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Norovirus-related chronic diarrhea in a patient treated with alemtuzumab for chronic lymphocytic leukemia
© Ronchetti et al.; licensee BioMed Central Ltd. 2014
Received: 28 December 2013
Accepted: 25 April 2014
Published: 6 May 2014
Norovirus infection is increasingly recognized as an important cause of persistent gastroenteritis in immunocompromised hosts and can be a potential cause of morbidity in these populations.
Here, we report a case of norovirus-related chronic diarrhea occurring in a 62-year-old immunocompromised patient treated with alemtuzumab for chronic lymphocytic leukemia. Despite different therapeutic strategies including tapering of immunosuppressive therapy and immunoglobulin administration, diarrhea unfortunately did not resolve and lasted for a total of more than twelve weeks with prolonged norovirus fecal excretion.
Norovirus infection can occur in the setting of alemtuzumab treatment, even as a single agent, and should be included in the differential diagnoses of acute and chronic diarrhea in these immunocompromised patients. Although the administration of oral immunoglobulin has been described as a promising efficient therapy, this was not the case in our patient. Clinical trials are thus clearly warranted to better define risk factors and efficient therapies for norovirus infection in immunocompromised populations.
KeywordsNorovirus Diarrhea Immunosuppression Alemtuzumab Chronic lymphocytic leukemia
Norovirus (NoV), a separate genus of the enteric virus family Caliciviridae, is actually recognized as the overall leading cause of acute gastro-enteritis (GE), being the first and second cause in adult and children, respectively, and accounts for more than 90% of GE outbreaks . In immunocompetent individuals, symptoms usually last for a few days but recent studies have shown that NoV infection can be chronic and severe among vulnerable populations like solid organ and bone marrow transplantation (BMT) recipients [2–4], inherited immune deficiencies  or HIV infected patients . Human mechanisms for protective immunity and clearance of NoV are not well defined. Although its precise mechanism is still unclear, it is hypothesized that cellular immunity plays an important role as suggested, for example, by the resolution of GE following the decrease of immunosuppressive therapy  or by the association between donor T cell recovery and NoV clearance  in BMT recipients.
Alemtuzumab is a humanized monoclonal IgG1 antibody directed toward the cell surface antigen CD52. It is largely used in chronic lymphoproliferative disorders like chronic lymphocytic leukemia (CLL), leading to profound T and B lymphocyte depletion and exposing patients to life-threatening opportunistic infections, particularly viruses, like CMV . Although NoV infection has never been described in patients treated with alemtuzumab alone, the use of alemtuzumab in the conditioning regimen of BMT has been interestingly reported to be a potential risk factor for NoV GE in two studies [4, 9].
NoV treatment in immunocompromised patients is challenging and mainly supportive as no specific therapy actually exists. Different strategies have been tested, from the adjustment of immunosuppressive treatment to the use of oral immunoglobulin (Ig) or antiviral drugs, but with controversial results . We report here a case of NoV-related chronic diarrhea, in an immunocompromised patient treated with alemtuzumab, which did not respond to Ig administrations.
At that time, the Ig level was low (IgG 5.6 g/L (normal: 6.7-12.5 g/L); IgA 0.25 g/L (normal: 1.04-3.33 g/L), IgM 0.57 g/L (normal 0.4-2.3 g/L)) and the lymphocyte count show profound T CD4 and CD8 depletion (CD4+ 0.03 G/L, CD8+ 0.05 G/L, B cell count of 0.9 G/L). Of note, two months before alemtuzumab treatment in October 2011, T CD4+/CD8+ counts were only slightly decreased at, respectively, 0.4 and 0.3 G/L. As the administration of parenteral or oral Ig has been suggested to be of potential interest in NoV GE after transplantation [11, 13–15], we tried these two therapeutic options but without success (see Figure 1). First, intravenous Ig was administrated at the dose of 0.5 g/kg for a single day, ten weeks after the beginning of alemtuzumab and four weeks after the diarrhea onset. Two weeks later, facing up to the persistence of diarrhea, we instilled Ig by oral route through a nasogastric tube at the same total dose but fractioned in four doses, every six hours for one day. Profuse diarrhea persisted and five further fecal NoV RT-PCRs were still positive for NoV GII.7/II.6 in a time period of eight weeks. Finally, evolution was fatal due to uncontrolled E. Coli bacteriemia.
