CASE REPORT

Cytomegalovirus Following Immunosuppressive Therapy for Lupus and Lupus Nephritis Naro OHASHI, Taisuke ISOZAKI, Kentaro SHIRAKAWA,Naoki Ikegaya, Tatsuo YAMAMOTO*and Akira HlSHIDA*

Abstract agents. Here, we report a patient with CMVcolitis, which developed after immunosuppressivetherapy for severe lupus Wereport a womanwith lupus nephritis complicated nephritis and lupus peritonitis. CMVcolitis was diagnosed with lupus peritonitis and (CMV)colitis. by and CMVantigenemia assay, and was suc- Diagnosis of lupus peritonitis was made by abdominal cessfully treated by ganciclovir. computed tomography scan, colonoscopy, and ascitic fluid analysis. Steroid and cyclophosphamide therapy re- sulted in the improvement of severe lupus nephritis and Case Report peritonitis. Thereafter, she developed multiple colonic ul- A 30-year-old womanwas admitted to our hospital for the cers as diagnosed by colonoscopy and positive CMV fifth time because of , abdominal pain, nausea, vom- antigenemia assay. Treatment with ganciclovir resulted iting, and hypocomplementemia on October 28,1999. She in the disappearance of colonic lesions. The low cluster of was first hospitalized in September 1996 for fever, lympha- differentiation (CD)4+ lymphocyte count (41/mm3) sug- denopathy, and hepatosplenomegaly. Although a definitive gested that the cell-mediated immunity of this patient diagnosis was not made, the symptoms subsided after treat- was comparableto that seen in patients with acquired ment with prednisolone (PSL). On her second admission in immunodeficiency syndrome (AIDS). November1996, insulin-dependent diabetes mellitus was di- (Internal Medicine 42: 362-366, 2003) agnosed; she has been treated with insulin since that time. On her third admission in November 1997, she was suffering Key words: systemic lupus erythematosus, CMVantigene- from central nervous system disturbances, nephrotic syn- mia, colonoscopy, CD4, ganciclovir, compro- drome, and joint pain; test results for antinuclear antibody mised host (ANA) and antiphospholipid antibody were positive, and SLEwas diagnosed. A renal was performed and the diagnosis of lupus nephritis (World Health Organization class Vb) was established. The patient was treated with ster- Introduction oid pulse therapy followed by oral PSL and mizoribine. This resulted in the disappearance of peripheral edema and im- Lupus peritonitis is a comparatively rare but important provement of laboratory test results. She was discharged in gastrointestinal complication of systemic lupus erythemato- May1998 on maintenance PSL (20 mg/day). However, ta- sus (SLE); it can be diagnosed by analysis of ascitic fluid pering of PSL to 15 mg/day was associated with increased (1). Treatment of lupus peritonitis usually requires strong proteinuria and worsening of hypocomplementemia.She was immunosuppressive therapy (2). Cytomegalovirus (CMV) admitted for the fourth time in January 1999. Steroid pulse is a frequent and sometimes life-threatening com- therapy followed by oral PSL treatment resulted in improve- plication in immune compromised patients such as those ment of serum complement levels. However, her proteinuria with acquired immunodeficiency syndrome (AIDS) (3). was unchanged. She was discharged from the hospital in Patients with lupus peritonitis are prone to develop CMV March 1999 on a PSL dose of 25 mg/day. Although PSL was disease after aggressive treatment with immunosuppressive tapered slowly, when PSL was reduced to 10 mg/day, gastro-

From the Division of Nephrology, Seirei Hamamatsu General Hospital, Hamamatsu and *the First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu Received for publication December 1 1, 2000; Accepted for publication January 20, 2003 Reprint requests should be addressed to Dr. Naro Ohashi, the First Department of Medicine, Hamamatsu University School of Medicine 1-20-1 Handayama, Hamamatsu, Shizuoka 431-3 192

