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Norovirus-related chronic diarrhea in a patient treated with alemtuzumab for chronic lymphocytic leukemia.

Ronchetti AM, Henry B, Ambert-Balay K, Pothier P, Decroocq J, Leblond V, Roos-Weil D - BMC Infect. Dis. (2014)

Bottom Line: 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.Although the administration of oral immunoglobulin has been described as a promising efficient therapy, this was not the case in our patient.

View Article: PubMed Central - HTML - PubMed

Affiliation: Hematology Department, Hôpital Pitié-Salpétrière, AP-HP, Université Pierre et Marie Curie Paris 06, GRC 11 (GRECHY), Paris, France. damien.roos-weil@inserm.fr.

ABSTRACT

Background: 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.

Case presentation: 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.

Conclusions: 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.

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Related in: MedlinePlus

Evolution of norovirus (NoV) loads and number of stools after alemtuzumab treatment. NoV loads are represented in black dashed lines and expressed in log copies per g of stool. Stools are represented in gray solid lines and expressed in number per day. First, fecal samples have been weighed and then suspended in phosphate-buffered saline (pH 7.5) at a concentration of 10%. Viral RNA was extracted with a QIAamp viral RNA kit (Qiagen, Hilden, Germany). The NoVs were detected by RT-PCR on an ABI Prism 7500 Fast detector (Life Technologies) using the TaqMan One-Step PCR Master Mix reagent (Life Technologies) and previously published primers and probes for GI[18] and GII[10]. For quantitative assessment of fecal viral load, the number of NoV RNA copies was estimated by comparing the sample CT value with standard curves. Among the five available samples, four were positive for GII.7 in the polymerase gene and for GII.6 in the capsid gene. Then, as described previously[10], the ORF1/ORF2 junction was sequenced using the same primers. The nucleotide sequences were aligned and compared to corresponding sequences of NoV strains available in the GenBank database using Fasta program. These sequences showed a homology of 92% and 98% for GII.7 and GII.6, respectively, and a 100% homology between them. Abbreviations: Ig, immunoglobulins; IV, intravenous; NoV, norovirus; W, week.
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Figure 1: Evolution of norovirus (NoV) loads and number of stools after alemtuzumab treatment. NoV loads are represented in black dashed lines and expressed in log copies per g of stool. Stools are represented in gray solid lines and expressed in number per day. First, fecal samples have been weighed and then suspended in phosphate-buffered saline (pH 7.5) at a concentration of 10%. Viral RNA was extracted with a QIAamp viral RNA kit (Qiagen, Hilden, Germany). The NoVs were detected by RT-PCR on an ABI Prism 7500 Fast detector (Life Technologies) using the TaqMan One-Step PCR Master Mix reagent (Life Technologies) and previously published primers and probes for GI[18] and GII[10]. For quantitative assessment of fecal viral load, the number of NoV RNA copies was estimated by comparing the sample CT value with standard curves. Among the five available samples, four were positive for GII.7 in the polymerase gene and for GII.6 in the capsid gene. Then, as described previously[10], the ORF1/ORF2 junction was sequenced using the same primers. The nucleotide sequences were aligned and compared to corresponding sequences of NoV strains available in the GenBank database using Fasta program. These sequences showed a homology of 92% and 98% for GII.7 and GII.6, respectively, and a 100% homology between them. Abbreviations: Ig, immunoglobulins; IV, intravenous; NoV, norovirus; W, week.