Noroviruses have been identified as an important cause of chronic diarrhea in immunocompromised hosts. Although there is growing number of case reports, it has never been described after the use of alemtuzumab as a single agent. Alemtuzumab is an anti-CD52 monoclonal antibody, which is used in CLL patients who failed fludarabine therapy and sometimes in frontline therapy in case of high-risk cytogenetic abnormalities. It has also been used in other circumstances, such as multiple sclerosis, or organ transplant rejection. The CD52 antigen is present on the surface of T, B and NK lymphocytes, and also on macrophages and dendritic cells. Alemtuzumab is a potent immunosuppressive therapy that can lead to a wide variety of severe infectious complications, especially viral and bacterial infections . In patients receiving alemtuzumab, the lymphocytic depletion is estimated in median at 5 years for the CD4+ and 3 years for the CD8+ fraction . In the case of our patient, the persistent NoV infection  despite the tapering of alemtuzumab also illustrates the very long lasting lymphocyte depletion due to this molecule, making a rapid diagnosis of infectious complications due to alemtuzumab more suitable. Although its precise role could not be certain in our observation, some arguments plead for the potential involvement of alemtuzumab in the onset of NoV infection. First, NoV diarrhea began six weeks after initiation of alemtuzumab, while the last immunosuppressive therapies (rituximab plus cyclophosphamide) have been administrated more than a year ago. Second, alemtuzumab was in a large extent responsible for the profound T-cell depletion as T-cell counts were near normal before its start. Moreover, as described above, the use of alemtuzumab is associated with severe infectious complications and has been recognized as a potential risk factor for NoV GE in allografted children when used in the conditioning regimen . NoV-related chronic diarrhea has also already been reported in the setting of hypogammaglobulinemia and after immunotherapy as it has been described in a CLL patient treated with rituximab .
Despite different therapeutic strategies, diarrhea did not resolve in the case of our patient and NoV viral loads in fecal samples remained positive. The most promising approach reported in the literature is the use of enteral Ig as it has been described successful in four immunocompromised patients: two children with small bowel transplantation  and two adults, one with cardiac  and the other with renal transplantation . The failure of this strategy in our patient could be due to the profound level of immunosuppression and/or the mode of Ig administration (rhythm, period) although we administrated the same total dose as in reported successful experiences.
NoV treatment in immunocompromised patients is challenging as no specific antiviral agent actually exists and as the tapering of immunosuppressive drugs is not always possible. Vaccine research is ongoing, but no vaccine is currently available. Although parenteral and oral Ig administrations have been reported to be efficient, it was not the case in our patient. Profound T cell depletion and hypogammaglobulinemia may explain this failure of NoV clearance. Given the prolonged survival of patients with hematological malignancies and the increasing use of immunotherapies, it is likely that there will be more reports of NoV infections. NoV should be included in the differential diagnoses of acute and chronic diarrhea in immunocompromised patients and clinical trials should also be developed to define risk factors and efficient therapies.
Written informed consent was obtained from the family of the patient for publication of this Case report. A copy of the written consent is available for review by the Editor of this journal.
The authors thank all clinicians and nurses who took care of the patient.
- Glass RI, Parashar UD, Estes MK: Norovirus gastroenteritis. N Engl J Med. 2009, 361 (18): 1776-1785. 10.1056/NEJMra0804575.View ArticlePubMedGoogle Scholar
- Bok K, Green KY: Norovirus gastroenteritis in immunocompromised patients. N Engl J Med. 2012, 367 (22): 2126-2132. 10.1056/NEJMra1207742.View ArticlePubMedGoogle Scholar
- Roos-Weil D, Ambert-Balay K, Lanternier F, Mamzer-Bruneel MF, Nochy D, Pothier P, Avettand-Fenoel V, Anglicheau D, Snanoudj R, Bererhi L, Thervet E, Lecuit M, Legendre C, Lortholary O, Zuber J: Impact of norovirus/sapovirus-related diarrhea in renal transplant recipients hospitalized for diarrhea. Transplantation. 2011, 92 (1): 61-69. 10.1097/TP.0b013e31821c9392.View ArticlePubMedGoogle Scholar
