Refractory adenovirus infection after simultaneous kidney–pancreas transplantation: successful treatment with intravenous ribavirin and pooled human intravenous immunoglobulin

Osemwegie E. Emovon1,2, Angello Lin1, David N. Howell3, Fuad Afzal1,2, Mark Baillie1, Jeffrey Rogers1, Prabhakar K. Baliga1, Kenneth Chavin1, Volker Nickeleit4, P. R. Rajagapalan1 and Sally Self5

1Department of Surgery, 2Department of Medicine, Medical University of South Carolina, Charleston, SC, 3Department of Pathology, Duke University Medical Center, Durham, NC, 4Department of Pathology, Nephropathology Laboratory, University of North Carolina, Chapel Hill, NC and 5Department of Pathology, Medical University of South Carolina, Charleston, SC, USA

Correspondence and offprint requests to: Osemwegie E. Emovon, MD, Division of Transplant Surgery, Medical University of South Carolina, 96 Jonathan Lucas Street, Charleston, SC 29425, USA. Email: emovonoe{at}musc.edu

Keywords: adenovirus infection; allograft dysfunction; anti-viral therapy granulomatous interstitial nephritis; kidney transplantation; viral inclusions



   Introduction
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 Introduction
 Case
 Discussion
 Appendix
 References
 
Adenovirus is a common pathogen known to cause respiratory, intestinal and ocular infections. This virus has also been linked to haemorrhagic cystitis in recipients of bone marrow and solid organ transplants [1,2]. We describe a case of refractory adenovirus infection in a recipient of a simultaneous kidney and pancreas (SKP) transplant that required treatment with ribavirin and pooled human intravenous immunoglobulin (i.v.IG) because the clinical course continued to deteriorate despite drastic reduction of maintenance immunosuppression.



   Case
 Top
 Introduction
 Case
 Discussion
 Appendix
 References
 
A 46-year-old African-American female underwent SKP transplantation with enteric drainage in July 2000. Her past history was significant for diabetes mellitus, hypertension and partial thyroidectomy. The patient was induced with simulect, and maintained on triple therapy consisting of tacrolimus, mycophenolate mofetil (MMF) and prednisone. Routine anti-microbial prophylaxis during the first 90 days following surgery included acyclovir, trimethoprim-sulfamethoxazole and nystatin. The post-transplant course was unremarkable until ~18 months after surgery when the serum creatinine level increased from 0.8 to 1.4 mg/dl. This prompted a renal allograft biopsy that showed mild to moderate interstitial fibrosis in stripped pattern suggestive of tacrolimus toxicity (Banff 97 score cg0, ci1-2, ct1-2, cv0) and no evidence of acute rejection. Rapamycin was substituted for MMF and the tacrolimus dose was lowered from 4 to 2 mg twice daily with the intention of reducing further tubulo-interstitial injury. The serum creatinine stabilized between 1.0 and 1.3 mg/dl until May 2002 when she presented with gross haematuria associated with dysuria, abdominal pain, fever, chills, myalgia and generalized malaise. She denied cough, chest pain or shortness of breath. Medications on admission included tacrolimus 2 mg twice daily (trough level <4.1ng/ml), rapamycin 6 mg daily (trough level 9.7 ng/ml) and prednisone 7.5 mg daily. Also, the patient had been receiving ciprofloxacin empirically for 5 days before admission because a urine specimen obtained during an outpatient visit for symptoms suggestive of a lower urinary tract infection showed pyuria and bacteruria, which was later identified as 1000 to 10 000 colony forming Gram-positive cocci. Physical examination revealed an acutely ill African-American female. Blood pressure was 112/53 mmHg, pulse was 88 beats/min and temperature was 101.4°F. The lungs were clear, but cardiac auscultation revealed a grade III systolic murmur. Examination of the abdomen revealed diffuse discomfort in the lower quadrants, but no tenderness over the renal allograft. The initial blood urea nitrogen (BUN) and creatinine levels were 36 and 2.5 mg/dl, respectively (baseline levels were 30 and 1.3 mg/dl, respectively). Serum sodium was 136 mEq/l, potassium was 3.9 mEq/l, chloride was 106 mEq/l and bicarbonate was 20 mEq/l. The white blood cell count was 2.7 and the haematocrit was 33.6%. Urinalysis showed few bacteria, 19 white blood cells and 1308 red blood cells per high power field. Cytomegalovirus (CMV) pp65 antiginaemia assay, blood and urine cultures were negative. Rapamycin was discontinued, and ciprofloxacin was changed to the i.v. formulation. On hospital day (HOD) 3, an ultrasound guided renal biopsy was performed. The transplanted kidney measured ~11 cm in length, with mild prominence of the collecting system, but no overt hydronephrosis, masses or stones. There was good blood flow to the pancreas, and no evidence of peri-pancreatic fluid collection. The biopsy specimen contained at least five glomeruli, all showing mild increase in mesangial matrix (Figure 1). There was diffuse interstitial oedema, widespread haemorrhage, extensive tubular necrosis and severe infiltration of the interstitial compartment by mononuclear cells. There were loosely formed tubulocentric granulomas and a few eosinophils scattered throughout the interstitium. Tubular epithelial intra-nuclear viral inclusions and smudge cells were readily seen. The blood vessels showed no morphological abnormalities. Tacrolimus was discontinued, and therapy with i.v. gancyclovir and CMV hyperimmune globulin (MedImmune, Inc.) was initiated because of histological findings suggestive of a viral nephropathy, possibly due to CMV. However, adenovirus nephropathy was confirmed subsequently after special histochemical studies. (Figure 2; see Appendix for details of immunohistochemical stain for adenovirus).



