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CASE REPORT
Adenovirus Infection as a Cause of Fever of Unknown Origin and Allograft Dysfunction in a Kidney Transplant Recipient

With the recent introduction of more potent modern immunosuppressive regimens in solid-organ trans-plant, new types of viral infections such as adenovirus are emerging as a potential cause for graft dysfunction and loss. We report a case of 41-year-old male patient with end-stage renal disease from recurrent kidney stones who underwent kidney transplant from a deceased 12-year-old female donor. He developed adenoviral infection with acute cystitis, microscopic hematuria, and necrotizing interstitial nephritis associated with graft dysfunction within the first month of the postoperative period. Diagnosis was made by graft biopsy that showed more than 60% necrosis with tubulointerstitial hemorrhage, thrombotic microangiopathy, and histologic features suggestive of viral infection with negative Cytomegalovirus and polyomavirus stains in the graft and elevated adenovirus PCR in the blood. Simultaneously, the patient had very low absolute total lymphocyte count of 70 cells/μL during which he received supratherapeutic tacrolimus at whole blood trough levels and mycophenolate mofetil. This prompted the tapering of immunosuppression and the discontinuation of all antimicrobial drugs. Within a 2-week period, the immune reconstitution was sufficient for the clearance of the infection and the subsequent gradual recovery of graft function.


Key words : Graft failure, Hemorrhagic cystitis, Immunosuppression, Necrotizing interstitial nephritis

Case Report

A 41-year-old male patient who had end-stage kidney disease secondary to recurrent nephrolithiasis underwent kidney transplant from a deceased 12-year-old female donor. He received a double J urinary catheter, which was placed intraoperatively. He received rabbit antithymocyte globulin Fresenius (Grafalon; Neovii, Waltham, MA, USA) as induction therapy with pulse corticosteroid therapy and then was maintained on tacrolimus (Prograf; Astellas Pharma, Tokyo, Japan), mycophenolate mofetil (CellCept; Hoffmann-La Roche, Basel, Switzerland), and steroids. At day 10 posttransplant, the patient developed urinary tract infection with a positive urine culture for Klebsiella pneumoniae. At day 14 posttransplant, he developed high-grade fever. His only symptoms were persistent urinary frequency, dysuria, and intermittency.

Physical examination revealed an anxious patient in no distress but an otherwise normal examination. Complete blood count was significant for leukopenia with lymphopenia (absolute lymphocyte count < 500 cells/μL), and the urine analysis showed microscopic hematuria. Initial blood and urine culture results, as well as blood cytomegalovirus (CMV) and Epstein-Barr virus (EBV) polymerase chain reaction (PCR) results, were negative. Graft Doppler ultrasonography was also normal (Figure 1A and 1B). The patient was started on wide-spectrum antibiotic therapy (imipenem/cilastatin [Tienam], Merck Sharp and Dohme, Whitehouse Station, NJ, USA; and vancomycin [Vancolone], Julfar, Dubai, UAE) with no improvement. At day 19 postoperatively, the double J catheter was removed. Repeated blood and urine cultures were still negative. Abdominal ultrasono-graphy examinations repeated on 3 separate occasions were also within normal limits. During this period, the patient had persistently high-grade fever.

At day 22 posttransplant, the patient developed mild graft dysfunction with an increase in serum creatinine level from 0.98 to 1.3 mg/dL. This occurred in the context of persistent high-grade fever with several repeated negative blood and urine cultures and negative EBV and CMV PCR results. Computed tomography of the chest, abdomen, and pelvis with intravenous contrast was performed at day 28 posttransplant, which showed enlarged graft with multiple cortical hypodensities suggestive of infectious pyelonephritis versus tissue infarct (Figure 1C and 1D). Kidney graft function continued to deteriorate with a rise in serum creatinine to 1.85 mg/dL.

A kidney biopsy performed at day 33 showed nearly 60% necrosis, thrombotic microangiopathy, interstitial fibrosis, and tubular atrophy. Viral inclusions were seen in tubular epithelial cell nuclei with ground glass appearance (Figure 2). Cytomegalovirus and polyomavirus stains were negative. Tacrolimus whole blood trough level was 22.5 ng/mL, which prompted immunosuppression tapering. Within 1 week, the patient started to defervesce. At day 37 posttransplant, blood adenovirus (ADV) PCR results revealed a level above 1.75 million copies/mL.

Given the considerable improvement in the patient’s clinical condition that was associated with the tapering of immunosuppression, all antimicrobial drugs were withheld. Cidofovir was not started out of concern of further renal damage due to its potential nephrotoxicity. The fever regressed progressively and disappeared within 2 weeks. One month later, graft function improved with a decrease in serum creatinine to 1.4 mg/dL that was paralleled by considerable drop in ADV blood PCR to 6850 copies/mL (Figure 3A-C). A second graft biopsy at 12 weeks posttransplant showed a significant resolution in the previously described histologic lesions that coincided with a drastic reduction in the viral load with decrease in ADV PCR to < 500 copies/mL and a considerable increase in absolute total lymphocyte count (Figure 3D).

