Management of Norovirus Infection in Solid Organ Transplant Recipients: A Scoping Review

Abstract

Background.

Norovirus infection causes significant morbidity in solid organ transplant (SOT) recipients, yet few treatments are available, and evidence for efficacy is sparse. In this scoping review, we identify and evaluate potential interventions for managing norovirus infections in SOT recipients.

Methods.

We searched electronic databases from inception to July 6, 2025. Eligible studies were analyzed for participants’ characteristics, intervention types, and reported outcomes.

Results.

After screening 245 abstracts, 58 studies were included (1 randomized controlled trial, 27 cohort studies, 5 case series and 25 case reports), mainly from the United States. Transplant types included kidney (n = 36), liver (n = 12), cardiac (n = 12), pulmonary (n = 7), pancreas (n = 6), small bowel (n = 7), and multiorgan (n = 13) transplants. The most frequently reported primary outcome was resolution of gastrointestinal (GI) symptoms. Interventions were diverse: immunosuppression modification (n = 14), nitazoxanide (n = 6), IVIG (n = 3), oral immunoglobulin (n = 10), combination of these (n = 19), fecal transplant (n = 2), supportive management (n = 4), and others not classified (n = 5). Limited quality evidence for the resolution of gastrointestinal symptoms was reported for immunosuppression modification (n = 7/14), nitazoxanide (n = 4/6), IVIG (n = 2/3), oral immunoglobulin alone (n = 10/10), fecal transplant (n = 2/2), supportive treatment (n = 4/4), and a combination of treatments (n = 10/19). A lack of clinical improvement was described in 13 of 58 studies.

Conclusions.

A wide range of interventions has been used to manage norovirus infections in SOT recipients; however, the evidence is limited to observational studies, and the findings are uncertain. High-quality randomized controlled trials are needed to establish treatment efficacy and safety.

INTRODUCTION

Norovirus is a single-stranded RNA virus from the Caliciviridae family,¹ with the GII.4 recognized as the most common cause of outbreaks of norovirus infection globally.^2-4 The disease is highly contagious and is a leading cause of acute gastroenteritis in people of all ages and settings,⁵ causing >20 million episodes of gastroenteritis and >200 000 deaths every year, worldwide.^6,7 It poses a significant financial burden, with estimates exceeding $4 billion in direct health system costs and $60 billion in societal costs yearly, and a high burden of disease disability-adjusted life years.^7-9 This impact is attributed to healthcare expenses and loss of productivity, highlighting the need for effective prevention and control measures to mitigate its spread.⁸ Infections in immunocompetent hosts typically resolve within a few days. However, disease may be severe and sometimes prolonged in immunocompromised patients, including solid organ transplant (SOT) recipients, causing major complications such as acute kidney injury, allograft dysfunction, and occasionally death.^10-13

Despite the disease’s severity, preventive and therapeutic measures are lacking. Noroviruses are a genetically and antigenically diverse group of RNA viruses, which makes it challenging to develop diagnostics and vaccines.¹⁴ In addition, there are currently no targeted antiviral treatments for norovirus gastroenteritis, and cases are typically managed with supportive therapy, including rehydration, electrolyte replacement, and immunosuppression reduction. Very few randomized controlled trials (RCTs) have analyzed the efficacy and safety of interventions to manage norovirus in SOT recipients.¹⁵ Furthermore, in vivo and in vitro data are lacking, because human norovirus is only known to infect humans; there are no robust and reproducible models available.^16,17 Well-designed, adequately powered RCTs are ultimately required to assess the safety and efficacy of interventions for managing norovirus infections in SOT recipients. As a necessary first step, we aimed to conduct a scoping review to systematically map and evaluate the existing literature on such interventions.

MATERIALS AND METHODS

The Preferred Reporting Items of Systematic Review and Meta-Analyses extension for Scoping Reviews and the Joanna Briggs Institute Manual for Evidence Synthesis were used to guide this work.

Inclusion Criteria

Eligible studies reported data on SOT recipients with a diagnosis of norovirus infection based on nucleic acid amplification testing of stool samples, such as real-time polymerase chain reaction. We searched databases from inception to July 2025, without language restrictions, accepting study designs including systematic reviews, RCTs, cohort studies, case series, case reports, and letters to the editor or editorials with relevant data. Reports on patients who did not have an SOT were ineligible.