362 Internal Medicine Vol. 42, No. 4 (April 2003) Lupus Nephritis/peritonitis, CMVColitis

Table 1. Laboratory Findings on Admission H em ato lo gy Im m u n olo gical ex a m in ation W B C 4 , 95 0 / m m3 CRP 1. 5 mg/ dl R B C 4 8 6x l O 7 m n r I mmu ne Com ple x 6.9 ug /ml P lt 4 1.9x lO7 m m 3 Antinuclear antibody 40x Hb 14.2 g/dl A nti-D NA an tibod y <2 IU/m l H t 3 9.S Anti-Sm antibody (-) CI-Lo 13 U/ml Bl ood Ch em ist ry C3 23 mg/dl T.P. 5.2 g/dl C4 3 mg/dl Albumin 2.6 g/dl Im muno globu lin G 99 3 mg /dl T. Bil. 0.3 mg/dl Im muno globu lin A 29 5 mg /dl AS T 1 6 U /Z Im mun oglo bul in M 41 mg/ dl AL T 7 U/ Z LD H 45 1 U/Z U rin a ly sis BU N 20 mg /d l P ro tein (3+ ) Cr 1.1 mg/dl S u gar (1+ ) Na 136 mEq /l O ccult b lo od (1+ ) Figure 1. Axial computed tomography image of the K 3.3 mEq/Z Protein/day 4.52 g/day abdomen on October 30, 1999, showing marked colonic C 1 100 roE q /Z C reatin in e clearan ce 63.8 //day wall thickening and massive ascites. T. Choi. 200 mg/dl N-acetylglucosaminidase 9.5 U// T.G. 354 mg/dl B2 microglobulin 1,210 ag/l Blood sugar 101 mg/dl A computed tomography scan of the abdomen showed Hb A ,C 9. 0 % marked wall thickness of the and the entire colon (Fig. 1), and colonoscopy revealed edematous wall thickening at the same lesion. Analysis of ascitic fluid T.P.: total protein, T. Bil: total bilirubin, AST: aspartate aminotransferase, ALT: alanine aminotransferase, LDH:lac- showed the exudative ascitic fluid, that is to say, total pro- tate dehydrogenase, BUN: blood urea nitrogen, Cr: serum tein, 2.1 g/dl (ascitic fluid/serum protein ratio, 0.53) and lac- creatinine, T. Choi.: total cholesterol, T.G.: triglyceride, tate dehydrogenase (LDH), 443 U// (ascitic fluid/serum LDH HbAiC: glycosolated hemoglobin, CRP: C-reactive protein, ratio, 0.92). Low complement levels (CH50, 0 U/ml; C3, 6 CH5o: complement activity. mg/dl; C4, 2 mg/dl) and slightly elevated IC levels (3.4 jug/ml) were also seen in the ascitic fluid. Although ANA was not examined, anti-DNA antibody was slightly elevated intestinal symptoms such as diarrhea, abdominal pain, nau- for the ascitic fluid (5 IU/ml). Cytologic examination of the sea and vomiting, and hypocomplementemia progressed. She fluid showed the presence of erythrocytes (1+) and mononu- was admitted to our hospital for the fifth time in October clear leukocytes (2+) but no malignant cells; results of a bac- 1999. terial culture werenegative. Basedon the abovefindings, a On admission, blood pressure was 118/68 mmHg,pulse diagnosis of lupus peritonitis was made(1). Accordingly, the rate was 120 beats/min with a regular rhythm, and tempera- patient received steroid pulse therapy (M-PSL 500 mg/day, ture was 37. 1°C. Physical examination showed pretibial pit- drip intravenous) for 3 consecutive days followed by oral ad- ting edema. The lower abdomen was distended due to ministration of PSL 40 mg/day. However, the gastrointesti- ascites. The abdomenwas tender, but there was no rebound nal symptoms did not improve. Consequently, the dose of tenderness or muscle guarding. Anemia, jaundice, cyanosis, oral PSL was increased to 60 mg/day. Three weeks of such and skin lesions were not detected. Results of a neurologic therapy resulted in improvement of the gastrointestinal examination were negative. symptoms and a marked fall in proteinuria to 0.3 g/day. The Results of laboratory tests indicated nephrotic syndrome same dose of oral PSL was continued for 6 weeks, and then and hypocomplementemia (Table 1) with total protein of 5.2 tapered gradually to 40 mg/day over 2 weeks, based on nor- g/dl, albumin 2.6 g/dl, blood urea nitrogen 20 mg/dl, serum malization of serum complement levels (CH5o, 49 U/ml; C3, creatinine 1.1 mg/dl, and urinary protein excretion of 4.52 47 mg/dl; C4, 20 mg/dl) (Fig. 2). Continuation of PSL at 40 g/day. ANAwas 40x (homologous), but anti-DNA antibody mg/day for 1 week, however, showed a decreasing tendency was negative. Amarked decrease in complementlevels was of complement levels (CH50, 33 U/ml; C3, 33 mg/dl; C4, 12 noted (complement activity [CH50], 13 U/ml; C3, 23 mg/dl; mg/dl). Therefore, intravenous (IV) cyclophosphamide C4, 3 mg/dl). Serum immune complex (IC) levels were ele- (CPA) pulse therapy ( 500 mg/day, drip intravenous) was ad- vated (6.9 fig/ml). The blood cell count was normal with ministered (Fig. 2) (4). This treatment resulted in the com- white blood cell count, 4,950/mm3; red blood cell count, plete disappearance of subjective gastrointestinal symptoms 486xlO4/mm3, lymphocyte count, 822 /mm3 ; hematocrit, and ascites, and prevented further falls in serum complement 39.9%; and platelet count, 41.9xlO7mm3. Results of plain levels. CT scan of the abdomen showed no colonic wall chest X-ray film and electrocardiogram were normal. thickness.

