What literature is available on the use of enteral immunoglobulin for the treatment of norovirus enteritis?
Introduction
Infection with norovirus is the leading cause of acute gastroenteritis in the United States, causing an estimated 900 deaths, 470,000 emergency department visits, and 2.3 million ambulatory care encounters annually.1 Due to the chronic nature of their immunosuppression, transplant recipients are at increased risk for recurrent or chronic norovirus infection, which contributes to the substantial morbidity and mortality in this population.2 A large, retrospective study of norovirus infection in heart, lung, and kidney transplant recipients showed that 22.8% of patients with norovirus develop a chronic infection. Data also indicates that adults over 65 years of age have an increased risk of mortality associated with norovirus infection, and children under the age of 5 years seek medical care frequently for norovirus symptoms, with the highest rates of norovirus-associated medical visits.1,3
Following a brief incubation period of 12 to 48 hours, symptoms of norovirus are typically associated with mild gastrointestinal symptoms, which can include nausea, vomiting, diarrhea, and abdominal pain, often in conjunction with fever, chills, headache, general malaise, and myalgias.4 In healthy, immunocompetent patients, the resolution of norovirus symptoms usually occurs within 2 to 3 days; however, in immunodeficient individuals (eg, transplant recipients) or patients with other underlying illnesses, a severe and more prolonged disease course can develop.2,4 In solid-organ transplant patients, norovirus is a frequent pathogen implicated in viral enteritis, along with adenovirus, rotavirus, and cytomegalovirus.2 Untreated diarrhea associated with norovirus infection in transplant recipients can lead to organ rejection and death. In a retrospective study of solid-organ transplant recipients, patients with norovirus infection experienced significantly protracted diarrhea, lasting on average 241 days in comparison to an average of 75 days in transplant recipients with other underlying causes of diarrhea (p=0.007 for comparison).5
Unfortunately, no Food and Drug Administration (FDA)-approved therapies are available to treat norovirus enteritis (NVE).4 Treatment for norovirus and the associated complications involves the use of supportive care focused on rehydration, with additional treatments added as necessary for complications of the condition (eg, analgesics, antidiarrheals, antiemetics). Off-label therapies that have been studied for NVE include enteral and parenteral immunoglobulin administration, breast milk, ribavirin, and nitazoxanide with mixed results.2,6 Although immunoglobulin is FDA-approved only for use via the parenteral route, enterally administered human immunoglobulin has been explored for the treatment of enteritis, with conflicting results.2
The mechanism by which the enteral administration of immunoglobulin improves symptoms of norovirus is thought to be related to the blockade of viral adherence to intestinal epithelial cells through the formation of viral complexes, as well as the modulation of pro-inflammatory and anti-inflammatory cytokines.6,7 Norovirus undergoes replication within the epithelial cells in the gastrointestinal tract; therefore, by blocking viral adherence, the further replication of norovirus is also inhibited, which reduces the persistence of infection.7 A pharmacokinetic analysis of orally administered human globulin has shown that enteral immunoglobulin can survive passage in the gastrointestinal tract in its active form, with approximately 50% of radiolabeled immunoglobulin recovered in feces over a 3-day period.8
Current Guidelines
The 2019 American Society of Transplantation Infectious Diseases Community of Practice (AST ID) guideline recommends that in solid-organ transplant recipients, all patients with diarrhea should have their medications reviewed and unnecessary agents stopped.9 Treatment of diarrhea caused by norovirus should be focused on symptomatic relief with rehydration, reducing immunosuppression, and antimotility agents, while addressing the causative pathogen. While the guideline recognizes that no specific therapies are available for the treatment of norovirus infection, nitazoxanide may reduce the time to resolution of symptoms. The guideline also acknowledges the conflicting and limited amount of evidence regarding the use of enteral immunoglobulin for NVE; however, the efficacy of enteral immunoglobulin for NVE treatment continues to be explored in the literature. The following is a summary of the evidence on enteral immunoglobulin for NVE treatment to date.
