Diarrhea in Organ Transplant Recipients
Authors: Aruna Subramanian, M.D.
Definitions
Diarrhea is defined as an increase in the frequency of defecation to three or more times per day (or passage of at least 200 g of stool per day) along with a decrease in consistency of stool (typically soft or liquid) (9, 13). “Acute diarrhea” is defined as diarrhea lasting up to 14 days. “Infectious diarrhea” is diarrhea due to an infectious etiology and may be accompanied by nausea, vomiting, or abdominal cramps (9, 13).
Epidemiology
In the United States, an estimated 211 million to 375 million episodes of diarrhea occur each year, resulting in 900,000 hospitalizations and 6000 deaths annually (13). Diarrhea is an extremely common complaint in solid organ transplant recipients due to medication side effects and infectious pathogens. Bacterial diarrhea often occurs following ingestion of infected foods; viral diarrhea tends to be spread person-to-person.
Because its significance is underappreciated, the epidemiology of infectious diarrhea in solid organ transplant (SOT) recipients is not well characterized despite the associated morbidity and mortality. In a retrospective study of 308 renal transplant patients from Turkey, 3.6% of all deaths and 5.1% of infection related deaths were secondary to diarrhea (1). In a recent review of the US Renal Data System Database of 41,442 renal transplant recipients in the US, the 3-year cumulative incidence of diarrhea was 22%, with 18% classified as non-infectious (4). Even episodes of non-infectious diarrhea doubled the hazard of graft loss and patient death.
Etiologic Agents
The most common etiologic agents of infectious diarrhea in solid organ transplant patients are bacteria, parasites and cytomegalovirus (CMV). In a study by Maes et al of 108 renal transplant patients in Belgium with diarrhea for more than 7 days, 17 were diagnosed with bacterial infection (11 Campylobacter jejuni, 2 Salmonella spp., 2 Clostridium difficile, 2 other), 4 with parasitic or protozoan infections, 8 with CMV infection, and 1 other viral infection (10). A study by Arslan et al from Turkey evaluated 52 diarrhea episodes in 43 liver and kidney transplant recipients (2). 77% of the episodes were found to have an infectious etiology: Giardia lamblia (9), Cryptosporidium parvum (7), CMV (6), Clostridium difficile (3), Camplylobacter jejuni (2), Shigella sonnei (2), Salmonella enteritidis (1), rotavirus (1), Entamoeba histolytica (1), and Blastocystis hominis (1).
Clinical Manifestations
Bacterial (5)
Acute Watery Diarrhea
Usually due to large volume small bowel secretory diarrhea: Enterotoxigenic E. coli, Non-typhoidal Salmonella spp., Campylobacter jejuni (often with fever, can cause symptoms of dysentery as well).
Dysentery
Defined by passage of bloody stools which suggests colonic involvement with invasion. Most commonly caused by: Shigella, Campylobacter, nontyphoidal Salmonella, and Shiga toxin producing E. coli. Shiga-toxin producing E. coli cause bloody diarrhea with more than 5 stools per day accompanied by severe abdominal cramps but usually without fever. The Shiga toxin can enter the blood stream and result in subsequent hemolytic-uremic syndrome.
Food Poisoning
Staphylococcus aureus usually causes vomiting within 6 hours of ingestion of a preformed toxin. Clostridium perfringens causes watery diarrhea without vomiting within 8-14 hours of ingestion of contaminated foods.
Traveler’s Diarrhea
Transplant recipients are much more likely to travel to tropical and semitropical areas for both work and pleasure now and are increasingly at risk for traveler’s diarrhea. More than half of the cases are due to enterotoxigenic E. coli and enteroaggregative E. coli, followed by shigella, salmonella, campylobacter, aeromonas, noncholeric vibrios, and plesiomonas. See below for possible chemoprophylaxis regimens for effective preventative measures in travelers.
Nosocomial Diarrhea
Clostridium difficile should be considered in hospitalized and non-hospitalized transplant recipients with clinically significant diarrhea, unexplained leukocytosis, especially with dilatation of the colon. Reports vary as to whether C. difficile associated disease is more severe in transplant patients, however it appears that steroids are a risk factor for severe disease (7, 12).
Viral
CMV
CMV is an important cause of enterocolitis in transplant recipients. Especially with the use of routine antiviral prophylaxis post transplantation, the incidence of CMV colitis is often delayed (3). In transplant patients with fatigue, fever, diarrhea, and leucopenia, the diagnosis of CMV colitis should be entertained early. Late CMV disease is associated with significant morbidity and mortality and severe extensive gastrointestinal disease appears to be predictive of relapse after therapy (3, 6).
Other-Rotavirus, Norovirus (13)
These illnesses associated with acute watery diarrhea and are more common in winter months. Norovirus may be passed within families and can be associated with outbreaks. Rotavirus is classically considered a pathogen in young children, but there is increasing evidence of its pathogenicity in adult transplant recipients (11).