Internal Medicine Vol. 42, No. 4 (April 2003) 363 Ohashi et al

Oct 28, 1999 July 13, 2000 admission discharge July1999 Aug Sep Oct Nov Dec Jan2000 Feb Mar Apr May Jun Jul : psl ^ y/////M&&^^V///// '6O'^^ 4»j^^^^^i20 y////j42Z6P^&

M-PSL500mgX3days XX 500 750 CPA (mg) ±^ ± GCV(mg)(div) Oj HO å å ! GCV(mg)(p.o.) M W[ isnnN^^a

CH50 (U/ml) \ a ^^#-#^ flV CMV Ag.

Figure 2. Clinical course after the present admission. PSL: prednisolone, M-PSL: methylprednisolone, CPA: cyclophosphamide, GCV:ganciclovir, CMVAg: cytomegalovirus antigenemia.

A follow-up colonoscopy, performed on January 17, 2000, showed multiple colon ulcers (Fig. 3). Although a bi- opsy specimen taken during the colonoscopy did not show the inclusion body of CMV, the CMV antigenemia assay was positive (10 positive Ieukocytes/1.5xl05 total leuko- cytes) (Fig. 2). Under the diagnosis of CMV colitis, IV ganciclovir was administered at 400 mg/day for 15 consecu- tive days. This treatment resulted in the disappearance of multiple colonic ulcers and negative results on a CMV antigenemia assay. Subsequently, results of the CMV antigenemia assay were positive 3 times after the discon- tinuation of IV ganciclovir therapy, and became negative again following resumption of ganciclovir therapy (Fig. 2). The lymphocyte count and the cluster of differentiation (CD)4+ lymphocyte count were 148/mm3 and 41/mm3, re- spectively, on May 22, 2000. The CMVantigenemia level was kept low by oral administration of ganciclovir (250 mg/- day). At that time, the lymphocyte count and CD4+lympho- cyte count were slightly elevated to 325/mm3 and 83/mm3, Figure 3. Colonoscopy on January 17, 2000. Note the respectively. Serum complement levels, lupus peritonitis, presence of edema, congestion and multiple ulcers in and lupus nephritis were controlled and she was discharged the sigmoid colon.

