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 Table of Contents  
CASE SERIES
Year : 2021  |  Volume : 1  |  Issue : 1  |  Page : 28-33

Norovirus infection in renal transplant patients with chronic diarrhea: A report of four cases and review of the literature


1 Department of Medical Gastroenterology, Apollo Hospitals, Chennai, Tamil Nadu, India
2 Department of Nephrology, Apollo Hospitals, Chennai, Tamil Nadu, India
3 Department of Histopathology, Apollo Hospitals, Chennai, Tamil Nadu, India
4 Department of Molecular Biology, Apollo Hospitals, Chennai, Tamil Nadu, India

Date of Submission17-Aug-2020
Date of Decision22-Sep-2020
Date of Acceptance23-Sep-2020
Date of Web Publication04-Dec-2020

Correspondence Address:
Sarojini Ashok Parameswaran
Department of Medical Gastroenterology, Apollo Hospitals, Greams Lane, Off Greams Road, Chennai - 600 006, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ghep.ghep_14_20

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  Abstract 


Diarrhea is not uncommon in immunocompromised patients We report here four renal transplant patients in whom a molecular testing panel for gastrointestinal pathogens revealed positive test for norovirus.

Keywords: Diarrhea, immunosuppressed, opportunistic infection


How to cite this article:
Parameswaran SA, Rao B S, Balasubramaniam S, Parameswaran A, Tarigopula A. Norovirus infection in renal transplant patients with chronic diarrhea: A report of four cases and review of the literature. Gastroenterol Hepatol Endosc Pract 2021;1:28-33

How to cite this URL:
Parameswaran SA, Rao B S, Balasubramaniam S, Parameswaran A, Tarigopula A. Norovirus infection in renal transplant patients with chronic diarrhea: A report of four cases and review of the literature. Gastroenterol Hepatol Endosc Pract [serial online] 2021 [cited 2021 Jan 17];1:28-33. Available from: http://www.ghepjournal.com/text.asp?2021/1/1/28/302216




  Introduction Top


Diarrhea in immunosuppressed patients is a diagnostic challenge, given the large variety of potential causes including medications, infections (bacterial, parasitic, and viral), allograft rejection, and graft-versus-host disease (GVHD) as well as unrelated chronic gastrointestinal (GI) disorders. Apart from Cytomegalovirus infection, it has been difficult so far to establish the role of viral pathogens in the causation of diarrhea in immunocompromised patients as histology is inadequate and electron microscopy, on which the diagnosis has been based, is not universally available. With the recent development of sensitive molecular assays, viral enteric pathogens such as Norovirus (NoV) have been demonstrated in the stool samples of immunocompromised patients with prolonged diarrhea, though their causative role in diarrhea in these patients remains to be established. We present four renal transplant patients with chronic diarrhea in whom NoV was detected in stool samples by multiplex GI platforms.


  Case Reports Top


Patient 1

A 28-year old male, renal allograft recipient (live-related renal transplant for IgA nephropathy 3 years ago) on mycophenolate, tacrolimus, and prednisolone, presented with large-volume watery diarrhea on and off for 6 months. He had anorexia and significant weight loss of 5–6 kg over the same period. There was no fever, abdominal pain, or vomiting. Laboratory evaluation revealed normal hemogram and mild azotemia. His stool routine examination was negative for parasitic ova or cysts, Cryptosporidia (modified acid-fast Bacilli [AFB] stain), or Clostridium difficile toxin. His upper GI endoscopy revealed antral gastritis and a granular appearing mucosa of the 2nd part of the duodenum. Gastric biopsy showed moderate chronic antral gastritis negative for Helicobacter pylori, and duodenal biopsy was reported as nonspecific chronic duodenitis with minimal villous deformity and increased intraepithelial lymphocytes, and no parasites. He was given nitazoxanide empirically to which he responded initially, but needed evaluation again 3 months later for recurring symptoms and further weight loss. The same tests were done and, in addition, an ileocolonoscopy, all of which were normal. The stool was this time also sent for stool GI pathogen panel film array (BioFire GI Panel Film Array, catalogue number RFIT-ASY-0104; manufacturer: BioFire Diagnostics, Salt Lake City, UT, USA). This was reported negative for all the bacteria and parasites tested, but was positive for NoV G1/GII. Subsequently, mycophenolate was discontinued and azathioprine was added, following which his symptoms settled. No follow-up testing of stool for NoV was carried out [Table 1].
Table 1: Symptoms, duration of symptoms, length of time after renal transplant when symptoms developed, pathogens detected by the panel in each patient, immunosuppression on board at the time of developing symptoms, and change of immunosuppression after symptoms developed