Parasitic
Giardia and Amebiasis
Both pathogens can be associated with chronic diarrhea. Giardia usually causes more of an enteritis with watery diarrhea, malabsorption, bloating and flatulence. Amebiasis can cause more of a colitis with bloody stools.
Cryptosporidium, Isospora, Microsporidiosis
All can cause a chronic diarrhea in solid organ transplant patients.
APPROACH TO DIAGNOSIS
Differential Diagnosis (8)
Medication-Related
The most common causative agent of diarrhea in solid organ transplant patients is mycophenolate mofetil (MMF). In some studies the incidence of diarrhea is as high as 51% in liver transplant recipients taking 3 gm of MMF daily (8). Often non-immunosuppressive agents can be implicated in diarrhea causation as solid organ transplant patients are often receiving a multitude of medicines (10).
Other less common causes of diarrhea in transplant recipients include
- Post Transplant Lymphoproliferative Disorder
- Graft-vs-Host Disease
- Inflammatory Bowel Disease
- Colon Cancer
- Bacterial Overgrowth Syndromes
Laboratory Evaluation (5, 9,13)
Conventional Stool Culture
Can be quite useful in the diagnosis of bacterial diarrhea with symptoms of dysentery. Yield is low with acute watery diarrhea. With bloody stools, the laboratory should be requested to look for Shiga toxin-producing E. coli. With seafood ingestion the laboratory should be requested to look for vibrios.
C. difficile Toxin/PCR
Stool can be tested for the presence of C difficile toxin A and B by EIA or cytotoxin assay, though some hospitals are moving toward use of PCR testing. Recent antibiotic use and hospitalization are traditional risk factors, but increasingly being seen in outpatients so there should be a low threshold for diagnostics with diarrhea and leukocytosis.
Stool Ova and Parasite Exam/Giardia Antigen
Send stool for O+P exam, giardia antigen testing especially with chronic diarrhea. Need to request modified acid-fast stain for Cryptosporidia, Cyclospora, Isospora and Trichrome stain for microsporidia.
Serum CMV PCR
Should be obtained in patients where CMV enterocolitis is considered, especially with other constitutional symptoms in moderate to high risk individuals. However, may have low level viremia and still have active GI disease.
Other Diagnostic Evaluation
Imaging
CT of abdomen may be useful in evaluation of colonic wall thickening and dilatation.
Endoscopy
Endoscopy with biopsy should be considered in patients where non-invasive testing is non-diagnostic. Pathology slides should be stained for CMV.
APPROACH TO THERAPY (5, 9,13)
Empiric Therapy
Oral rehydration solution or intravenous electrolyte and fluid replacement should be considered when appropriate.
Specific Therapy
Shigellosis, Aeromonas, Plesiomonas shigelloides, noncholereic vibrios, Enteroinvasive E. Coli
- Ciprofloxacin: 750 mg po qd for 3 days or azithromycin 500 mg po qd for 3 days
- Nontyphoidal salmonellosis: Levofloxacin 500 mg qd or Azithromycin 500 mg qd for 14 days
- C jejuni: Azithromycin 500 mg po qd for 3 days
- Typhoid fever: Levofloxacin 500 mg qd or Azithromycin 500 mg qd for 7 days
- Shiga-toxin producing E. coli: No treatment
- Cholera: Doxycline or tetracycline for 3 days or macrolide for 3 days
- C. difficile Diarrhea: Metronidazole 500 mg po tid for milder cases, vancomycin 125 mg po qid for more severe illness.
- Giardia lamblia: Metronidazole 250 mg po tid for 5 days or tinidazole 2 gm single dose
- Amebiasis: Metronidazole 500-750 mg po or IV tid for 7-10 days, or tinidazole 2 gm po qd x 3 days, then iodoquinol 650 mg po tid x 21 days or paromomycin 500 mg po qid x 7 days.
ADJUNCTIVE THERAPIES
Consider preventative strategies for traveler’s diarrhea in solid organ transplant patients traveling to high risk areas: rifaximin 200 mg once or twice daily or bismuth subsalicylate with each meal and at bedtime.
ENDPOINTS FOR MONITORING THERAPY
Generally clinical endpoints such as resolution of diarrhea are used to monitor therapy and follow up stool diagnostics are generally not recommended.
OTHER ISSUES
Expected Outcome and Prognosis (3, 4)
Many cases of acute infectious diarrhea can be self-limited. However, diarrhea is associated with increased risk of graft loss and patient mortality. Late CMV disease is also associated with significant morbidity and mortality.
Secondary Prophylaxis or Long-Term Therapies
Generally secondary prophylactic strategies are not used for infectious diarrhea, except in rare cases. With relapsing severe C. difficile colitis, occasionally long term therapy with slow taper of treatment is recommended. Also, with severe, extensive CMV colitis sometimes long term therapy is warranted to prevent relapse (6).
REFERENCES
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