| Table 1. Studies examining enteral immunoglobulin use in NVE.7,10-15 | ||||
|---|---|---|---|---|
| Study design | Subjects | Interventions | Results | Conclusions |
| van Kampen et al 202210 Case report | 1 adult subject with CVID and chronic NVE Immunological eval yielded low IgG (1.7 g/dL), low IgA (<0.01 g/dL), low IgM (<0.30 g/L), and low number of absolute memory B lymphocytes (7 cells/mL) | 25 mg/kg/dose human immunoglobulin (Privigen®) 4 times daily via ND tube for 2 days Had previously ↑ IVIG dose to 0.8 g/kg/dose, received oral nitazoxanide for 14 days, then oral ribavirin, then interferon alpha-2a SC | · 13 days post-dose, plasma vRNA undetectable, fecal vRNA levels decreased · After 45 days, negative for vRNA in plasma and feces · Resolution of GI symptoms | · Enteral human immunoglobulin effective for resolution of NVE in 1 patient |
| Nussbaum et al 202011 Retrospective chart review | 9 solid-organ transplant recipients with NVE (age range: 40-72 years) Median duration of diarrhea prior to intervention, ~12 weeks | 10 mL of OHIG 15–18% given 4 times daily for 8 doses MMF ↓ or stopped in 6 of 9 patients upon admission 3 patients received IVIG and 1 received nitazoxanide prior to OHIG | · At time of discharge, 6 had diarrhea resolution, 1 had improvement, 1 had no change, and 1 had died · Mean time to discharge, 4.1 days · No readmissions within 30 days due to NVE · Mycophenolate reinitiated after discharge in 2 patients, who did not have relapse | · OHIG effective in 6 of 9 patients for resolution of NVE |
| Gairard- Dory et al 201412 Retrospective chart review | 12 lung-transplant recipients (mean age 60 years) with NVE (≥ 3 soft or aqueous stools/24 hours for 2 days) | Supportive care + OHIG (Sandoglobuline® or Privigen®) at 25 mg/kg 4 times daily for 2 days 7 of 12 patients had MMF temporarily reduced prior to IgG without resolution of diarrhea | · Mean time to normalization of GI symptoms, 3 ± 1 days · 11/12 patients successfully treated; 1 mildly improved · 4 patients had recurrence of NVE · 6 diarrhea episodes associated with elevated tacrolimus levels (> 15 mg/L) · No significant adverse effects with treatment | · OHIG effective for resolution of NVE in 11 of 12 patients, though 4 patients experienced disease recurrence |
| Ronchetti et al 201413 Case report | 62-year-old patient receiving alemtuzumab for CLL with NVE Immunological eval yielded low IgG (5.6 g/dL), normal IgA (0.25 g/dL, normal IgM (0.57 g/dL), and profound depletion of CD4+ and CD8+ T lymphocytes (0.03 G/L and 0.05 G/L, respectively) | Subsequently given IgG 125 mg/kg via NG 4 times daily for 1 day 0.5 g/kg IVIG given prior, 10 weeks after alemtuzumab start and 4 weeks after diarrhea onset | · Persistence of perfuse diarrhea over subsequent 8-week period · Further fecal exams still positive for norovirus | · OHIG not effective for NVE resolution in 1 patient at higher doses over short period (1 day) |
| Chagla et al 201314 Case report | 56-year-old prior renal and pancreatic transplant recipient with NVE Onset of diarrhea 18 months prior | 45 mg/kg IgG (Gamunex®) given via NJ tube 4 times daily for 2 days | · Diarrhea resolution within 1 day · Norovirus PCR undetectable 7 days after dose of IgG · No recurrence within 2-month follow-up time frame | · Enteral human immunoglobulin effective for NVE resolution in 1 patient |
| Florescu et al 20117 Matched case-control study | Immunocompromised patients with NVE treated with oral IgG (n=12) matched 1:1 by age and gender to immunocompromised patients with NVE not treated with oral IgG (n=12) 20 of 24 patients solid organ transplant recipients; 16 patients were pediatric (median age 2 years) 8 patients were coinfected with either Clostridioides difficile or rotavirus | 25 mg/kg/dose OHIG (Gamunex®) based on ABW given 4 times daily for 2 days (8 doses total) Immunosuppression also decreased in 68.18% of patients | · Treatment with oral IgG favored diarrhea resolution (p=0.078) and decreased stool output after 7 days (p=0.09), but was not significantly improved · No impact on time to resolution of diarrhea vs none (mean 12.08 vs 11.91 days) · No impact on length of hospitalization (p=0.31) or cost of stay (p=0.32) | · Potential efficacy with OHIG for resolution of NVE · Difficult to extrapolate results given small sample size small and heterogeneous population (type and degree of immunosuppression differed) |
