Norovirus and sapovirus (both Caliciviridae) are common causes of viral gastroenteritis and may pose clinical challenges, particularly in immunocompromised patients. We present 3 pediatric kidney transplant cases seen at Başkent University Hospital to highlight variability in clinical presentation and management of norovirus and sapovirus infection in transplant recipients. Case 1 (18-year-old male, transplant 13 years earlier) presented with acute onset watery diarrhea and mild dehydration. Direct microscopic stool examination was unremarkable, and norovirus was detected on viral panel testing. Supportive therapy proved effective without immunosuppression adjustment. Symptoms resolved within 1 week, with stable renal function. Case 2 (10-year-old male, transplant 1 year earlier) presented with prolonged diarrhea, weight loss, and worsening kidney functions. Polymerase chain reaction detected norovirus in stool. Severity and duration of symptoms required hospitalization and intravenous hydration. Temporary immunosuppression reduction helped control viral infection; recovery was slow (several weeks) with intermittent relapses. Clinical symptoms ameliorated with oral human immunoglobulin therapy, highlighting its potential to manage severe norovirus gastroenteritis in immunocompromised pediatric transplants. Case 3 (9-year-old male, transplant 5 years earlier) presented with watery diarrhea lasting for 3 months, dehydration, and weight loss. Laboratory analysis revealed increased serum creatinine. He was hospitalized with intravenous hydration. Stool polymerase chain reaction revealed sapovirus as the cause. His kidney function slowly recovered with extensive hydration and close monitoring. Norovirus and sapovirus are common enteric pathogens that usually cause acute gastroenteritis. In solid-organ transplant recipients, these viruses can cause prolonged, severe gastroenteritis, which can lead to dehydration, weight loss, and possible graft loss. Solid-organ transplant recipients are immunocompromised, so disease course can be severe and management can be difficult. Patients may need hospitalization and immunosuppression adjustment. Early diagnosis and tailored supportive treatment are necessary to avoid complications. In selected patients, other treatments (eg, orally administered human immunoglobulin) could be used.

Key words : Diarrhea, Immunosuppression, Pediatric kidney transplantation, Viral gastroenteritis

Introduction
Norovirus and sapovirus are nonenveloped, single-stranded RNA viruses belonging to the Caliciviridae family and are among the most common causes of acute viral gastroenteritis worldwide across all age groups.¹ Norovirus, in particular, is responsible for a substantial proportion of both sporadic cases and outbreaks in community and health care settings.² Transmission occurs primarily via the fecal-oral route, including person-to-person contact, contaminated food or water, and environmental surfaces. The low infectious dose, prolonged viral shedding, and environmental stability of these viruses contribute to the high transmissibility of norovirus and sapovirus.³ In immunocompetent individuals, infection is typically self-limited and presents with acute-onset diarrhea, vomiting, abdominal cramps, and low-grade fever, with symptom resolution within a few days. However, in immunocompromised populations, especially solid-organ transplant recipients, the clinical course may be markedly different.⁴ Impaired cellular immunity and ongoing immunosuppressive therapy predispose these patients to prolonged viral replication, chronic diarrhea, significant fluid and electrolyte imbalance, weight loss, and malnutrition.⁵ In transplant recipients, norovirus infection may persist for weeks to months, with documented cases of viral shedding lasting beyond 1 year. Chronic infection can lead to recurrent hospitalizations, acute kidney injury secondary to dehydration, and challenges in maintaining adequate immunosuppressive drug levels due to altered absorption. Furthermore, reduction of immunosuppressive therapy (which is often required to facilitate viral clearance) carries the risk of precipitating acute rejection.⁶ Diagnostic approaches have evolved with the widespread use of multiplex polymerase chain reaction (PCR) panels, which have significantly improved detection rates versus conventional stool cultures. Currently, there is no specific antiviral therapy with proven efficacy against norovirus or sapovirus; management remains largely supportive, including fluid replacement and careful adjustment of immunosuppressive regimens. Nitazoxanide and immunoglobulin therapy have been used in selected cases, although evidence of efficacy remains limited and inconsistent.^7,8 Given the potential for chronicity, morbidity, and effect on graft function, norovirus and sapovirus infections represent a clinically significant concern in solid-organ transplant recipients and should be considered early in the differential diagnosis of posttransplant diarrhea.⁹ In this report, we present 3 pediatric kidney transplant recipients to highlight the variability in clinical presentation, disease course, and management of norovirus and sapovirus infections in this vulnerable population.

