Infectious Gastroenteritis in Transplantation

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Gastrointestinal infections in both pediatric and adult patients account for significant morbidity and mortality worldwide.1 Immunocompromised hosts, including HIV patients, solid-organ transplant recipients, hematopoetic stem cell transplant recipients, or patients requiring therapy for chronic inflammatory diseases, have an increased susceptibility to gastrointestinal infections.2 Patients with severe diarrhea may be hospitalized and some may develop more serious sequelae such as Guillain Barre syndrome and hemolytic uremic syndrome (HUS), and in some cases death,3 while mild cases of diarrhea can lead to absenteeism from school or work and may require treatment by a health care provider. Nearly 3% of neonatal mortality and 17 % of under-five child mortality is attributable to diarrhea.4 Diarrheal disease can be caused by a number of pathogens including viruses, bacteria, and parasites. Presentations of gastrointeritis with an unidentified source post a challenge to health care providers as the same clinical presentation can be caused by many different etiologies. Knowing the identity of the casual agent in symptomatic (both acute and chronic gastrointeritis) adult and pediatric patients can aid in diagnosis and patient management.5

Diarrhea is a major cause of morbidity and mortality in transplantation, both in hematopoietic stem cell transplant (HSCT) and solid organ transplant (SOT) recipients. Nearly every HSCT recipient experiences at least one diarrheal episode, of which 40% is of infectious origin.6 Differentiation between infectious and non-infectious causes of diarrhea is challenging. Key non-infectious causes of diarrhea include HSCT conditioning regimen-associated mucositis, acute GVHD of the gut, antibiotic-associated diarrhea, and immunosuppressive agent-associated diarrhea. A major clinical concern is that misdiagnosis of infectious gastroenteritis as graft versus host disease (GVHD) or graft rejection will lead to inappropriate augmented immunosuppression.7 It has been shown that increased immunosuppression in the presence of viral infection can significantly worsen symptoms and adversely affect outcome; conversely, a reduction in immunosuppression may be critical to resolving infection.

Of the infectious causes of diarrhea, viruses are the most common and while no therapy has been shown to be effective, establishing an etiology has proven essential.6 Early identification enables effective clinical action to help reduce the prolonged and persistent course of diarrheal illness and associated hospital stays.6 Clinical measures include reduction in immunosuppression, administration of IVIG, and supportive care.8,9 Establishing an etiology is required when preventing or controlling nosocomial of diarrheal pathogens. Meticulous infection control practices are required due to the highly infectious nature of these pathogens along with prolonged excretion patterns in the transplant setting.6

Viracor-IBT Viral Gastroenteritis Menu

Viracor-IBT offers a full range of molecular diagnostic tests for viral gastroenteritis with the fastest turn-around times available, enabling clinicians to make prompt and effective treatment decisions. Due to increasing concern regarding the significant clinical and financial implications of nosocomial outbreaks, sensitive and rapid detection of these pathogens has never been more important. Implementation of effective infection control measures begins with reliable and rapid laboratory results.

Classification

Assay

Viral Gastroenteritis

Gastrointestinal Pathogen Panel (GPP) PCR

Adenovirus Quantitative Real-time PCR

Norovirus Real-time RT-PCR


Gastrointestinal Pathogen Panel (GPP) PCR

The Gastrointestinal Pathogen Panel (GPP) PCR utilizing Luminex® xTAG® is an FDA-cleared multiplexed nucleic acid test intented for the simultaneous qualitative detection of multiple viral, parasitic, and bacterial nucleic acids in human stool specimens from individuals with signs and symptoms of infectious colitis or gastroenteritis. The following pathogens types, subtypes and toxin genes are identified using the xTAG GPP:

  • Campylobacter (C. jejuni, C. coli and C. lari only)*
  • Clostridium difficile (C. difficile) toxin A/B*
  • Cryptosporidium (C. parvum and C. hominis only)*
  • Escherichia coli (E. coli) O157*
  • Enterotoxigenic E. coli (ETEC) LT/ST*
  • Giardia (G. lamblia only, also known as G. intestinalis and G. duodenalis)*
  • Norovirus GI/GII*
  • Rotavirus A*
  • Salmonella*
  • Shiga-like Toxin producing E. coli (STEC) stx 1/stx 2*
  • Shigella (S. boydii, S. sonnei, S. flexneri and S. dysenteriae)*
  • Adenovirus (serotypes 40 and 41 only)**
  • Yersinia enterocolitica**
  • Vibrio cholerae**
  • Entamoeba histolytica**

