKenna RW, Nesbit ME, et al. Virus-associated hemophagocytic syndrome: a benign histiocytic proliferation distinct from malignant histiocytosis. Cancer 44: , ) Reiner AP, Spivak JL. Hematophagic histiocytosis: a report of 23 new patients and a review of the literature. Medicine (Baltimore) 67: , ) Cline MJ. Histiocytes and histiocytosis. Blood 84: , ) Tsuda H. Hemophagocytic syndrome (HPS) in children and adults. Int J Hematol 65: , ) Potter MN, Foot AB, Oakhill A. Influenza A and the virus associated haemophagocyticsyndrome: cluster of three cases in children with acute leukaemia. J Clin Pathol 44: , ) Boruchoff SE, Woda BA, Pihan GA, Durbin WA,Burstein D, Blacklow NR. Parvovirus B 19-associated hemophagocytic syndrome. Arch Intern Med 150: , ) GoodgameRW.Gastrointestinal cytomegalovirus disease. Ann Intern Med 154

5 SLE with CMVInduced HPS and Colitis 119: , ) Dieterich DT, Rahmin M. Cytomegalovirus colitis in AIDS: presentation in 44 patients and a review of the literature. J Acquir ImmuneDefic Syndr 4 Suppl l: S29-35, ) Wilcox CM, Chalasani N, Lazenby A, Schwartz DA. Cytomegalovirus colitis in acquired immunodeficiency syndrome: a clinical and endoscopic study. Gastrointest Endosc 48: 39-43, ) Buckner FS, Pomeroy C. Cytomegalovirus disease of the gastrointestinal tract in patients without AIDS. Clin Infect Dis 17: , ) Kaufman HS, Kahn AC, Iacobuzio-Donahue C, Talamini MA, Lillemoe KD, Hamilton SR. Cytomegaloviral enterocolitis: clinical associations and outcome. Dis Colon Rectum 42: 24-30, ) Goodman ZD, Boitnott JK, Yardley JH. Perforation of the colon associated with cytomegalovirus infection. Dig Dis Sci 24: , ) Page MJ, Dreese JC, Poritz LS, Koltun WA. Cytomegalovirus enteritis: a highly lethal condition requiring early detection and intervention. Dis Colon Rectum 41: ,