Case Report

Case 1
An 18-year-old male pediatric kidney transplant recipient presented to Başkent University Hospital with acute-onset watery diarrhea lasting 2 days, accompanied by mild dehydration. He did not have fever, vomiting, or abdominal pain. Kidney transplant had been performed 13 years earlier due to end-stage renal disease, and the patient had been on stable maintenance immunosuppressive therapy since then. At presentation, vital signs were stable, and physical examination revealed mild dehydration without signs of acute abdomen. Laboratory evaluation showed stable serum creatinine levels versus baseline, with no significant electrolyte imbalance. Stool samples were obtained for direct microscopic examination and viral testing. Direct microscopy did not reveal significant inflammatory findings, and bacterial stool cultures were negative. Stool viral analysis identified norovirus as the causative agent. The patient was managed with supportive therapy, including oral rehydration and close outpatient follow-up. No adjustment was made to the immunosuppressive regimen, given the mild clinical course and preserved graft function. Diarrhea resolved completely within 1 week, and renal function remained stable throughout follow-up.

Case 2
A 10-year-old male kidney transplant recipient, who had undergone transplant 1 year earlier, was admitted with a 3-week history of persistent watery diarrhea, progressive weight loss, and decreased oral intake. The patient also exhibited signs of dehydration and reported fatigue. Physical examination revealed moderate dehydration and weight loss versus previous outpatient visits. Laboratory investigations demonstrated worsening renal function, with elevated serum creatinine levels versus baseline. Stool examinations, including bacterial cultures and parasitological analysis, were initially unremarkable. Due to the prolonged course and severity of symptoms, stool PCR testing was performed and detected norovirus. The patient required hospitalization for intravenous fluid replacement and close monitoring of renal function. Given the severity and persistence of symptoms, a temporary reduction in immunosuppressive therapy was implemented to facilitate viral clearance. Despite supportive treatment, the patient experienced a prolonged clinical course with intermittent relapses of diarrhea over several weeks. Human immunoglobulin at a dose of 300 mg/kg was orally administered to treat refractory symptoms and ongoing renal dysfunction. Following oral immunoglobulin administration, gradual clinical improvement was observed, with resolution of diarrhea and stabilization of kidney function. The patient was discharged with careful outpatient follow-up and stepwise re-escalation of immunosuppressive therapy.

Case 3
A 9-year-old male recipient with a history of kidney transplant 5 years earlier was referred to our center with chronic watery diarrhea lasting approximately 3 months. The patient also presented with dehydration, weight loss, and reduced appetite. There was no history of recent travel or known exposure to gastrointestinal pathogens. On admission, physical examination revealed signs of dehydration and growth faltering. Laboratory evaluation showed elevated serum creatinine levels versus the patient’s baseline state, which raised concern for dehydration-related graft dysfunction. Initial stool analyses, including routine cultures and microscopic examination, were negative for pathogens. Given the chronic nature of symptoms and negative routine test results, stool PCR testing was performed and identified sapovirus as the causative agent. The patient was hospitalized and managed with intensive intravenous hydration and close monitoring of renal function and nutritional status. No changes were made to the immunosuppression regimen. Over the course of hospitalization and follow-up, diarrhea gradually improved, and serum creatinine levels returned toward baseline. The patient was discharged with recommendations for close outpatient monitoring and supportive care.