| Ebdrup et al 201115 Case report | 64-year-old heart transplant recipient with NVE | Human immunoglobulin (Vivaglobin®) 45 mg/kg via ND tube 4 times daily for 2 days on days 49 and 50 MMF was discontinued to rule out drug-induced diarrhea | · 1 day-post treatment, stool frequency declined from 8 to 3 daily stools · 3 days-post treatment, stool had normalized | · Enteral human immunoglobulin effective for NVE resolution in 1 patient |
| Abbreviations: ABW=actual body weight; CLL=chronic lymphocytic leukemia; CVID=chronic variable immune deficiency; GI=gastrointestinal; IgA=immunoglobulin A; IgG=immunoglobulin G; IgM=immunoglobulin M; IVIG=intravenous immune globulin G; MMF=mycophenolate mofetil; ND=nasoduodenal; NG=nasogastric; NJ=nasojejunal; NVE=norovirus enteritis; OHIG=orally administered human immunoglobulin; PCR=polymerase chain reaction; SC=subcutaneous; vRNA=viral RNA |
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Literature Review
There is a paucity of data in the literature evaluating the use of enteral immunoglobulin therapy as an off-label treatment for NVE, with mixed outcomes regarding efficacy.7,10-15 No data are available on the use of enteral immunoglobulin for NVE in immunocompetent individuals; the populations that enteral immunoglobulin has been studied in thus far are immunodeficient. While 2 case reports have shown effective resolution of NVE or decreased stool output after 2 days of enteral immunoglobulin use with doses ranging from 25 mg/kg up to 45 mg/kg 4 times daily, 1 case report that utilized dosing of 125 mg/kg 4 times daily over a 1-day period showed no effect on diarrhea persistence, and the patient continued to have polymerase chain reaction (PCR)-positive fecal samples for norovirus.13-15 In 1 small cohort study, improvements in NVE were observed in most patients, although several experienced disease recurrence, while in another small cohort study, no significant improvements in the time to diarrhea resolution, stool output after 7 days, and no impact on the length of hospitalization were observed in patients treated with enteral immunoglobulin versus no treatment.7,12 Recent literature published since the 2019 AST ID guideline includes 1 case report in a patient with chronic variable immunodeficiency (CVID) and 1 small retrospective chart review of solid organ transplant recipients.9-11 Enteral immunoglobulin use was successful for NVE resolution in 7 of the 10 patients evaluated, although dosing regimens varied, and included a regimen of 25 mg/kg administered 4 times daily for 2 days in the case report, versus 10 mL of 15 to 18% human immunoglobulin per dose administered 4 times daily for 2 days in the cohort study.10,11
Conclusions
The treatment of norovirus gastroenteritis remains a persistent issue, with no FDA-approved medications available. Based on AST ID recommendations, the current treatment of diarrhea due to norovirus infection consists of supportive care measures, antimotility agents, nitazoxanide, and the potential reduction of immunosuppressive medications in solid-organ transplant recipients. Studies to date of enteral immunoglobulin for NVE involve immunodeficient patients and inconsistency across dosing regimens, with no studies available in immunocompetent individuals. While most studies employ the oral route for the administration of immunoglobulin, several involve administration via the nasoduodenal, nasogastric, and nasojejunal routes. Due to a lack of consistency in dosing and small sample sizes in the available literature, the extrapolation of study findings is difficult. Based on the aforementioned low-quality evidence, the use of enteral immunoglobulin for the treatment of NVE warrants further investigation regarding its efficacy, as well as the optimal dosing regimen for use in larger, confirmatory clinical trials.