Search Strategy

We developed the search strategy in Medline, reviewed it according to the Peer Review of Electronic Search Strategies guidelines, and adapted it for use in Embase, CINAHL, and the Cochrane Central Register of Controlled Trials. We also assessed the reference lists of studies included to identify relevant articles. Appendix 1 (SDC, https://links.lww.com/TXD/A868) highlights the search strategy used in this scoping review.

Evidence Selection and Screening

Two researchers (T.M.M. and A.L.) independently screened titles and abstracts to determine their inclusion based on the eligibility criteria. If any discrepancies could not be resolved, a final decision was made by a third party (G.W.). Following this, the same pair of researchers independently screened all full-text articles for inclusion. Any discrepancies were resolved through discussion between the 2 researchers. A third party (G.W.) made a final decision on the disparity if the disagreements could not be resolved.

Data Extraction

A spreadsheet was developed to capture standardized data from included studies, including authorship, publication year, study characteristics, study design, country of study and setting. Participant information, including age, sex, and sample size, was also collected, along with the study objectives: specifically, the population, intervention, comparator, and outcome. Data were extracted by a single researcher (T.M.M.) and verified by a second (A.L.).

Data Analysis, Summary, and Presentation

Data were analyzed with STATA version 19 and RStudio.^18,19 Demographic data were presented descriptively as mean and SD or median and interquartile range, depending on the data distribution.

RESULTS

Literature Search

Figure 1 shows the literature search results. The search yielded 235 studies, of which 127 were excluded after title and abstract screening. Disagreements on inclusion were resolved through full-text retrieval and review, resulting in the further exclusion of 50 studies due to their full-text screening, as they did not contain the relevant data or were otherwise ineligible. A total of 58 studies were included in this review.

FIGURE 1.

Flow diagram illustrating the study selection process.

Characteristics of the Included Studies

Table 1 presents the methods, populations, interventions, and outcomes of each study. The studies’ designs included in this scoping review were RCTs (n = 1; 2%), cohort studies (n = 27; 46%), case series (n = 5; 9%), and case reports (n = 25; 43%). The studies’ sample sizes ranged from 1 to 280 participants. The included studies were conducted in 14 countries. Table 2 summarizes the key outcomes across different treatment strategies (monotherapy and combined).

TABLE 1.

Study characteristics (N = 58)

Study characteristics	n (%)
Publication year
Before 2000	0
2000–2009	4 (7)
2010–2019	29 (50)
2020 onward	25 (43)
Study type
RCT	1 (2)
Cohort	27 (46)
Case series	5 (9)
Case reports	25 (43)
Sample size
0–9	33 (57)
10–49	10 (17)
50–99	7 (12)
100–199	7 (12)
>200	1 (2)
Population subgroups
Adults	44 (76)
Children	14 (24)
Type of transplanta
Kidney transplant alone	28 (48)
Solid organ transplants, including kidney, heart, lung, liver, intestine, and combined multiple transplants	36 (62)
Solid organ transplants and others (hemopoietic stem cell transplants, immunosuppressed patients, including hematological malignancies and solid tumors)	3 (5)
Interventionsb
Monotherapies
Immunosuppressive therapy modification	14 (24)
Nitazoxanide alone	6 (10)
Intravenous immunoglobulin therapy	3 (5)
Oral and enteral immunoglobulin therapy	10 (17)
Combination of treatments	19 (33)
Fecal microbiota transplant	2 (3)
Supportive management	4 (7)
Others	5 (9)
Reported outcomes
Improvement in GI symptoms	39 (67)
Improvement of extra-GI symptoms	2 (3)
Reporting on graft-related outcomes	19 (33)
Evidence of eradication of norovirus in stool	5 (9)
No/minimal improvement in symptoms	13 (22)
Reporting of adverse drug reactions	14 (24)

^aSome studies included multiple types of transplants.

^bSome studies reported multiple treatment strategies.

GI, gastrointestinal; RCT, randomized controlled trial.

TABLE 2.

