LETTER TO THE EDITOR
Year : 2018 | Volume
: 29 | Issue : 6 | Page : 1519--1522
Norovirus-associated hemolytic uremic syndrome in a renal transplant recipient
Lovy Gaur, Anurag Gupta, Aakash Shingada, AK Bhalla, Ashwani Gupta, Manish Malik, Vinant Bhargava, DS Rana
Department of Nephrology, Sir Gangaram Hospital, New Delhi, India
Dr. Lovy Gaur
Department of Nephrology, Sir Gangaram Hospital, New Delhi
|How to cite this article:|
Gaur L, Gupta A, Shingada A, Bhalla A K, Gupta A, Malik M, Bhargava V, Rana D S. Norovirus-associated hemolytic uremic syndrome in a renal transplant recipient.Saudi J Kidney Dis Transpl 2018;29:1519-1522
|How to cite this URL:|
Gaur L, Gupta A, Shingada A, Bhalla A K, Gupta A, Malik M, Bhargava V, Rana D S. Norovirus-associated hemolytic uremic syndrome in a renal transplant recipient. Saudi J Kidney Dis Transpl [serial online] 2018 [cited 2020 Aug 3 ];29:1519-1522
Available from: http://www.sjkdt.org/text.asp?2018/29/6/1519/248289
To the Editor,
Hemolytic uremic syndrome (HUS) has been reported to occur from a number of causes in the posttransplant period. Several infections have been reported to be the inciting factors. In this report, we describe HUS occurring in a renal allograft recipient following diarrhea secondary to Norovirus. Considering the ability of Norovirus to bind to specific blood group antigens, the pathogenesis behind probable association to HUS merits further studies. To the best of our knowledge, this is the first report describing Norovirus-associated HUS in a renal transplant recipient.
Informed consent was obtained from the relatives of the patient before reporting the case. A 42-year-old female presented to casualty in 2012 with complaints of nausea, decreased appetite, and generalized weakness. She had a history of chronic intake of analgesics for pain in her legs; kidney biopsy revealed chronic interstitial nephritis. She was initiated on maintenance hemodialysis (HD). About 1½ years later, she underwent live-related renal transplantation in 2014, donor being her father. She was induced with antithymocyte globulin; tacrolimus, mycophenolate mofetil, and steroids were used for maintenance immunosuppression. Immediate postoperative period was uneventful except for recurrent perigraft collection, for which she underwent marsupialization. Graft function was good, with baseline serum creatinine being 1.0 mg/dL. She remained apparently well till December 2016, when she developed loose stools. She was managed with hydration and withdrawal of mycophenolate mofetil. Cyto-megalovirus (CMV) polymerase chain reaction (PCR) revealed active replication (4376 copies/mL). Upper gastrointestinal endoscopy and colonoscopy were negative for invasive disease. She was initiated on intravenous ganciclovir administered for two weeks. CMV PCR became negative following which, oral valganciclovir was continued for another three weeks. Mycophenolate was reintroduced at a lower dose (500 mg/day). By this time, her serum creatinine declined to 1.2 mg/dL. Two weeks later, she developed fever and cough. Computerized tomography scan of the thorax revealed nodulo-parenchymal lesions clustered in bilateral lung fields. Sputum culture grew Aspergillus fumigatus. She was initiated on amphotericin which was administered for eight days following which, she improved and was discharged on oral voriconazole. Meanwhile, mycophenolate mofetil was withdrawn and the dose of tacrolimus was reduced to 2 mg/day. Graft function improved following therapy and serum creatinine reached a nadir of 1.7 mg/dL.
About three weeks later, the patient presented with complaints of loose stools and decreased urine output. On examination, she was conscious and alert and blood pressure was 156/92 mm Hg. Laboratory evaluation revealed hemoglobin of 9.7 g/dL, leukocytes of 5300/μL, platelets of 21,000/μL, serum creatinine of 4.88 mg/dL, total bilirubin of 1.8 mg/dL, and direct bilirubin being 0.88 mg/dL. Peripheral smear examination revealed normocytic normo-chromic cells with Schistocyte Index of 8.9%. Serum lactate dehydrogenase and uric acid levels were elevated at 1346 IU/L and 11.2 mg/dL, respectively; direct and indirect Coomb’s test were negative; tacrolimus level was 4.2; and urine examination revealed proteinuria (1+) and red blood cells of 2–3/high-power field. Blood and urine cultures were negative. CMV real-time quantitative PCR was negative (limit of detection of assay was 43 copies/mL). Blood and urine tested negative for BK virus amplification. Serologies were also negative for antinuclear antibodies, anti-dsDNA, anticytoplasmic antibodies, anti-phospholipid antibodies as well as for donor-specific antibodies. Routine examination of stool was unremarkable except that it tested positive for occult blood. The stool sample was tested with qualitative multiplexed nucleic acid-based in vitro diagnostic test (Biofire, Film array multiplex PCR), which was positive for norovirus GI/GII. Given the evidence of worsening of renal function and with markers of nonimmune intravascular hemolysis, the diagnosis of HUS posttransplant was made with probable association with norovirus diarrhea. Kidney biopsy could not be done in view of severe thrombocytopenia. Intravenous immunoglobulin and fresh-frozen plasma were administered. Allograft function did not respond to this therapy, and she needed intermittent HD in view of worsening uremia. Despite all these therapies, the patient continued to deteriorate and eventually succumbed.