- Roddie C, Paul JP, Benjamin R, Gallimore CI, Xerry J, Gray JJ, Peggs KS, Morris EC, Thomson KJ, Ward KN: Allogeneic hematopoietic stem cell transplantation and norovirus gastroenteritis: a previously unrecognized cause of morbidity. Clin Infect Dis. 2009, 49 (7): 1061-1068. 10.1086/605557.View ArticlePubMedGoogle Scholar
- Frange P, Touzot F, Debre M, Heritier S, Leruez-Ville M, Cros G, Rouzioux C, Blanche S, Fischer A, Avettand-Fenoel V: Prevalence and clinical impact of norovirus fecal shedding in children with inherited immune deficiencies. J Infect Dis. 2012, 206 (8): 1269-1274. 10.1093/infdis/jis498.View ArticlePubMedGoogle Scholar
- Wingfield T, Gallimore CI, Xerry J, Gray JJ, Klapper P, Guiver M, Blanchard TJ: Chronic norovirus infection in an HIV-positive patient with persistent diarrhoea: a novel cause. J Clin Virol. 2010, 49 (3): 219-222. 10.1016/j.jcv.2010.07.025.View ArticlePubMedGoogle Scholar
- Saif MA, Bonney DK, Bigger B, Forsythe L, Williams N, Page J, Babiker ZO, Guiver M, Turner AJ, Hughes S, Wynn RF: Chronic norovirus infection in pediatric hematopoietic stem cell transplant recipients: a cause of prolonged intestinal failure requiring intensive nutritional support. Pediatr Transplant. 2011, 15 (5): 505-509. 10.1111/j.1399-3046.2011.01500.x.View ArticlePubMedGoogle Scholar
- Elter T, Vehreschild JJ, Gribben J, Cornely OA, Engert A, Hallek M: Management of infections in patients with chronic lymphocytic leukemia treated with alemtuzumab. Ann Hematol. 2009, 88 (2): 121-132. 10.1007/s00277-008-0566-9.View ArticlePubMedGoogle Scholar
- Robles JD, Cheuk DK, Ha SY, Chiang AK, Chan GC: Norovirus infection in pediatric hematopoietic stem cell transplantation recipients: incidence, risk factors, and outcome. Biol Blood Marrow Transplant. 2012, 18 (12): 1883-1889. 10.1016/j.bbmt.2012.07.005.View ArticlePubMedGoogle Scholar
- Sdiri-Loulizi K, Ambert-Balay K, Gharbi-Khelifi H, Sakly N, Hassine M, Chouchane S, Guediche MN, Pothier P, Aouni M: Molecular epidemiology of norovirus gastroenteritis investigated using samples collected from children in Tunisia during a four-year period: detection of the norovirus variant GGII.4 Hunter as early as January 2003. J Clin Microbiol. 2009, 47 (2): 421-429. 10.1128/JCM.01852-08.View ArticlePubMedGoogle Scholar
- 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. 10.1016/j.jcv.2013.06.009.View ArticlePubMedGoogle Scholar
- Ludwig A, Adams O, Laws HJ, Schroten H, Tenenbaum T: Quantitative detection of norovirus excretion in pediatric patients with cancer and prolonged gastroenteritis and shedding of norovirus. J Med Virol. 2008, 80 (8): 1461-1467. 10.1002/jmv.21217.View ArticlePubMedGoogle Scholar
- Florescu DF, Hermsen ED, Kwon JY, Gumeel D, Grant WJ, Mercer DF, Kalil AC: Is there a role for oral human immunoglobulin in the treatment for norovirus enteritis in immunocompromised patients?. Pediatr Transplant. 2011, 15 (7): 718-721. 10.1111/j.1399-3046.2011.01556.x.View ArticlePubMedGoogle Scholar
- Florescu DF, Hill LA, McCartan MA, Grant W: Two cases of Norwalk virus enteritis following small bowel transplantation treated with oral human serum immunoglobulin. Pediatr Transplant. 2008, 12 (3): 372-375. 10.1111/j.1399-3046.2007.00875.x.View ArticlePubMedGoogle Scholar
- Martin SI, Marty FM, Fiumara K, Treon SP, Gribben JG, Baden LR: Infectious complications associated with alemtuzumab use for lymphoproliferative disorders. Clin Infect Dis. 2006, 43 (1): 16-24. 10.1086/504811.View ArticlePubMedGoogle Scholar
- Capizzi T, Makari-Judson G, Steingart R, Mertens WC: Chronic diarrhea associated with persistent norovirus excretion in patients with chronic lymphocytic leukemia: report of two cases. BMC Infect Dis. 2011, 11: 131-10.1186/1471-2334-11-131.View ArticlePubMedPubMed CentralGoogle Scholar
- Ebdrup L, Bottiger B, Molgaard H, Laursen AL: Devastating diarrhoea in a heart-transplanted patient. J Clin Virol. 2011, 50 (4): 263-265. 10.1016/j.jcv.2010.11.007.View ArticlePubMedGoogle Scholar
- Lyman WH, Walsh JF, Kotch JB, Weber DJ, Gunn E, Vinje J: Prospective study of etiologic agents of acute gastroenteritis outbreaks in child care centers. J Pediatr. 2009, 154 (2): 253-257. 10.1016/j.jpeds.2008.07.057.View ArticlePubMedGoogle Scholar
- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2334/14/239/prepub
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