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Patient 2

A 52 -year old male presented 7 months following a live-related renal transplant with a 2 month history of watery diarrhea , mild periumbilical pain and weight loss of 10 kg in the past 2 yrs. He also had urosepis (Klebsiella on urine culture). His immunosuppression consisted of tacrolimus, mycophenolate, and prednisolone. Because diarrhea was a significant problem, his stool was submitted for routine examination, modified AFB stain, and stool GI pathogen film array (Biofire film array), which tested positive for Norovirus GI/GII and negative for all other pathogens. With the reduction of mycophenolate dose from 1 g/day to 500 g/day, his diarrhea subsided though he continued to have recurrent urinary tract infection. No follow-up stool testing for virus was done [Table 1].

Patient 3

A 62-year-old male, a renal allograft recipient on tacrolimus, prednisolone, and mycophenolate, presented 3 years posttransplant with a 4-month history of diarrhea and weight loss. His stool examination was negative for parasites and C. difficile toxin. Esophagogastroduodenoscopy and gastric/duodenal biopsies were done; the duodenal biopsy revealed moderate villous atrophy and moderate increase in intraepithelial lymphocytes. Stool GI pathogen panel film array (Biofire film array) was positive for NoV G1/GII and negative for other pathogens. He was evaluated at the same time for hyperpigmented skin lesions over the lower limbs, biopsy of which was suggestive of Kaposi’s sarcoma. He was switched to everolimus in addition to prednisolone and referred to an oncologist. He received three cycles of low-dose chemotherapy and expired subsequently; the details of his final illness are not available [Table 1].

Patient 4

A 53-year-old male, with a history of renal transplant 7 years prior, and a history of treatment for disseminated tuberculosis 6 months ago, was seen for watery diarrhea for 3 months with marked weight loss, vomiting on and off, edema, and hypoproteinemia. Stool microscopy revealed Strongyloides larvae; he underwent esophagogastroduodenoscopy and colonoscopy, which showed multiple, ulcerated, nodular lesions in the stomach, duodenum, and colon, with histopathological evidence of Strongyloides in all the three sites. He was treated with two courses of ivermectin, but he had persistent diarrhea, malabsorption, and weight loss. His stool was tested for GI pathogen panel and was positive for NoV GII (Luminex xTAG GI pathogen panel catalog number I032C0316; Luminex Molecular Diagnostics, Toronto, Canada). The significance of this positive test in the background of definite strongyloidiasis was not clear, and he was advised to repeat the test after 8 weeks but was lost to follow-up with the gastroenterology department, until his readmission 2 years later with complaints of recurrent episodes of loose stools, with marked weight loss and hypoproteinemia. Stool routine examination: modified AFB stain and cultures were negative. His esophagogastroduodenoscopy showed esophageal candidiasis and duodenal erosions/ulcers and a nodule in the 2nd part of duodenum: biopsy showed mild duodenal villous atrophy with mild increase in the intraepithelial lymphocytes. Ileocolonoscopy was normal. Stool GI pathogen panel (Biofire film array) was positive for NoV GI and GII and negative for any other pathogen. A considered decision was made after discussing with the patient, to withdraw all immunosuppression, except prednisolone. After 3 months, during which time the patient showed marked reduction in GI symptoms, everolimus was introduced in addition to steroids. He continues to do well with subsidence of his diarrhea, with weight gain and normalization of serum protein levels [Table 1].