Discussion
Norovirus and sapovirus are well-recognized causes of acute viral gastroenteritis in the general pediatric population; however, the clinical course of these 2 pathogens may be significantly prolonged and complicated in solid-organ transplant recipients.^1-4 Immunosuppression, impaired viral clearance, and altered gut immune responses contribute to increased disease severity, chronicity, and risk of complications in this group.^4-6 Our 3 cases illustrate the wide spectrum of calicivirus-associated gastroenteritis in pediatric kidney transplant recipients. Although case 1 demonstrated an acute, self-limited course responding to supportive care alone, case 2 and case 3 were characterized by prolonged diarrhea, dehydration, weight loss, and deterioration in kidney function. These differences suggest that disease severity may be influenced by factors such as time since transplant, intensity of immunosuppression, and individual immune response. Norovirus has been increasingly recognized as one of the leading viral causes of posttransplant diarrhea, particularly in kidney transplant recipients. In immunocompromised patients, norovirus infection may persist for weeks or months and is often associated with relapse symptoms and graft dysfunction.⁹ In case 2, prolonged symptoms necessitated hospitalization, reduction of immunosuppressive therapy, and oral administration of human immunoglobulin. Although evidence remains limited, oral administration of human immunoglobulin has been reported as a potential therapeutic option in severe or refractory norovirus infections, possibly by enhancing viral clearance.¹⁰ Although there is no standardized dosing regimen for oral immunoglobulin in viral gastroenteritis among transplant recipients, previously reported doses have varied across centers. A large multicenter retrospective cohort by Engen and colleagues, including 40 pediatric kidney transplant recipients with PCR-confirmed norovirus infection, has provided important context.⁴ In that study, the median age at transplant was 5.4 years, and the median time from transplant to infection was 1.9 years. The median duration of diarrhea was 16 days, with a substantial proportion of patients developing prolonged disease; 23% had persistent diarrhea and 30% progressed to chronic diarrhea. Morbidity was considerable, as 53% of patients developed acute kidney injury and 88% required supplemental fluid therapy. Immunosuppression reduction was implemented in 20% of patients for a median duration of 22 days. Additional therapeutic interventions were variably employed, including nitazoxanide and oral immunoglobulin (each in 13% of cases), underscoring the absence of standardized management strategies. Acute rejection occurred in 8% of patients with 2 patients who ultimately experienced graft loss; however, reassuringly, no sustained decline in estimated glomerular filtration rate was observed at 12 months following diarrhea resolution.⁴ Our 3 cases reflect a similar clinical spectrum, ranging from self-limited infection to prolonged disease with transient graft dysfunction that required hospitalization and immunosuppression adjustment. Parallel with the previously published multicenter data, recovery was ultimately achieved without permanent graft impairment, which further supports the generally favorable long-term renal outcomes despite significant short-term morbidity. A prospective parallel cohort pilot study by Bonani and colleagues investigated the mechanisms underlying chronic diarrhea in renal transplant recipients with chronic norovirus infection.¹¹ In that single-center study, 7 adult kidney transplant recipients with chronic symptomatic norovirus infection were compared with 8 transplant recipients with chronic diarrhea of nonnoroviral origin. After exclusion of primary lactase deficiency, all patients underwent lactose hydrogen breath tests and lactose tolerance tests. Remarkably, secondary lactose maldigestion was identified in 100% of patients with chronic norovirus infection, versus only 12.5% in the control group, which suggested a strong association between chronic norovirus infection and acquired lactose maldigestion. The authors proposed that persistent viral enteropathy may impair brush-border enzyme activity, contributing to ongoing diarrhea. Although limited by small sample size, the study by Bonani and colleagues provided a potential pathophysiological explanation for prolonged or refractory diarrhea in transplant recipients with chronic norovirus infection.¹¹ Sapovirus infection is less frequently reported in transplant populations versus norovirus; however, emerging data suggest that it may also cause chronic gastroenteritis in immunocompromised hosts.¹² Our case 3 demonstrated that sapovirus can lead to prolonged diarrhea and renal dysfunction, emphasizing that sapovirus should be included in the differential diagnosis of chronic diarrhea in pediatric kidney transplant recipients. These cases also underscored the diagnostic importance of molecular stool testing. Routine stool cultures and antigen-based assays often fail to identify viral pathogens in transplant recipients, whereas PCR-based testing allows for early and accurate diagnosis. Early identification enables timely supportive management, careful monitoring of renal function, and appropriate adjustment of immunosuppressive therapy when necessary. A recent comprehensive review on postsurgery kidney transplant infections has highlighted the observation that infectious complications remain a major source of morbidity throughout the transplant course.¹³ Early infections are typically health care-associated, whereas late infections are more often discovered to be a community-acquired phenomenon. Opportunistic viral infections, including BK polyomavirus, cytomegalovirus, Epstein-Barr virus, and norovirus, are particularly relevant within the first year after transplant, influenced by the intensity of immunosuppression and prior prophylaxis strategies. The review underscores that enteric viral infections such as norovirus are increasingly recognized causes of significant posttransplant morbidity, emphasizing the importance of preventive strategies, timely diagnosis, and individualized management in this vulnerable population.¹³ Overall, our 3 cases highlight that norovirus and sapovirus infections can result in significant morbidity in pediatric kidney transplant recipients. Awareness of these pathogens and a tailored, patient-specific management approach are essential to prevent dehydration, prolonged hospitalization, and graft dysfunction.

Conclusions
Norovirus and sapovirus are common enteric pathogens that usually cause acute gastroenteritis; however, in pediatric kidney transplant recipients, these infections may lead to prolonged and severe disease. Early diagnosis, close monitoring, and individualized supportive treatment are crucial. In selected cases, additional therapeutic options such as orally administered human immunoglobulin may be considered to improve outcomes.