Summary of the reported key outcomes across different treatment strategies (monotherapy and combined)

No. of studies (and study types) describing the treatment strategies and the reported outcomes	Descriptive summary of findingsa
Immunosuppression modification (total studies: N = 14: [cohort studies, n = 10; case studies, n = 4])
Clinical response20-26	Complete resolution of GI symptoms was reported in 6 studies, with symptom resolution rates ranging from 50% to 100% Partial resolution or improvement of GI symptoms was reported in 2 studies
Viral response21,23,25,27,28	Complete viral eradication was not reported in any study. Prolonged viral shedding was described in 5 studies, with reported prevalence ranging from 15% to 82% among included participants
Time to response20-22,29	Time to clinical response was reported in 4 studies and ranged from 2 wk to 6 mo
Graft outcomes21,23,24,30	Persistent graft dysfunction was reported in 2 studies; 1 study reported 48% of the included participants experienced graft dysfunction. The other study did not specify the graft dysfunction rates. Graft rejection was reported in 3 studies, affecting 3.1%, 5%, and 13% of affected patients, respectively. Development of de novo DSA was described in a single study
Adverse effects23,30	Acute rejection after norovirus infection and subsequent modification of immunosuppression was reported in 2 studies, occurring in 5% and 13% of patients, respectively
Nitazoxanide (total studies: N = 6 [RCT, n = 1; cohort studies, n = 2 and, case studies, n = 3])
Clinical response24,31-34	Complete resolution of GI symptoms was reported in 3 studies, with rates ranging from 35% to 100%. One additional study reported partial symptom improvement, but the proportion of affected patients was not specified
Time to response31,32,35	Time to clinical response was reported in 4 studies, ranging from 2 to 14 d
Adverse effects32	One study reported no serious adverse effects
OIG therapy (total studies: N = 7 [cohort studies, n = 5; case studies, n = 2])
Clinical response24,36-41	Complete resolution of GI symptoms was reported in 4 studies, with rates ranging from 42% to 100%. Partial resolution or improvement of GI symptoms was reported in 3 studies, with rates ranging from 53% to 100%
Viral response39	Complete viral eradication was not reported in any study. Prolonged viral shedding was described in 1 case report
Time to response36-38	Time to response was reported in 3 studies: a range of 3–8 d in 2 case studies, and a median of 7.5 d in a cohort study
Graft outcomes24	Graft status and renal dysfunction were reported in 1 study, but the proportions were not specified
Adverse effects36-38	No reported side effects or reactions to OIG were reported in 3 studies
Enteral immunoglobulin therapy (total studies: N = 3 [case studies, n = 3])
Clinical response42-44	Resolution of GI symptoms was reported in 3 case reports, with proportions of patients experiencing complete symptom resolution ranging from 50% to 100%, and partial symptom resolution was reported in 50%
Viral response42-44	Complete viral eradication was reported in all 3 studies, with 100% of included patients achieving it
Time to response42-44	Time to response was reported in all 3 studies, with an overall range of 1 to 3 d
Adverse effects42	One study reported abdominal discomfort in a single participant after a third dose of nasojejunal enteral immunoglobulin
Intravenous immunoglobulin therapy alone (total studies: N = 3 [cohort studies, n = 2; case studies, n = 1])
Clinical response24,45	Complete resolution of GI symptoms was reported in 2 studies, 29% and 72% of included patients, respectively Partial resolution or improvement of GI symptoms was reported in 56% of included patients in 1 study
Graft outcomes24,45	Persistent graft dysfunction reported in 2 studies; proportions not specified
Combination strategies (total studies: N = 19 [cohort studies, n = 10; case studies, n = 9])
Clinical response46-55	Complete resolution of GI symptoms was reported in 5 studies, with the proportions of patients experiencing symptom resolution ranging from 33% to 100% Improvement of GI symptoms was reported in 5 studies, with the proportions of patients experiencing symptom improvement ranging from 33% to 85%
Viral response55,56	Complete viral eradication was reported in one study, with a clearance achieved in 33% of included patients. Another study reported prolonged viral shedding, with a median duration of 78 d (range, 20–360 d)
Time to response46-48,51,52,54,55	Time to response was reported in 7 studies, with an overall range of 3–45 d
Graft outcomes48,57,58	Persistent graft dysfunction was reported in one study, affecting 21% of included SOT recipients Acute rejection was reported in 2 of 3 cardiac transplant recipients in one case report Stable allograft function was reported in a kidney transplant recipient in one case report although follow-up duration was not specified
Adverse effects47,48,54,58,59	In two studies, rejection episodes and worsening graft function were reported as adverse effects; the proportion attributed to individual treatments was not specified. In one case report, acute rejection occurred in 2 of 3 cardiac transplant recipients and was considered likely related to the reduction of immunosuppression. Severe allograft rejection after OIG treatment in an intestinal transplant patient in another case report
Fecal microbiota transplant (total studies: N = 2 [case studies, n = 2])
Clinical response60,61	In a single case report, complete resolution of GI symptoms was reported in one affected patient One case series reported improvement in GI symptoms, with all patients experiencing symptom improvement
Viral response61	Complete viral eradication was reported in a single case report
Adverse effects61	One study reported no serious adverse effects
Supportive management (total studies: N = 4 [case studies, n = 4])
Clinical response62-65	Symptom resolution was reported in all case studies
Viral response65	One study reported a steady reduction in fecal viral load during the study follow-up duration
Time to response65	The time to response was not specifically reported; however, one patient experienced prolonged norovirus shedding for >5 y before resolution
Graft outcomes63-65	No change in graft function was reported in 2 studies. In 1 case report, reduced graft function, chronic antibody-mediated rejection, and development of de novo DSAs were described