  Discussion Top


NoV infection is well recognized as a common cause of acute gastroenteritis in both adults and children, and usually results in a short self-limited illness in immunocompetent patients. In recent years, with the development of multiplex molecular assays, it has been increasingly identified as a cause of chronic diarrhea in immunocompromised patients, where it may sometimes cause a debilitating and life-threatening illness.

NoVs are small, nonenveloped, single-stranded RNA viruses, belonging to the genus NoV of the family Caliciviridae, and consist of six genotypes (genotypes G I to G VI), divided into further subtypes: G I and G II being the strains usually associated with human disease and G II-4 being the subtype most often associated with outbreaks.[1] A similar finding was noted in a study in India where stool samples were tested for NoV in children aged <5 years hospitalized with diarrhea, as well as in children from the community with or without symptoms. In the community, the most frequently identified genotype was G II– 4, followed by G II– 2, whereas in the hospital, G II– 3 was the most frequently identified genotype followed by G II– 1 and G II –4 in equal proportions.[2] Infection is usually transmitted by the feco–oral route, though occasionally aerosolized viruses from vigorous vomiting can cause air-borne transmission.[3] NoV infection can occur sporadically or as outbreaks, accounting for 5%–36% of sporadic cases and for 47%–96% of outbreaks of acute gastroenteritis reported from around the world.[4] Outbreaks of infection have been attributed to contaminated food or water, or person-to-person spread from family members or health-care workers. NoVs are extremely resistant to harsh environmental conditions, including heat, cold, and detergent exposure, and fecal shedding of virus can persist for several weeks after symptoms subside. Although infectivity is most common during the symptomatic period, pre- and post-symptomatic transmission has also been described. After a short incubation period (24–48 h), the typical clinical features of vomiting, diarrhea, headache, myalgia, and fever develop and generally last for 1-3 days. Infection is more common in the winter season, hence it is commomly referred to as winter vomiting.

In children, a large number of case studies have described NoV infection in a setting of immunosuppression, either due to inherited immune disorders,[5] or acquired as a result of immunosuppressive therapy following small-bowel transplantation,[6] kidney transplantation,[7] hematopoietic stem cell transplantation (HSCT),[8] or cancer chemotherapy.[9] In a study of 62 children with inherited immune deficiencies, the prevalence of NoV infection was found to be 25% and viral shedding was found to be prolonged, with 57.1% of fecal samples still being positive after a median of 9.5 months of follow-up.[5]

The first description of NoV as a cause of chronic diarrhea in adult immunosuppressed patients was a study by Roddie et al. of a series of 12 adult allogeneic HSCT recipients with diarrhea.[10] The infection was diagnosed in these patients by reverse transcriptase -polymerase chain reaction (RT-PCR) in stool samples. Ten of these patients had vomiting at onset and six patients had marked weight loss necessitating enteral or parenteral nutrition. In ten patients, diarrhea lasted for a median duration of 3 months (range, 0.5–14 months); the remaining two patients died after 4 months of diarrhea – one due to unrelated complications and the other as a result of severe malnutrition. Viral shedding was high during the diarrheal episode, but only four of the ten patients who survived underwent follow-up testing. In three patients, stool samples were negative at 4, 6, and 14 months after the onset of illness. In the fourth patient, low-level viral loads were found in two stool samples though the patient was asymptomatic, but gastroenteritis recurred 27 months after the first episode, coinciding with a period of increased immunosuppression.

Closely following this study, Westhoff et al. reported NoV infection in two renal transplant patients who presented with watery diarrhea, nausea, and vomiting.[11] In both patients, diarrhea resolved within 4–5 days. One patient remained asymptomatic even though serial stool samples remained positive for NoVs for up to 6 months; he subsequently cleared the virus without reduction in immunosuppression. The other patient had repeated episodes of diarrhea over the next 3 months, once with abdominal pain and another time with fever, with resultant weight loss and hypoalbuminemia. Deep duodenal biopsies during one of the episodes, revealed partial villous atrophy and acute and chronic inflammatory cells in the lamina propria with CD8+ intraepithelial T lymphocytes in the upper normal range. The patient had persistent viral excretion in stool for 3 months. Immunosuppression was reduced at this point; following this, diarrhea resolved, he gained weight and stool tested negative for NoV.