364 Internal Medicine Vol. 42, No. 4 (April 2003) Lupus Nephritis/peritonitis, CMVColitis from the hospital on July 13, 2000. Furthermore, Bitran et al (9) reported that the addition of CPAto steroids improves the outcome of lupus peritonitis Discussion with ascites. In the present case, the CPApulse therapy of two times allowed tapering of the PSLtherapy without exac- The incidence of gastrointestinal involvement in patients erbating the lupus nephritis or lupus peritonitis. with SLE varies from 10% to 40% (5). Ascites occurs rarely Aggressive immunosuppressionresulted in marked clini- in SLE patients (8% to 11%), often as a manifestation of cal improvement, but was associated with the development nephrotic syndrome (5). In SLE, ascites can be due to many of CMVcolitis. Previous studies have reported that the inci- other complications such as lupus peritonitis, , dence of CMVinfection in Japanese children younger than mesenteric vasculitis, , protein-losing enteropa- 2 years is more than 90%and that a large proportion of these thy, and malignancy (5). Analysis of ascitic fluid, together cases subsequently becomeasymptomatic carriers of CMV with evaluation of gastrointestinal symptoms, is useful for (10). However, overt CMVinfection can develop in patients the differential diagnosis of underlying diseases. The com- with disordered cell-mediated immunity such as those with plement level of the ascitic fluid is low with nephrotic syn- organ transplants, AIDS, or on immunosuppressive therapy. drome, liver , and peritonitis carcinomatosa (6, 7). Thus, early diagnosis and treatment of overt CMVinfection However, the complement level of the ascitic fluid in this is important because the condition is life-threatening in com- case was remarkably low, and consumption by this lesion promised hosts. was remarkable. These findings lead to the diagnosis of Recent studies have emphasized the usefulness of the lupus peritonitis. CMVantigenemia assay in the diagnosis, monitoring, and Nephrotic syndromeis associated with transudative ascitic treatment of immune compromised patients (10, ll). The fluid and the patient usually does not present with abdominal CMV antigenemia assay is designed to detect leukocyte pain. Onthe other hand, lupus peritonitis is accompanied by intranuclear CMV antigen using monoclonal antibody abdominal pain and analysis of ascitic fluid often shows against CMVimmediate early antigen (IEA). Active prolif- exudative fluid with high levels of anti-DNA antibody and eration of CMVresults in the increased production of IEA. low complement levels. Moreover, ascites due to lupus peri- Therefore, positive leukocyte counts reflect the activity of tonitis is steroid-responsive (1, 5). The differentiation be- overt CMVinfection. CMVantigenemia assay is highly sen- tween lupus vasculitis and lupus peritonitis is difficult. In sitive and becomes positive rapidly during the early stages of lupus vasculitis, ischemic necrosis results in ulceration and the disease; more than one positive Ieukocyte/1.5xl05 total hemorrhage of mucosa and submucosa, where lymphocytes, leukocytes is clinically significant (1 1). plasma cells and neutrophils infiltrate. The depositions of IC Although CMVcolitis is a commonviral infection that by immunohistochemistry lead to the definitive diagnosis of typically occurs during the course of humanimmunodefi- lupus vasculitis. Oncolonoscopy, both multiple round dis- ciency virus (HIV) infection, manifesting as intermittent di- crete ulcers, so called punched-out ulcers, and larger, deeper arrhea accompanied with fever and weight loss (12), CMV and variable-shaped ulcerations have been described (8). colitis complicated with SLE is relatively rare (13, 14). Here, In the present case, the patient had nephrotic syndrome the differential diagnosis of lupus vasculitis and CMVcolitis but presented with severe abdominal pain. Examination of becomes a problem in the present case. Intermittent diarrhea ascitic fluid samples showed exudative fluid containing low accompanied with fever and weight loss is the commonclini- levels of complement. Administration of high doses of PSL cal symptom between lupus vasculitis and CMVcolitis (8, markedly improved abdominal symptoms and ascites. 12). Dieterich and Rahmin reported that 41% of the patients Colonoscopy revealed edematous wall thickening, but did present with a localized and patchy colitis, and 34% of the not reveal any ulcers. Thus we considered that the ascites patients had a diffuse colitis as well as the present case (15). was caused by lupus peritonitis. The inadequate response to Moreover, the colonoscopic findings of CMVcolitis usually initial PSLtreatment was probably related to poor absorption appears as a mucosal erosion or ulceration (16). Therefore, of oral PSLdue to markededemaof the gastrointestinal the differentiation of lupus vasculitis and CMVcolitis is dif- tract. ficult. Although the final decision for CMVcolitis is due to Following the successful control of lupus activity by high- a characteristic cytopathic effect [a large 25- to 35 \im cell dose PSL, we faced 2 conflicting problems. Onone hand, containing a basophilic intranuclear inclusion, the so-called high-dose PSL therapy might cause unfavorable adverse ef- owl's eye effect (16)], it was not detected in the present case. fects such as bleeding and opportunistic In the present case, the diagnosis of CMVcolitis was made . Onthe other hand, SLEseemed to be uncontrolla- by colonoscopy, which showedmultiple colonic ulcers and ble by maintenance doses of PSL, as episodes recurred re- positive CMVantigenemia; further, the activity of SLE was peatedly at 10 to 15 mg/day of PSL. To solve these controlled. IV administration of ganciclovir resulted in al- problems, CPA pulse therapy was used. In this regard, most complete disappearance of multiple colonic ulcers and Boumpaset al (4) reported that pulse CPAis more effective negative CMVantigenemia assay. Ganciclovir, an acyclovir than pulse M-PSLin the preservation of renal function and derivative, is effective in approximately 75% of cases (17). prevention of exacerbation of severe lupus nephritis. The initial treatment of active CMV infection with