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Fig. 1. Haematoxylin and eosin stain of the second kidney biopsy demonstrating tubulocentric, necrotizing, granulomatous inflamation (arrow). There is prominent interstitial oedema and haemorrhage (20x).

 


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Fig. 2. Immunoperoxidase labelling for adenovirus (40x).

 
Despite stopping tacrolimus and rapamycin, and reducing prednisone to 5 mg daily, the patient remained acutely ill, spiking high fevers up to 105°F with persistent gross haematuria, progressive renal allograft dysfunction (peak serum creatinine of 4.8 mg/dl), severe arthralgia, anorexia and generalized malaise. This prompted therapy with i.v.IG (HOD8) and i.v. ribavirin (HOD12). The patient dramatically improved 3 days after beginning ribavirin, with resolution of gross haematuria, and she was discharged with a BUN and serum creatinine of 42 and 1.7 mg/dl, respectively. Therapy with ribavirin was continued for a total of 14 days. The patient remained euglycaemic throughout the period of hospitalization without any need for supplemental insulin therapy or oral hypoglycaemic agents. In addition, serum amylase and lipase levels remained within the normal range throughout the period of hospitalization, and during subsequent outpatient clinic visits. Tacrolimus was restarted at 1 mg twice daily one week following discharge, and both pancreas and kidney function remained stable 7 months after hospitalization with a fasting blood glucose of 71 mg/dl and a BUN and creatinine of 24 and 1.2 mg/dl, respectively.



   Discussion
 Top
 Introduction
 Case
 Discussion
 Appendix
 References
 
Adenovirus is a well-recognized cause of morbidity and mortality in bone marrow transplantation [2], and appears to be gaining notoriety among recipients of kidney transplants [1,36]. Most people acquire type-specific life-long immunity by early adulthood after exposure to the virus. These early infections are generally self-limited, and are usually followed by a prolonged period of latency. Reactivation of adenovirus either harboured by the recipient pre-transplant or transmitted with the renal allograft is believed to be responsible for most post-transplant infections; however, acquisition of novel strains after transplantation may result in disseminated disease [3]. Gross haematuria with or without renal dysfunction is the most common clinical manifestation [1,2,4,5], but case fatalities are not uncommon [3,7].

In the present report, we described the clinical course of a SKP transplant recipient who presented with an acute illness that initially manifested as dysuria, but rapidly progressed to a systemic illness. There was no evidence of co-infection with other bacteria, fungi or viruses, particularly CMV. The presentation was unusual because the patient had not recently received therapy for acute rejection, and the episode of infection occurred ~2 years after transplantation. Furthermore, symptoms indicative of respiratory involvement were absent, suggesting that this case was likely due to reactivation of latent virus rather than acquisition of a novel strain. This report bears some similarities to the case described by Mathur et al. [6]. Pancreatic involvement was absent in both cases, as evidenced by euglycaemia and stable serum lipase and amylase levels, underscoring the predilection of adenovirus for kidney tissue and uro-epithelium.