Mentions: A French 62-year-old man was hospitalized in our institution for severe invasive aspergillosis. His medical history was remarkable for chronic lymphocytic leukemia (CLL), diagnosed in 1998 and first requiring therapy in 2006. From 2006 to 2010, our patient received several lines of treatment comprising polychemotherapies with anthracyclines (in 2006), purines analogs (fludarabine) (in 2007), alkylating agents (cyclophosphamide) (in 2010), high dose corticosteroids and immunotherapy (rituximab) (in 2006, 2007 and 2010), alternatively or in combination. Last relapse of CLL occurred in December 2011 and motivated a new therapeutic sequence with alemtuzumab and dexamethasone. In January 2012, three weeks after the initiation of alemtuzumab, he developed fever, cough and subacute vision loss of the left eye, revealing a multi-organ aspergillosis that involved lung, eyes and also brain. Apart from this severe infectious complication that required prolonged antifungal therapy with voriconazole, the clinical evolution during hospitalization was marked by the persistence of intermittent fever and the progressive onset of fluctuating watery diarrhea, which started six weeks after the first alemtuzumab dose (February 2012). Diarrhea lasted for a total of more than twelve weeks. Diarrheal stools were profuse but contained neither blood nor mucus. The patient had no concomitant abdominal pain, vomiting or myalgia. He had no recent travel history, no family history of vomiting or diarrhea and there was no argument for any nosocomial outbreak at this time in our department. All potential medications that can induce diarrhea, including voriconazole and alemtuzumab, were withdrawn but without efficacy. Empiric antibiotic therapies (successively ceftriaxone, ciprofloxacine, metronidazole and piperacillin/tazobactam) were also unsuccessful. Of note, repeated microbiological stool examinations, including cultures and assays for pathogenic bacteria (C. difficile, Camplyobacter spp., Salmonella spp., and Yersinia spp.) and standard detection of protozoans (including searches for Microsporidium sp., Cryptosporidium sp., Isospora sp. and Giardia lamblia), were negative. Serum cytomegalovirus (CMV) and adenovirus polymerase chain reactions (PCRs), stool rotavirus and adenovirus PCRs were also negative. Colonoscopy did not find any ulcerative lesion and pathologic examination of colonic biopsies any cytopathic effect. There was also no argument for aspergillosis involvement in the gastrointestinal tract. The persistence of diarrhea and the negativity of standard pathogenic microorganisms responsible for GE finally raised the possibility of NoV infection. Fecal NoV reverse transcriptase (RT)-PCR was positive for recombinant genogroup II, genotype 7 and genotype 6 (GII.7/II.6). Sequencing of the ORF1/ORF2 junction, as described previously[10], excluded the possibility of co-infection of two NoV genotypes. More, NoV viral loads have been retrospectively calculated for four fecal samples (see Figure 1). Values ranged from 2.4 × 108 copies/g up to 2.3 × 109 copies/g of stool. Our results are concordant with reported values in previous studies which ranged from 103 to 1011 copies/g of stool, with median/mean values between 107 and 108 copies/g[11,12] and consistent with prolonged viral excretion.


Norovirus-related chronic diarrhea in a patient treated with alemtuzumab for chronic lymphocytic leukemia.

Ronchetti AM, Henry B, Ambert-Balay K, Pothier P, Decroocq J, Leblond V, Roos-Weil D - BMC Infect. Dis. (2014)

Evolution of norovirus (NoV) loads and number of stools after alemtuzumab treatment. NoV loads are represented in black dashed lines and expressed in log copies per g of stool. Stools are represented in gray solid lines and expressed in number per day. First, fecal samples have been weighed and then suspended in phosphate-buffered saline (pH 7.5) at a concentration of 10%. Viral RNA was extracted with a QIAamp viral RNA kit (Qiagen, Hilden, Germany). The NoVs were detected by RT-PCR on an ABI Prism 7500 Fast detector (Life Technologies) using the TaqMan One-Step PCR Master Mix reagent (Life Technologies) and previously published primers and probes for GI[18] and GII[10]. For quantitative assessment of fecal viral load, the number of NoV RNA copies was estimated by comparing the sample CT value with standard curves. Among the five available samples, four were positive for GII.7 in the polymerase gene and for GII.6 in the capsid gene. Then, as described previously[10], the ORF1/ORF2 junction was sequenced using the same primers. The nucleotide sequences were aligned and compared to corresponding sequences of NoV strains available in the GenBank database using Fasta program. These sequences showed a homology of 92% and 98% for GII.7 and GII.6, respectively, and a 100% homology between them. Abbreviations: Ig, immunoglobulins; IV, intravenous; NoV, norovirus; W, week.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4016654&req=5