Internal Medicine Vol. 42, No. 4 (April 2003) 365 Ohashi et al ganciclovir requires daily IV administration via a central line diagnosed by the immunological findings in the peritoneal fluid. Jpn J for several weeks. Recently, Spector et al (3) reported that Gastroenterol 87: 1465-1469, 1990 (in Japanese). 2) Toy LS, Mayer L. Nonhepatic gastrointestinal manifestations of sys- oral ganciclovir significantly reduces the risk of CMVdis- temic lupus erythematosus. in: Systemic Lupus Erythematosus, 3rd ed. ease including CMV colitis in advanced AIDS patients. Academic Press, San Diego, 1999: 733-746. Therefore, we used oral administration of ganciclovir in the 3) Spector SA, McKinley GF, Lalezari JP, et al. Oral ganciclovir for the present case. prevention of cytomegalovirus disease in persons with AIDS. NEngl Development of overt CMV infection depends on the J Med 334: 1491-1497, 1996. 4) Boumpas DT, Austin HA, Vaughn EM, et al. Controlled trial of pulse CD4+lymphocyte count in immunecompromised patients. methylprednisolone versus two regimens of pulse cyclophosphamidein Although there is no conclusive report on the relationship be- severe lupus nephritis. Lancet 340: 741-745, 1992. tween CMVinfection and a decrease in the CD4+lympho- 5) Wallece DJ. Gastrointestinal and hepatic manifestations, in: Dubois' Lupus Erythematosus, 5th ed. Williams and Wilkins, Baltimore, 1997: cyte count in SLE, several studies have reported a correlation 835-850. between these cells and AIDS. Spector et al (3) proposed the 6) WangSS, Lee FY, Chao Y, et al. Clinical significance of complements definition of immunocompromised AIDS patients with a his- in ascitic diseases: elevated complement levels disapproving the liver tory of an AIDS-defining opportunistic infection as: "pa- disease origin. Proc Natl Sci Counc Repub China B 20: 51-57, 1996. tients with CMVinfection and CD4+lymphocyte count <50 7) Akalin HE, Fisher KA, Laleli Y, Caglar S. Bactericidal activity of or 100/mm3". Dieterich and Rahmin (15) reported that CMV ascitic fluid in patients with nephrotic syndrome. Eur J Clin Invest 15: colitis occurs when the CD4+lymphocyte count falls below 138-140, 1985. 8) Grimbacher B, Huber M, von Kempis J, et al. Successful treatment of 100/mm3 in HIV infection. In the present case, the CD4+ gastrointestinal vasculitis due to systemic lupus erythematosus with in- lymphocyte count was 4I/mm3, suggesting a greatly disor- travenous pulse cyclophosphamide:a clinical case report and review of dered cell-mediated immunity as seen in severe AIDS pa- the literature. Br J Rheumatol 37: 1023-1028, 1998. tients. The remarkable decrease in CD4+lymphocytes may 9) Bitran J, McShane D, Ellman MH.Ascites as the major manifestation be the reason that aggressive treatment with immuno- of systemic lupus erythematosus. Arthritis Rheum 19: 782-785, 1976. 