Schorn et al. found NoV infection in 13 (16.7%) out of 78 kidney allograft recipients, presenting with diarrhea, over a 2-year period, of which 9 were diagnosed to have chronic infection (defined as 3 positive stool samples over 3 months).[12] Intermittent diarrhea and persistent virus shedding occurred in these patients for a duration of 97–898 days. Diarrheal symptoms, but not viral shedding, correlated with the intensity of immunosuppression. Detailed molecular analysis of virus isolates demonstrated continuous viral evolution in patients unable to clear the infection for prolonged periods. However there was no evidence of nosocomial transmission in this case series.

An overview of complications and chronic sequelae of NoV infection was obtained by Petrignani et al. by a systematic review of literature, covering studies done between 1974 and 2017, with 70% of studies from the latter decade of this period.[13] Chronic diarrhea was found in immunocompromised patients in 9%–100% of investigated cohorts (70 papers), with the duration of diarrhea varying from 4 weeks up to 9 years. In a third of patients, chronic diarrhea led to wasting, weight loss, or failure to thrive. Apart from this, other significant complications of NoV chronic diarrhea in renal, solid organ, heart, pancreas, or human stem cell transplant patients included renal failure (eight studies) and adverse transplant events (3 studies).

The diagnosis of NoV infection in immunocompromised patients is difficult to make from the clinical features alone, though significant vomiting accompanying the diarrhea may be a pointer in acute infection. Patients with chronic infection may, however, present with intermittent diarrhea without vomiting; when the infection is prolonged, this may lead to malnutrition, weight loss, and even graft dysfunction.[14],[15] Duodenal biopsies done as part of the diagnostic workup for diarrhea in immunocompromised patients have shown partial villous atrophy, increased intraepithelial lymphocytes and apoptotic bodies, and changes also seen in GVHD and patients on mycophenolate,[15],[16],[17] though apoptosis is a less pronounced feature in NoV infection. A sensitive and specific diagnostic assay is therefore crucial. Electron microscopy (EM) was initially the only diagnostic tool for detecting NoVs in stool. Though highly specific, it has a low sensitivity (15%) and requires trained laboratory staff, moreover EM facilities are not widely available.[18] Immunological tests (enzyme-linked immunosorbent assay and immunochromatographic studies), which use anti-NoV antibodies for the detection of NoV antigens in stool samples, have a moderate overall sensitivity but a very low sensitivity for G-1 type.[19]

Currently, the test that is most widely used is the RT-PCR method, which has a high specificity and sensitivity.[20] Recently, several multiplex molecular assays have been developed, which incorporate oligonucleotide primers for a large number of GI pathogens (viral, bacterial, and parasitic) in the same platform. The Biofire film array GI panel tests for 22 common GI pathogens, including viruses, bacteria, and protozoa, that cause infectious diarrhea [Table 2], using nested polymerase chain reaction with melting curve analysis,[21] and is validated and FDA –approved.[21],[22] The Luminex xTAG GPP tests for 15 common GI pathogens (14 FDA approved and validated[21],[23]) including viruses, bacteria, and protozoa in stool samples [Table 2], and uses PCR + xTAG technology (fluorescent bead based detection).[21]
Table 2: Targets included in two commercial Food and Drug Administration-cleared assays for the detection of gastrointestinal pathogens

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The advantages of these syndromic panels are (a) there is a broad coverage and there is no need to choose a particular assay, (b) co-infections can be picked up, (c) only a small sample volume is required, and (d) the results are rapidly obtained, usually within 1–2 h. The disadvantages include the high cost and the high number of asymptomatic infections that are picked up.[21] Fecal viral shedding has been demonstrated in asymptomatic healthy adult volunteers challenged with Norwalk virus, in challenged volunteers with gastroenteritis even after resolution of their symptoms, and in immunocompromised patients after resolution of diarrhea, making it difficult to definitely ascribe a protracted diarrheal illness in an immunosuppressed patient to NoV infection.[24]