Figure 1: Evolution of norovirus (NoV) loads and number of stools after alemtuzumab treatment. NoV loads are represented in black dashed lines and expressed in log copies per g of stool. Stools are represented in gray solid lines and expressed in number per day. First, fecal samples have been weighed and then suspended in phosphate-buffered saline (pH 7.5) at a concentration of 10%. Viral RNA was extracted with a QIAamp viral RNA kit (Qiagen, Hilden, Germany). The NoVs were detected by RT-PCR on an ABI Prism 7500 Fast detector (Life Technologies) using the TaqMan One-Step PCR Master Mix reagent (Life Technologies) and previously published primers and probes for GI[18] and GII[10]. For quantitative assessment of fecal viral load, the number of NoV RNA copies was estimated by comparing the sample CT value with standard curves. Among the five available samples, four were positive for GII.7 in the polymerase gene and for GII.6 in the capsid gene. Then, as described previously[10], the ORF1/ORF2 junction was sequenced using the same primers. The nucleotide sequences were aligned and compared to corresponding sequences of NoV strains available in the GenBank database using Fasta program. These sequences showed a homology of 92% and 98% for GII.7 and GII.6, respectively, and a 100% homology between them. Abbreviations: Ig, immunoglobulins; IV, intravenous; NoV, norovirus; W, week.
Mentions: A French 62-year-old man was hospitalized in our institution for severe invasive aspergillosis. His medical history was remarkable for chronic lymphocytic leukemia (CLL), diagnosed in 1998 and first requiring therapy in 2006. From 2006 to 2010, our patient received several lines of treatment comprising polychemotherapies with anthracyclines (in 2006), purines analogs (fludarabine) (in 2007), alkylating agents (cyclophosphamide) (in 2010), high dose corticosteroids and immunotherapy (rituximab) (in 2006, 2007 and 2010), alternatively or in combination. Last relapse of CLL occurred in December 2011 and motivated a new therapeutic sequence with alemtuzumab and dexamethasone. In January 2012, three weeks after the initiation of alemtuzumab, he developed fever, cough and subacute vision loss of the left eye, revealing a multi-organ aspergillosis that involved lung, eyes and also brain. Apart from this severe infectious complication that required prolonged antifungal therapy with voriconazole, the clinical evolution during hospitalization was marked by the persistence of intermittent fever and the progressive onset of fluctuating watery diarrhea, which started six weeks after the first alemtuzumab dose (February 2012). Diarrhea lasted for a total of more than twelve weeks. Diarrheal stools were profuse but contained neither blood nor mucus. The patient had no concomitant abdominal pain, vomiting or myalgia. He had no recent travel history, no family history of vomiting or diarrhea and there was no argument for any nosocomial outbreak at this time in our department. All potential medications that can induce diarrhea, including voriconazole and alemtuzumab, were withdrawn but without efficacy. Empiric antibiotic therapies (successively ceftriaxone, ciprofloxacine, metronidazole and piperacillin/tazobactam) were also unsuccessful. Of note, repeated microbiological stool examinations, including cultures and assays for pathogenic bacteria (C. difficile, Camplyobacter spp., Salmonella spp., and Yersinia spp.) and standard detection of protozoans (including searches for Microsporidium sp., Cryptosporidium sp., Isospora sp. and Giardia lamblia), were negative. Serum cytomegalovirus (CMV) and adenovirus polymerase chain reactions (PCRs), stool rotavirus and adenovirus PCRs were also negative. Colonoscopy did not find any ulcerative lesion and pathologic examination of colonic biopsies any cytopathic effect. There was also no argument for aspergillosis involvement in the gastrointestinal tract. The persistence of diarrhea and the negativity of standard pathogenic microorganisms responsible for GE finally raised the possibility of NoV infection. Fecal NoV reverse transcriptase (RT)-PCR was positive for recombinant genogroup II, genotype 7 and genotype 6 (GII.7/II.6). Sequencing of the ORF1/ORF2 junction, as described previously[10], excluded the possibility of co-infection of two NoV genotypes. More, NoV viral loads have been retrospectively calculated for four fecal samples (see Figure 1). Values ranged from 2.4 × 108 copies/g up to 2.3 × 109 copies/g of stool. Our results are concordant with reported values in previous studies which ranged from 103 to 1011 copies/g of stool, with median/mean values between 107 and 108 copies/g[11,12] and consistent with prolonged viral excretion.

Bottom Line: 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.Although the administration of oral immunoglobulin has been described as a promising efficient therapy, this was not the case in our patient.

View Article: PubMed Central - HTML - PubMed

Affiliation: Hematology Department, Hôpital Pitié-Salpétrière, AP-HP, Université Pierre et Marie Curie Paris 06, GRC 11 (GRECHY), Paris, France. damien.roos-weil@inserm.fr.

ABSTRACT

Background: 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.

Case presentation: 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.

Conclusions: 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.

Show MeSH
Related in: MedlinePlus