Reducing or briefly withdrawing immunotherapy may be all that is required for treating adenovirus infections involving the kidney and collecting system. However, specific anti-viral therapy is necessary if there are signs of systemic illness or if the clinical course does not improve after alteration of baseline immunosuppression. This case appears to be the first report of combined i.v.IG and ribavirin therapy for severe adenovirus infection in a SKP transplant recipient. In spite of the severe morphological changes noted on biopsy, it is remarkable that the clinical course was ultimately favourable. We attribute the successful outcome in this case to early diagnosis and institution of appropriate therapy. Other investigators have successfully utilized i.v. ribavirin either alone or in combination with i.v.IG in treating adenovirus infection occurring after bone marrow and lung transplantation [810].

This case illustrates that adenovirus is an important pathogen capable of causing significant morbidity among recipients of kidney transplants, and underscores the importance of early diagnosis and treatment. Because there is a risk of death from disseminated infection, specific anti-viral therapy should be promptly instituted if the clinical status does not improve after stopping maintenance immunosuppression.



   Appendix
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 Introduction
 Case
 Discussion
 Appendix
 References
 
Sections of formalin-fixed, paraffin-embedded tissue were deparaffinized, rehydrated, incubated in 0.6% H2O2 in absolute methanol to block endogenous peroxidase, and subjected to immunoperoxidase staining using standard techniques. Enzyme-induced epitope retrieval was performed using 0.25% trypsin for 13 min at 37–40°C. Non-specific protein binding was blocked by incubation with normal horse serum, diluted 1:20 in PBS. Sections were sequentially incubated with an adenovirus-specific monoclonal antibody cocktail (#MAB805, Chemicon International, Inc., Temecula, CA) for 60 min at 37°C, horse anti-mouse biotinylated secondary antibody for 20 min at 37°C and horseradish peroxidase labelled streptavidin (Jackson Immunoresearch Laboratories, West Grove, PA) for 20 min at 37°C, with intervening PBS washes. Sections were developed with 3,3'-diaminobenzidine plus H2O2, counterstained with haematoxylin, and permanently mounted.



   Acknowledgments
 
We wish to thank James L. Burchette, Jr, Immunopathology Laboratory Duke University Medical Center Durham, North Carolina, for the adenovirus immunohistochemical stain, and Barbara Salami for assistance in preparing this manuscript.

Conflict of interest statement. None declared.



   References
 Top
 Introduction
 Case
 Discussion
 Appendix
 References
 

  1. Shiramizu T, Satoh T, Jinushi K, Oka N, Inokuchi K. Renal allograft dysfunction with acute hemorrhagic cystitis caused by adenovirus in a recipient of a transplanted kidney. Tokai J Exp Clin Med 1986; 11:371–375[Medline]
  2. Baldwin A, Kingman H, Darville M et al. Outcome and clinical course of 100 patients with adenovirus infection following bone marrow transplantation. Bone Marrow Transplant 2000; 26:1333–1338[CrossRef][ISI][Medline]
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  5. Shinohara Y, Hashimoto K, Ikegami M et al. Hemorrhagic kidney graft pyelonephritis caused by type 37 adenovirus infection. Transplant Proc 1992; 24:1565–1566[ISI][Medline]
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  7. Stalder H, Hierholzer JC, Oxman MN. New human adenovirus (candidate adenovirus type 35) causing fatal disseminated infection in a renal transplant recipient. J Clin Microbiol 1977 6: 257–265
  8. Miyamura K, Hamaguchi M, Taji H et al. Successful ribavirin therapy for severe adenovirus hemorrhagic cystitis after allogeneic marrow transplant from close HLA donors rather than distant donors. Bone Marrow Transplant 2000; 25:545–548[CrossRef][ISI][Medline]
  9. Murphy GF, Wood DP Jr, McRoberts JW, Henslee-Downey PJ. Adenovirus-associated hemorrhagic cystitis treated with intravenous ribavirin. J Urol 1993; 149:565–566[ISI][Medline]
  10. Sabroe I, McHale J, Tait DR, Lynn WA, Ward KN, Shaunak S. Treatment of adenoviral pneumonitis with intravenous ribavirin and immunoglobulin. Thorax 1995; 50:1219–1220[Abstract]
Received for publication: 18. 2.03
Accepted in revised form: 16. 5.03





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