          *Performed as an FDA-cleared test

          **Performed as a laboratory developed test

GPP positive results are presumptive and FDA-cleared results must be confirmed by a second FDA-cleared test or other acceptable reference method according to the package insert. The detection and identification of specific gastrointerstinal microbial nucleic acid from individuals exhibiting signs and symptoms of gastrointestinal infection aids in the diagnosis of gastrointestinal infection when used in conjuction with clinical evaluation, laboratory findings, and epidemiological information. A gastrointestinal microoganism multiplex nucleic acid-based assay also aids in the detections and identifcation of acute gastrointeritis in the context of outbreaks.5

Adenovirus

Severe morbidity and mortality due to adenovirus infection has been observed in both HSCT and SOT recipients.10 Early diagnosis and intervention provides the best chance of reducing the risk of illness and death among transplant recipients.10 Molecular detection of adenovirus in stool specimens of allogeneic HSCT recipients has been shown to precede viremia, suggesting that intestinal infections may represent a common source of virus reactivation and dissemination.11 A recent study reported a critical threshold of 1x106 copies per gram stool preceded the onset of viremia by a week or more.8 Intervention at this early stage may prevent or delay disseminated adenovirus disease.12 Adenovirus Quantitative Real-time PCR detects all known serotypes of adenovirus and does not differentiate between species F (serotypes 40 and 41), which are common causes of diarrhea, from other species and serotypes of adenovirus.

Norovirus

Norovirus infection can cause severe disease with significant morbidity and mortality after transplantation, in both SOT and HSCT (before and after engraftment). Due to the similar and nonspecific features of norovirus gastroenteritis and gut GVHD, differentiation requires laboratory testing. Misdiagnosis of norovirus as GVHD may lead to inappropriate augmentation with immunosuppressants, which has been shown to significantly worsen symptoms and adversely affect outcome.7 Conversely, a reduction in immunosuppression may be critical to resolving infection.7 Thus, norovirus should always be considered in the differential diagnosis of gut GVHD or graft rejection.13 This allows for early diagnosis in these vulnerable patients and prevents escalation of immunosuppression for wrongly suspected GVHD or graft rejection. Norovirus Real-time RT-PCR detects norovirus group I and group II.


References

1. Schlenker C, Surawicz CM. Emerging infections of the gastrointestinal tract. Best Pract Res Clin Gastroenterol. 2009:23(1):89-99.

2. Thom K, Forrest G. Gastrointestinal infections in immunocompromised hosts. Curr Opin Gastroenterol. 2006 Jan;22(1):18-23.

3. Fischer Walker CL, Sack D, Black RE. Etiology of diarrhea in older children, adolescents and adults: a systematic review. PLoS Negl Trop Dis. 2010 Aug 3:4(8):e768.

4. Patel A, Mamtani M, Dibley MJ Badhoniya N, Kulkarni H. Therapeutic value of zinc supplementation in acute and persistent diarrhea: a systematic review. PLos One. 2010 Apr 28:5(4):e10386.

5. Information derivced from the xTAG Gastrointestinal Pathogen Panel test kit package insert (Luminex, Inc.)

6. Liakopoulou E, Mutton K, Carrington D, et al. Rotavirus as a significant cause of prolonged diarrhoeal illness and morbidity following allogeneic bone marrow transplantation. Bone Marrow Transplant. 2005 Oct:36(8):691-4.

7. Kaufman SS, Chatterjee NK, Fuschino ME, et al. Calicivirus enteritis in an intestinal transplant recipient. Am J Transplant. 2003 Jun:3(6):764-8.

8. Thielman NM, Guerrant RL. Clinical practice. Acute infectious diarrhea. N Engl J Med. 2004 Jan 1:350(1):38-47.

9. Guerrant RL, Van Gilder T, Steiner TS, et al. Practice guidelines for the management of infectious diarrhea. Clin Infect Dis. 2001 Feb 1:32(3):331-51.

10. Echavarria M. Adenoviruses in immunocompromised hosts. Clin Microbiol Rev. 2008 Oct:21(4):704-15.

11. Lion T, Baumgartinger R, Watzinger F, et al. Molecular monitoring of adenovirus in peripheral blood after allogenic bone marrow transplantation permits early diagnosis of disseminated disease. Blood. 2003 Aug 1:102(3):1114-20.

12. Lion T, Kosulin K, Landlinger C, et al. Monitoring of adenovirus load in stool by real-time PCR permits early detection of impending invasive infection in patients after allogeneic stem cell transplantation. Leukemia. 2010 Apr:24(4):706-14.

13. Roddie C, Paul JP, Benjamin R, et al. Allogeneic hematopoietic stem cell transplantation and norovirus gastrenteritis: a previously unrecognized cause of morbidity. Clin Infect Dis. 2009 Oct 1:49(7):1061-8.