While our patient did not undergo any genetic workup with respect to complement activity, the presence of clear instigating factors and no prior history of HUS strongly suggest that this variant of HUS was an acquired or “posttransplant” variant.
Human norovirus, earlier designated as Norwalk virus, was first identified in stool specimens collected during an outbreak of gastroenteritis in Norwalk. It was the first viral agent demonstrated to cause gastroenteritis. Noroviruses are nonenveloped, positive-sense, single-stranded RNA viruses, measuring about 27 nm in diameter. They belong to the genus Norovirus in the family Caliciviridae and are divided into six major geno groups designated GI through GVI. The majority of Norovirus strains associated with human disease belong to GI and GII and are further divided into about thirty genotypes.
Norovirus is the overall leading cause of acute gastroenteritis and accounts for >90% of outbreaks of gastroenteritis.,, These viruses are highly resistant to harsh environmental conditions, and the oral dose known to cause human disease is estimated to be <20 viral particles.
The mechanism by which the virus invades the intestinal epithelium is interesting. Studies of viral attachment to cultured gastrointestinal epithelial cells (Caco-2) using recombinant virus-like particles indicate that specific histo–blood group antigens play a key role in the attachment of the virus to the host cells. Recombinant Norovirus-derived virus-like particles have been demonstrated to bind to the apical surface of cells from the pyloric and duodenum epithelia of secretor individuals, but noticeably not in nonsecretor individuals.
Fecal excretion of Norovirus infection in asymptomatic individuals is common, especially in children varying from 11.6% to 49.2% across various studies. The incubation period is relatively brief in most infected individuals who develop symptoms, with a mean of 48 h (range being 29–96 h). A systematic review of the literature concluded that the median incubation period for genotype I and II infections is 1.2 days (95% confidence interval, 1.1–2.2 days). The dominant symptoms of Norovirus infection are vomiting (25.5%–80%) and diarrhea (66%–87.5%) and are generally of a relatively short duration. Other manifestations may be abdominal pain, fever, chills, headache, neck stiffness, photophobia, and obtundation.
The illness is usually benign with mean duration of symptoms being 2.1 ± 1.5 days, with most of the patients having symptom resolution within one to three days. However, extremes of age groups may be associated with greater degree and severity of complications. Norovirus outbreaks have been observed to be significantly associated with mortality in the oldest age group (≥85 years), with peaks coinciding with the emergence of new Norovirus variants (studied in the year 2002–2003). As in adults, Norovirus infection in term and preterm neonates causes the full range of symptoms and signs, but may also be associated with bloody diarrhea and very serious complication such as necrotizing enterocolitis.
Norovirus infection-associated illness may be more prolonged and severe in immunocom-promised individuals. Sporadic infections as well as outbreaks have been described in hematopoietic stem cell transplants and solid organ transplant recipients. In a retrospective study describing 96 renal transplant recipients hospitalized with diarrhea, one-sixth of them tested positive for Norovirus. Ninety-nine percent of these had chronic diarrhea. When compared with bacterial and parasitic infections, Norovirus infections were associated with a greater weight loss at the time of admission, an 8.7-fold longer duration of symptoms and a more frequent need for mycophenolic acid dosage reduction (56% cases). Eighty-one percent of these patients experienced acute renal failure. Nearly 30% of these subsequently developed biopsy-proven acute graft rejection. Another important observation noticed in this subset of patients was prolonged shedding of virus ranging 97–898 days.
A number of unusual manifestations have been described in both otherwise healthy population and transplant recipients, raising questions about the lesser known manifestations of the entire spectrum of disease. Hemophagocytic lymphohistiocytosis was reported in association with chronic Norovirus infection in a 24-month-old child following bone marrow transplantation for treatment of relapsed myelogenous leukemia. A case of febrile neutropenia in a pediatric renal allo-graft recipient has been described, which resolved together with the resolution of symptoms of Norovirus infection.
Calcineurin inhibitors-associated TMA/HUS has been described most commonly 9.3 ± 7.9 months after transplantation, while our patient had tolerated tacrolimus well for >2 years before presenting with features suggestive of thrombotic microangiopathy. Second, blood levels of tacrolimus were quite low at the time of presentation.
While the exact molecular mechanism of norovirus-causing HUS is unknown, the fact we already know is the ability of norovirus to bind to blood group antigens. These antigens are also expressed on endothelial cells. We postulate that possibly the virus binds to endothelial cells, probably leading to disequilibrium between vasoactive peptides, leading to arteriolar vasoconstriction.
To our knowledge, there has been only a single case reporting the occurrence of a possible HUS with diarrheal prodrome caused by Norovirus described in an 82-year-old Japanese male with chronic kidney disease Stage 3. However, this is the only case report describing its occurrence in a renal transplant recipient.
Also, this represents the only second reported case of Norovirus-associated HUS described in literature.
Conflict of interest: none declared.
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