^aOutcomes are reported descriptively as presented in the original studies; no pooling or quantitative synthesis was performed. A formal GRADE assessment is not methodologically appropriate for a scoping review.

DSA, donor-specific antibody; GI, gastrointestinal; GRADE, Grading of Recommendations, Assessment, Development and Evaluation; OIG, oral immunoglobulin; RCT, randomized controlled trial.

The studies included kidney (n = 36), liver (n = 12), cardiac (n = 12), pulmonary (n = 7), pancreas (n = 6), small bowel (n = 7), and multiorgan transplant recipients (n = 13), with some studies covering multiorgan transplant recipients. The treatment strategies included in these studies were diverse. Of the 58 studies, one study comprised multiple treatments (n = 1). The treatments included were immunosuppression modification (n = 14), nitazoxanide (n = 6), IVIG (n = 3), oral immunoglobulin (n = 10, including enteral immunoglobulin n = 3), combination therapies including immunosuppression modification and nitazoxanide (n = 5), combined immunosuppression modification, nitazoxanide, and oral/intravenous immunoglobulin (n = 8), immunosuppression modification and oral immunoglobulin (n = 3), nitazoxanide and combined immunoglobulins therapies (n = 3), fecal transplant (n = 2), supportive management (n = 4), and others not classified (n = 5).

Figure 2 shows the reported outcomes across the different studies. The resolution of gastrointestinal (GI) symptoms was the most frequently assessed outcome, described in 39 of 58 studies (67%). Only 19 studies (33%) reported on graft outcomes, and 14 studies (24%) on adverse events associated with treatment. Most did not provide details on study duration and follow-up time.

FIGURE 2.

Reported outcomes across the included studies. GI, gastrointestinal.

Figure 3 shows the reported success rates by treatment type and sample size for the included studies. The treatment success rate is the percentage of patients in the study population who achieve symptom resolution after treatment. The case reports and smaller studies frequently reported higher treatment success rates than the larger studies, which reported partial responses and lower rates.

FIGURE 3.

Reported success rates by treatment types and sample size of the included studies. The success rate of treatment is defined by the percentage of patients in the study population who experience resolution of symptoms after receiving the treatment. FMT, microbiota transplant; IG, immunoglobulin; ISM, immunosuppression modification; N, nitazoxanide; OIG, oral immunoglobulin.

INTERVENTIONS TO TREAT NOROVIRUS INFECTIONS

Monotherapies

Immunosuppression Modification Alone

Overall, 14 studies (n = 791) reported modifications in immunosuppression among individuals diagnosed with norovirus infection. These studies included recipients of kidney, heart, lung, liver, pancreas, intestine, and multiorgan SOTs, as well as hematopoietic stem cell transplants, in both adults and children. Of these, the most common immunosuppressive changes were the reduction or withdrawal of antiproliferative agents (4 studies) and tacrolimus (3 studies). Other changes included conversion from mycophenolate to azathioprine (2 studies), conversion to mammalian target of rapamycin (2 studies), and conversion from tacrolimus to cyclosporine (1 study). Three studies did not specify the reduction or modification of immunosuppressive drugs.