References
- Burke RM, Mattison CP, Pindyck T, et al. Burden of Norovirus in the United States, as Estimated Based on Administrative Data: Updates for Medically Attended Illness and Mortality, 2001-2015. Clin Infect Dis. 2021;73(1):e1-e8. doi:10.1093/cid/ciaa438.
- Abbas A, Zimmer AJ, Florescu D. Viral Enteritis in Solid-Organ Transplantation. Viruses. 2021;13(10):2019. doi:10.3390/v13102019.
- Hall AJ, Lopman BA, Payne DC, et al. Norovirus disease in the United States. Emerg Infect Dis. 2013;19(8):1198-1205. doi:10.3201/eid1908.130465.
- Cardemil CV, Parashar UD, Hall AJ. Norovirus Infection in Older Adults: Epidemiology, Risk Factors, and Opportunities for Prevention and Control. Infect Dis Clin North Am. 2017;31(4):839-870. doi:10.1016/j.idc.2017.07.012.
- Lee LY, Ladner DP, Ison MG. Norovirus infection in solid organ transplant recipients: a single-center retrospective study. Transpl Infect Dis. 2016;18(6):932-938. doi:10.1111/tid.12622.
- Tsai H, Yune P, Rao M. Norovirus disease among older adults. Ther Adv Infect Dis. 2022;9:20499361221136760. doi:10.1177/20499361221136760.
- Florescu DF, Hermsen ED, Kwon JY, et al. Is there a role for oral human immunoglobulin in the treatment for norovirus enteritis in immunocompromised patients?. Pediatr Transplant. 2011;15(7):718-721. doi:10.1111/j.1399-3046.2011.01556.x.
- Losonsky GA, Johnson JP, Winkelstein JA, Yolken RH. Oral administration of human serum immunoglobulin in immunodeficient patients with viral gastroenteritis. A pharmacokinetic and functional analysis. J Clin Invest. 1985;76(6):2362-2367. doi:10.1172/JCI112248.
- Angarone M, Snydman DR; AST ID Community of Practice. Diagnosis and management of diarrhea in solid-organ transplant recipients: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019;33(9):e13550. doi:10.1111/ctr.13550.
- van Kampen JJA, Dalm VASH, Fraaij PLA, et al. Clinical and In Vitro Evidence Favoring Immunoglobulin Treatment of a Chronic Norovirus Infection in a Patient With Common Variable Immunodeficiency. J Infect Dis. 2022;226(10):1781-1789. doi:10.1093/infdis/jiac085.
- Nussbaum EZ, Azar MM, Cohen E, McManus D, Topal JE, Malinis M. Orally Administered Human Immunoglobulin Therapy for Norovirus Enteritis in Solid Organ Transplant Recipients: A Case Series at a Single Academic Transplant Center. Clin Infect Dis. 2020;71(8):e206-e209. doi:10.1093/cid/ciaa093.
- Gairard-Dory AC, Dégot T, Hirschi S, et al. Clinical usefulness of oral immunoglobulins in lung transplant recipients with norovirus gastroenteritis: a case series. Transplant Proc. 2014;46(10):3603-3605. doi:10.1016/j.transproceed.2014.09.095.
- Ronchetti AM, Henry B, Ambert-Balay K, et al. Norovirus-related chronic diarrhea in a patient treated with alemtuzumab for chronic lymphocytic leukemia. BMC Infect Dis. 2014;14:239. doi:10.1186/1471-2334-14-239.
- Chagla Z, Quirt J, Woodward K, Neary J, Rutherford C. Chronic norovirus infection in a transplant patient successfully treated with enterally administered immune globulin. J Clin Virol. 2013;58(1):306-308. doi:10.1016/j.jcv.2013.06.009.
- Ebdrup L, Böttiger B, Mølgaard H, Laursen AL. Devastating diarrhoea in a heart-transplanted patient. J Clin Virol. 2011;50(4):263-265. doi:10.1016/j.jcv.2010.11.007.
Prepared by:
Christie Denton, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy
March 2023
The information presented is current as February 20, 2023. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.