10) Yoshihara S, Fukuma N, Masago R. Cytomegalovirus infection associ- suppressive agents was frequently needed for the control of ated with immunosuppressive therapy in collagen vascular diseases. SLEand for the frequent relapse when PSL was tapered. In Ryumachi 39: 740-748, 1999 (in Japanese, Abstract in English). this regard, Yoshihara et al (10) reported that CMV ll) Koyama I, Tanabe K, Takahashi K, et al. Successful diagnosis, moni- toring, and treatment of 3 cases of postrenal transplant CMVinfection antigenemia became positive in 9 of 15 patients with colla- by CMVantigenemia assay. Jpn J Transplant 31: 234-238, 1996 (in gen vascular diseases following treatment with PSLat a dose Japanese, Abstract in English). exceeding 30 mg/day, suggesting that overt CMVinfection 12) Wilcox CM,Friedman SL. Gastrointestinal manifestations of the ac- frequently occurs during immunosuppressive therapy. quired immunodeficiency syndrome, in: Gastrointestinal and Liver In summary, we reported a case of lupus nephritis with se- Disease, 6th ed. Saunders, Philadelphia, 1998: 387-409. vere lupus peritonitis that was barely controlled by high-dose 13) Sakamoto O, Ando M, Yoshimatsu S, Kohrogi H, Suga M, Ando M. therapy and CPA. She developed CMVcolitis Systemic lupus erythematosus complicated by cytomegalovirus- after strong immunosuppressive therapy was initiated. induced hemophagocytic syndrome and colitis. Intern Med 41: 151- Colonoscopy and analysis of ascitic fluid were useful for the 14) Mimori A, Hirata K, Nara H, et al. Three patients with systemic lupus diagnosis of lupus peritonitis. Early detection of CMVcolitis erythematosus155,complicated by cytomegalovirus2002.colitis. Nihon Rinsho was possible by CMVantigenemia assay and colonoscopy. Meneki Gakkai Kaishi 23: 156-162, 2000 (in Japanese, Abstract in IV and oral ganciclovir were effective in the treatment of English). 15) Dieterich DT, Rahmin M. Cytomegalovirus colitis in AIDS: Presen- CMVcolitis. Determination of the CD4+lymphocyte count tation in 44 patients and a review of the literature. J Acquir Immune was useful for determining the level of cell-mediated immu- Defic Syndr 4 Supp 1: S29-S35, 1991. nity. 16) GoodgameRW.Gastrointestinal cytomegalovirus disease. AnnIntern Med 119: 924-935, 1993. 17) MarkmanA, Faulds D. Ganciclovir: An update of its therapeutic use in References cytomegalovirus infection. Drugs 3: 455-484, 1994.

1) Fujita J, Shimada N, Akashi K, et al. A case of lupus peritonitis

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