Across all studies, responses to immunosuppression modification varied. Six studies reported resolution within weeks to 12 mo,^20-23,27,29 whereas 7 found improvement to be inconsistent, often transient, or absent.^{24,25,28,30,66-68} In a cohort study of 39 kidney transplant recipients (29 with norovirus), reducing or withdrawing antiproliferative agents (with 6 switching from tacrolimus to cyclosporine) resulted in symptom resolution. However, the time to resolution was not reported. Similar results were observed in other studies.^21,22,25 In a larger cohort of 280 patients with norovirus infection comprising both adult and pediatric SOT and hematopoietic stem cell transplant recipients, an inconsistent response with immunosuppression reduction was reported.²⁴ There were no reported cases of acute rejection or de novo donor-specific antibody formation after reducing immunosuppressive doses. Conversely, a single case study reported de novo donor-specific antibody development after withholding mycophenolate for >1 wk.³⁰

Nitazoxanide Alone

High-quality evidence assessing the effects of nitazoxanide for the treatment of norovirus in SOT is sparse. Six studies (n = 130) included kidney, heart, lung, liver, intestine, and multiorgan transplant recipients^24,31-35 analyzed the benefits and harms of nitazoxanide for treating norovirus infections. A single RCT (n = 31 SOTs, nitazoxanide = 16 and placebo = 15) found no evidence of benefits over placebo in time to clinical resolution or viral shedding.³² A cohort study of 91 transplant recipients reported sustained resolution in 35.2%, transient improvement in 52.7%, and no change in 12.1%.²⁴ Three case reports described transient improvement in GI symptoms among heart and kidney transplant recipients.^31,34,35

IVIG Alone

Three studies (n = 54) evaluated IVIG alone in SOT recipients with norovirus infections. In a single-cohort study (n = 18), all participants achieved GI symptom resolution, but 10 (56%) remained stool-positive for norovirus polymerase chain reaction. Duration, dose, and time to resolution of symptoms were not reported.⁴⁵ A multicenter observational study (n = 34 SOTs) reported no improvement in 14.7%, sustained resolution in 29.4%, and temporary improvement in 55.9% of all participants.²⁴ One case report described treatment failure with a combination of IVIG and fresh frozen plasma in a kidney transplant recipient who developed hemolytic uremic syndrome and died.⁶⁹ However, none of the studies explicitly included hypogammaglobulinemia as an inclusion criterion, adding uncertainty to its severity and impact on treatment response.

Oral and Enteral Immunoglobulin Alone

Ten studies (n = 196) assessed oral (7 studies; n = 193) and enteral immunoglobulin (3 studies; n = 3) for the treatment of norovirus-associated diarrhea in SOT recipients. Across these studies, improvement in GI symptoms was described in all recipients. In most studies, immunoglobulin was administered orally, citing prior evidence reporting the stability of IgG through proteolytic digestion in the stomach and upper intestinal tract, as well as concerns regarding the risks associated with enteric tube placement in highly immunosuppressed patients.^36,70 Enteral immunoglobulin was given in 3 case reports, with clinical improvement observed in all 3 patients.^42-44 One patient developed abdominal pain after a third dose of nasojejunal enteral immunoglobulin, which resolved with conservative management.⁴²

There was considerable variability in the doses and timing of treatment, ranging from 25 mg/kg every 6 or 8 h for 2 d³⁷ to 100–300 mg/kg/d for 1–5 d.³⁸ Resolution of diarrhea was reported in most studies.^{36,39,40,42,44} In 4 studies, clinical improvement occurred within 2–7 d of treatment initiation.^36,37,41,43 One study reported a broader time to response, with improvement observed within 4–21 d for acute diarrhea, and 28–90 d for chronic cases.³⁸ A single case series (n = 4) reported variable responses, with no change in symptoms reported in 1 (25%), temporary improvement in 3 (75.0%), and none had sustained resolution.⁴⁰

Fecal Microbiota Transplant

Two case series (n = 5) reported fecal microbiota transplant (FMT) for the management of chronic norovirus gastroenteritis in SOT recipients.^60,71 Improvement and resolution of symptoms were reported in all patients in both studies.

Combined Therapies

Immunosuppression Modification and Nitazoxanide

Combined management with immunosuppression modification and nitazoxanide was reported in 5 studies (n = 199), comprising 4 case reports in kidney and liver transplant recipients^38-41 and 1 cohort study (n = 195) in kidney, liver, heart, lung, and pancreas transplant recipients.⁴⁶ Most case reports reported symptom resolution. In a cohort of 195 SOT recipients, nitazoxanide was associated with greater symptom improvement and shorter time to improvement. However, no benefit was observed with immunosuppression modification alone.⁴⁶

Immunosuppressive Therapy Modification, Nitazoxanide and Other Combination Therapies