NoV infection has to be differentiated from mycophenolate mofetil (MMF)-induced diarrhea especially in the posttransplant setting. Diarrhea in patients on MMF has been reported in frequencies varying from 19.3% to 38.4%, in different studies,[25],[26],[27] and a recent meta-analysis estimated the relative risk of diarrhea associated with the use of MMF to be 1.57.[28] Duodenal villous atrophy and Crohn’s-like inflammatory lesions have both been described on histology in patients with MMF-induced diarrhea.[29],[30] Reduced intestinal regeneration through inhibition of inosine monophosphate dehydrogenase (rate-limiting enzyme in purine synthesis) combined with inflammatory damage caused by tumor necrosis factor-alpha (secreted by mononuclear cells stimulated by acyl glucuronide, a metabolite of MMF) is believed to be the underlying mechanism of MMF-induced diarrhea.[31] However, the occurrence of diarrhea does not correlate with the dose of MMF or its metabolite and, also, most of the studies did not include screening for NoV infection, which has been observed to show similar histological changes. Hence, it is speculated that MMF-induced diarrhea is overestimated, and the reduction in diarrhea following MMF discontinuation may be due to a decrease in NoV-associated diarrhea (or other pathogen-related diarrhea).[32]

The treatment of NoV infection is mainly supportive (fluid and electrolyte replacement, antiemetics and antidiarrheals, and analgesics) as there is no antiviral agent that has been proved to be effective. Ribavirin and interferons were shown to inhibit viral replication in a Norwalk viral replicon system,[33] but no clear clinical benefit has been demonstrated in the limited data available.[34] Nitazoxanide, an antiprotozoal agent with a wide antimicrobial spectrum, has been shown to reduce the severity of symptoms and to shorten the time to resolution of symptoms.[35],[36] In addition, it is reported to cause cessation of fecal shedding, but further studies are needed.[37] Treatment strategies employing passive antibody, immunoglobulin, and breast milk have been largely anecdotal. In the absence of an effective agent, the main therapeutic measure that is currently recommended is to reduce the dose of immunosuppressants to the lowest possible that will maintain graft function or to switch over to a different class of immunosuppressant drug (mTor inhibitor such as everolimus instead of mycophenolate or azathioprine).

As of now, there is no effective vaccine, and hence measures for the prevention of NoV infection, especially in immunosuppressed individuals, include rigorous hand hygiene; avoidance of uncooked meat, eggs, fish, and unboiled water; and avoidance of contact with persons suffering from acute gastroenteritis. It is not yet clear whether it is necessary to isolate those immunosuppressed patients who are asymptomatic, or who have recovered from infection, but have persistent viral shedding, as their role in transmission is questionable in the absence of documented secondary cases.

All the four patients presented here had chronic intermittent diarrhea, anorexia, and significant weight loss [Table 2]. Impaired graft function was seen in one patient. Duodenal biopsy in three patients showed mild-to-moderate villous atrophy and variable increase in intraepithelial lymphocytes. In two of the patients, the role of NoV in the causation of diarrhea seems to be fairly well established, as it responded to alteration of immunosuppression in one (azathioprine instead of mycophenolate) and temporary withdrawal and later introduction of alternative immunosuppressive regimen (everolimus and prednisolone) in the other. It would have been useful to obtain follow-up stool test for NoV, but this was not done mainly because of the cost involved. In the other two patients, the role of NoV seems less clear, as urosepsis can also present with diarrhea and there was no follow-up in the patient with Kaposi’s sarcoma.


  Conclusion Top


NoV infection should be considered in the differential diagnosis of chronic diarrhea in immunocompromised patients, especially when accompanied by weight loss, malnutrition, and impairment of graft function. Further prospective studies with large sample sizes are needed in order to firmly establish the role of NoV in the causation of chronic diarrhea. As the only treatment now is supportive and reduction of immunosuppression, it is crucial to encourage continued research toward discovering an effective antiviral drug as well as a preventive vaccine.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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