Discussion

Adenoviruses are nonenveloped double-stranded DNA viruses that infect human epithelial cells, exhibiting a characteristic cytopathic effect. They are ubiquitous, and transmission of infection typically occurs through respiratory droplets, via fecal oral routes, or by contact from contaminated fomites. Although most infections are subclinical or self-limited in immunocompetent hosts, they harbor high morbidity and mortality in immune compromised patients. In the latter cases, infection can be the result of a reactivation of a prior latent infection or a newly acquired one. Adenovirus infection is more likely to occur during the first several months after transplant.1,2 The most common manifestation of ADV infection in kidney transplant patient is acute hemorrhagic cystitis, sometimes complicated by interstitial nephritis. This syndrome is almost exclusively associated with subgroup B types 11, 34, and 35.3,4 The diagnosis of ADV interstitial nephritis is usually made by positive culture or PCR from blood, urine, or tissue sampling, as well as observation of histopathology changes.3-6 Typical histopathology findings in ADV nephropathy include tubular cell necrosis associated with severe interstitial inflammation and viral cytopathic effects, including peripheral condensed chromatin, basophilic nuclear inclusions, and nuclear enlarge-ment. Immunoperoxidase staining is used to document the presence of viral particles within the tissue. The viral particles are visible under an electron microscope.2,3 The role of antiviral drugs remains uncertain. Of interest, cidofovir, a nucleoside analog with broad-spectrum antiviral activity, has been shown to have good in vitro activity against ADV. In several case series and case reports with a variety of clinical ADV syndromes, cidofovir appeared to be associated with clinical improve-ments in a subset of patients, although fatality still occurred and significant nephrotoxicity was noted. Brincidofovir (CMX001; Chimerix, Inc. Durham, NC, USA) is a new lipid ester derivative of cidofovir; it exhibits enhanced in vitro activity against ADV and has lower potential for nephrotoxicity.1-8

In our case, the diagnosis of ADV interstitial nephritis was documented by positive PCR in blood (although the specific type was not identified), typical histopathologic features of viral nephritis reflected by an extensive necrotizing tubuloin-terstitial nephritis, and tubular necrosis with tubular epithelial cells showing nuclei with ground glass appearance of intranuclear inclusions (Figure 2). These presentations were accompanied by profound immunosuppression (absolute total lymphocyte count < 500 cells/μL) and negative PCR results for CMV, EBV, and polyomavirus. The patient’s condition started to improve with immunosup-pression tapering alone, which allowed immune reconstitution reflected by a gradual increase in the absolute lymphocyte count, clearance of the viremia, and subsequent clinical and functional improvement and recovery of graft function (Figure 3).

Conclusions

Adenovirus infection has been increasingly recognized as a cause of fever and graft dysfunction in kidney transplant recipients with risk factors involving the use of antithymocyte globulin, potent maintenance immunosuppressive therapy, and absolute total lymphocyte count below 500 cells/μL. In some cases, as shown in ours, reduction in immunosuppression and subsequent restoration of immune function can be sufficient for the resolution of the infection and the reversal of graft dysfunction.


References:

  1. Flomenberg F, Kojaoghlanian T. Epidemiology and clinical manifestations of adenovirus infection. In: Hirsch MS, Kaplan SL, eds. Up To Date 2017. www.uptodate.com. Accessed April 27, 2016.
  2. Rhee E, Barouch D. Adenovirus. In: Bennett JE, Dolin R, Blaser MJ, eds. Mandell, Douglas and Bennett‘s Principle and Practice of Infectious Disease. 8th ed. Philadelphia, PA: Elsevier Saunders; 2015, chapt 145:1787-1791.
  3. Kolankiewicz LM, Pullman J, Raffeld M, Kopp JB, Glicklich D. Adenovirus nephritis and obstructive uropathy in a renal transplant recipient: case report and literature review. NDT Plus. 2010;3(4):388-392.
    CrossRef - PubMed
  4. Barraclough K, Oliver K, Playford EG, et al. Life-threatening infection in a kidney transplant recipient. NDT Plus. 2009;2(3):250-253.
    CrossRef - PubMed
  5. Rady K, Walters G, Brown M, Talaulikar G. Allograft adenovirus nephritis. Clin Kidney J. 2014;7(3):289-292.
    CrossRef - PubMed
  6. Nanmoku K, Ishikawa N, Kurosawa A, et al. Clinical characteristics and outcomes of adenovirus infection of the urinary tract after renal transplantation. Transpl Infect Dis. 2016;18(2):234-239.
    CrossRef - PubMed
  7. Klein J, Kuperman M, Haley C, et al. Late presentation of adenovirus-induced hemorrhagic cystitis and ureteral obstruction in a kidney-pancreas transplant recipient. Proc (Bayl Univ Med Cent). 2015;28(4):488-491.
    PubMed
  8. Park UJ, Hyun SK, Kim HT, Cho WH, Han SY. Successful treatment of disseminated adenovirus infection with ribavirin and intravenous immunoglobulin in an adult renal transplant recipient: a case report. Transplant Proc. 2015;47(3):791-793.
    CrossRef - PubMed


DOI : 10.6002/ect.2017.0181


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From the the 1Rafik Hariri University Hospital, Beirut, Lebanon; and the 2King Saoud University, Riyadh, Saudi Arabia
Acknowledgements: The authors have no sources of funding for this study and have no conflicts of interest to declare.
Corresponding author: Antoine Barbari, Professor of Medicine, Lebanese Faculty of Medical Sciences, Department of Internal Medicine and Renal Transplant Unit, Rafik Hariri University Hospital, Bir Hassan, Beirut, Lebanon
Phone: +961 3326556 (mobile), +961 1831550/1831551 (office)
E-mail: barbariantoine@gmail.com