Across all studies, different combinations of immunosuppressive therapy modification with adjunctive therapies have been trialed for norovirus-related diarrhea in SOT recipients, with mixed outcomes. A single case report found that symptom improvement occurred only after reducing mycophenolate doses.⁵⁷ A combination of immunosuppression adjustments, nitazoxanide, and oral immunoglobulin was assessed in 5 studies (n = 234), and most followed a stepwise approach of supportive care, immunosuppression reduction, then nitazoxanide, or oral IgG.^47-49,72,73 Clinical responses were inconsistent, with some reporting uncertain benefits,^72,73 others limited improvement,⁴⁹ and a few documenting symptom resolution.^47,48 Two larger cohort studies (N = 272) assessed the modification of immunosuppression with nitazoxanide and IVIG, showing efficacy in 1 study but inconclusive benefits in the other.^50,58 Smaller studies (N = 42) suggested that immunosuppression adjustment combined with oral IgG was associated with symptom improvement within 2–7 d.^51-53 Overall, the evidence was limited to retrospective cohorts and case reports, which restricted the certainty of these findings.

Nitazoxanide and Other Adjunctive Therapies

The evidence base for nitazoxanide-based combination therapy in norovirus infection among SOT recipients remains sparse and inconclusive. A single case report in an intestinal transplant recipient described an unfavorable outcome, with no clinical or virologic response to combined nitazoxanide and oral Ig therapy.⁵⁹ Similarly, a small retrospective cohort study evaluating the use of nitazoxanide and IVIG in 4 intestinal transplant recipients with norovirus infection found that symptoms were prolonged, and efficacy could not be ascertained.⁵⁶ A larger study (N = 152) assessing the effectiveness of nitazoxanide, IVIG, and antimotility treatment suggested that nonintestinal transplant recipients required more frequent or prolonged use of combination treatment compared with intestinal SOTs.⁷¹

Other Treatments

Supportive Management

A total of 4 studies (n = 7) reported symptom resolution with supportive management (intravenous fluids with or without loperamide and dimenhydrinate) in kidney and multiorgan SOT recipients with norovirus-associated diarrhea.^62-65 One case report described a patient who successfully underwent kidney transplantation after bilateral lung transplantation, with resolution of symptoms occurring approximately 10 wk after kidney transplantation.⁶⁵

Other Studies not Classified

Three studies (n = 13) investigated the use of breast milk, favipiravir, and metronidazole for the management of norovirus-associated diarrhea in SOT recipients. These studies have found responses to treatment varied from temporary and sustained symptom resolution to no improvement.^24,49,74 The other 2 case reports (n = 3) reported rare complications of norovirus infection, such as agranulocytosis and elevated aminotransferases.^75,76 All had shown improvement with resolution of norovirus with trials of various treatments (modification of immunosuppression, IVIG, and ceftriaxone); however, the efficacy of these treatments was uncertain, as they were given after failure of other treatments.

DISCUSSION

This scoping review identified 1 RCT, 27 cohort studies, 5 case series, and 25 case reports evaluating interventions for norovirus infections in SOT recipients. The most frequently analyzed interventions were immunosuppressive therapy modification, nitazoxanide, immunoglobulin (intravenous or oral), combination regimens, FMT, and supportive care. Symptom resolution was most consistently reported with oral immunoglobulin, FMT, and supportive care, whereas the literature on other interventions was more heterogeneous, showing variable effectiveness. In addition, the smaller studies reported higher treatment success rates than the larger cohort studies, reflecting publication and selection biases that may overestimate treatment effects.

Overall, we found insufficient high-quality evidence to conclude with certainty that any of the described interventions are effective in treating norovirus infection in SOT recipients. The included studies exhibited substantial methodological heterogeneity, with inconsistent comparisons, variable outcome measures, and limited data on harms. Most reports were case studies, presenting descriptive or narrative findings, which are inherently susceptible to a higher risk of bias due to their selective nature, absence of systematic methodology, and limited generalizability.⁷⁷ The existing literature was unable to address likely differences in treatment response relating to patient factors, such as degree of immunosuppression, acute versus chronic persistent infections, or advanced stages of disease. Moreover, comparisons with control groups were not reported in any of the observational studies. Given the limitations of the available evidence, it was not possible to explore and summarize the estimates of potential complications arising from any of the proposed treatments.

The transferability of the findings from these studies into clinical practice needs to be taken with caution. First, many small, observational studies reported highly varied outcomes. For example, no specific time to symptom resolution was documented in >80% of these studies. Second, there was minimal data on adverse effects for any of the interventions proposed. Third, it is unclear whether the resolution of symptoms, such as abdominal pain and diarrhea, indicates eradication of norovirus, with implications for infection control.

A key feature that distinguishes norovirus infections in SOT recipients is their tendency to become chronic and refractory, in contrast to the acute, self-limiting course observed in immunocompetent individuals. Most published studies of therapeutic strategies have focused on hospitalized transplant recipients with chronic norovirus infections. The true incidence of acute self-limited gastroenteritis in this population remains unclear. A single study of 60 hospitalized kidney transplant recipients reported that nearly 50% had acute norovirus infection,⁴⁵ a proportion that is likely to be higher when outpatient episodes are included. Furthermore, it is unclear whether early adjustment of immunosuppression in the acute setting (eg, withholding mycophenolate) prevents the illness from progressing to a chronic infection. Effective therapeutic strategies should therefore aim to both prevent progression to chronic disease and halt established chronic or refractory infections.

The strength of this review lies in its comprehensive and up-to-date synthesis of the published evidence, conducted through a thorough and rigorous electronic database search. By including all available studies to date, we have provided the most complete overview of therapeutic strategies for norovirus infection in SOT recipients. However, our study has several limitations. First, the heterogeneity in study designs, population characteristics, types of interventions, and outcomes reporting precluded the derivation of pooled summary estimates that could be reliably applied in clinical practice. Second, most included studies were small, retrospective cohorts or single case reports, limiting both internal validity and generalizability. Third, we were unable to formally assess for reporting or publication bias without pooling the data, which is particularly important given that smaller studies are more likely to overestimate the actual treatment effects. Finally, the absence of standardized measures and inconsistent follow-up times further limited the ability to conclude effectiveness across studies. While considering the above-mentioned limitations, for all acute norovirus infections, we recommend supportive treatment followed by modification of immunosuppression if the infection does not resolve within a few days. For chronic persistent infections, despite modification of immunosuppression, we should consider combination treatments with immunoglobulins and nitazoxanide.

Accordingly, well-designed and adequately powered RCTs are urgently needed to establish the efficacy and safety of interventions for norovirus in SOT recipients. These trials should seek to compare commonly used strategies, such as nitazoxanide and immunoglobulin preparations, with immunosuppression modification against supportive care. In addition, microbiota-targeted therapies should be trialed to assess their effect on regulating microbial dysbiosis, which may be associated with norovirus infections. Standardized outcome measures, including both clinical symptom resolution and virological clearance, should be consistently reported, alongside data on adverse outcomes. Notably, studies should differentiate between acute, self-limited infections and chronic or refractory disease to inform stage-specific management. Multicenter collaboration, standardized trial protocols, and integration of patient-reported outcomes will be critical to generate robust evidence that can be appropriately translated into clinical practice, guidelines, and policies. Table 3 shows our recommendations for future research on interventions for norovirus infection in SOT recipients.

TABLE 3.

Recommendations for future research on interventions for norovirus infection in solid organ transplant recipients

Priority areas	Recommendations/reporting on
Trial design	Conduct well-designed, adequately powered RCT
Comparator	Compare commonly used strategies, such as nitazoxanide, and other immunoglobulin preparations, against immunosuppression modification and supportive care
Outcome measures	Use standardized measures: • Clinical symptom resolution • Virological clearance • Adverse outcomes • Patient and graft outcomes • Hospitalization rates • Adverse events
Disease stage differentiation	Clearly distinguish between: • Acute, self-limited infections • Chronic, or refractory infections
Patient-centered outcome	Include validated measures of quality of life, patient-reported symptom burden, functional status, treatment acceptability, and satisfaction
Translation to practice	Incorporation of economic and process evaluation Ensure that the evidence generated informs clinical practice, guidelines, and policy development

RCT, randomized controlled trial.

CONCLUSIONS

Our review identified a range of strategies that may offer benefits in managing norovirus infections among SOT recipients. However, the supporting evidence remains inconclusive and limited. Alternative interventions, including therapies targeting microbiota, warrant further investigations. There is a pressing need to evaluate the efficacy and safety of these novel interventions in RCTs to establish the effectiveness and safety of these approaches, strengthen the certainty of evidence, and address current knowledge gaps. Such trials should use standardized definitions, outcome measures, and intervention protocols to ensure that findings are robust, comparable, and directly translatable across diverse clinical settings worldwide.