Critical Care Medicine

Infections following organ transplantation (Including Solid Organ and Hematopoietic Stem cell): Presenting with Gastrointestinal Manifestations

Colitis, gastroenteritis, gastritis, C. difficile-associated diarrhea, esophagitis; cholangitis; diverticulitis; biliary sepsis; typhlitis; abdominal surgical site infections; gastrointestinal graft-versus-host disease

Synonyms

Gastrointestinal infections in the immunocompromised host, intra-abdominal sepsis

Related conditions

C. difficile infection, pseudomembranous colitis, megacolon, Candida esophagitis, CMV esophagitis, HSV esophagitis, CMV gastritis, CMV enteritis, CMV colitis, strongyloidiasis, Salmonella, Shigella, Vibrio, Campylobacter, E. coli enteritis, traveler's diarrhea, norovirus, rotavirus, enterovirus, cryptosporidiosis, Listeria, MAI, graft-vs-host disease, bile leaks, bilomas, biliary stricture, cholangitis, cholecystitis, perforated viscus, intra-abdominal abscess, diverticular abscess, post-transplant lymphoproliferative disease, mucositis, Helicobacter pylori, Aeromonas, antibiotic-associated diarrhea, medication toxicity, Lactobacillus, probiotics, hepatitis, hepatosplenic candidiasis

1. Description of the problem

What every clinician needs to know

Solid organ and hematopoietic cell transplant recipients are vulnerable to a wide variety of infections involving the gastrointestinal tract. Some of these also occur in immunocompetent individuals (such as C. difficile-associated diarrhea and cholecystitis) but may be more frequent or severe in transplant recipients, while some conditions are seen mainly in the immunocompromised host (such as CMV colitis and GI graft-versus-host disease).

An understanding of the timetable of post-transplant infections (see "Infections Following Organ Transplantation: Presenting Without Localizing Signs") as well as the patient's degree of immunosuppression and environmental exposures (including food, water, travel, pets) can help to narrow down the wide differential diagnosis.

Broad categories of clinical scenarios in this population include diarrheal syndromes, intra-abdominal infection and other infections (including distant hematogenous spread of abdominal organisms).

Clinical features

For diarrheal syndromes: diarrhea, abdominal pain, nausea and vomiting are the most common presenting symptoms and signs of infectious processes in this category. Depending on the etiology, fevers, chills and sweats may or may not be present. These symptoms may be acute, chronic or intermittent.

Causes of diarrhea in this population are many and include C. difficile (as antibiotics are frequently used in transplant recipients); foodborne and other enteric bacterial pathogens (Salmonella, Shigella, Campylobacter, E. coli 0157:H7, Aeromonas); viruses (norovirus, rotavirus, CMV, adenovirus); parasitic (Cryptosporidium, Giardia, Strongyloides); and more unusual pathogens (mycobacteria, Vibrio, Microsporidia, Cyclospora).

It is important to remember that some common pathogens such as norovirus and rotavirus may cause protracted syndromes in the transplant recipient, although they are symptomatic for much shorter times in immunocompetent hosts.

Adenovirus infection may present with fever and diarrhea in a transplant recipient and may be associated with hepatitis; nephritis in the renal transplant recipient; and hemorrhagic cystitis in the HSCT recipient.

Transplant-related medications may also be associated with diarrhea, particularly mycophenolate mofetil and oral magnesium.

For intra-abdominal infection: This may be related to the surgical site (superficial or deep wound infection) or may relate to the transplant operation itself. Anatomic complications of abdominal organ transplantation such as bile leaks, bilomas and biliary strictures in liver transplantation; duodenal leaks in pancreas transplantation; or intra-abdominal collections in intestinal transplantation all frequently lead to infection with enteric organisms.

During the second time period of the post-transplant infection timetable (2-6 months post-transplant), opportunistic infections may be manifested, including tissue-invasive CMV in the GI tract (CMV esophagitis, gastritis, enteritis, or colitis) and EBV-related post-transplant lymphoproliferative disease presenting in the GI tract (with hemorrhage or intestinal perforation).

In neutropenic patients, processes such as cholecystitis, appendicitis and diverticulitis may occur and may have muted abdominal signs on exam due to lack of inflammation in the absence of WBC. Abdominal pain (with or without fever and hypotension) may be the main presenting symptom.

In HSCT recipients, the GI tract is one of the most common sites of acute graft-versus-host disease (GVHD), which typically presents with high-volume diarrhea, abdominal pain and cramping, and sometimes nausea and fever. GVHD of the skin and/or liver may or may not be present concomitantly.

In HSCT recipients or other post-chemotherapy patients, diarrhea may also be indicative of chemotherapy-induced intestinal mucositis.

In neutropenic patients, typhlitis (involvement of the right colon by Gram-negative organisms that can progress to full-thickness necrosis) can be a serious problem, presenting with fever, diarrhea, right lower quadrant pain and sometimes bacteremia.

Fever and chills with or without demonstrable bacteremia may follow manipulations of the biliary tract, such as removing and replacing an internal-external biliary stent in a liver transplant recipient with an anastomotic stricture.

Odynophagia may be related to candidal, HSV or CMV esophagitis, or to noninfectious esophagitis (reflux or medication-associated injury).

Key management points

  1. Establish secure IV access and initiate hydration.

  2. Obtain cultures of blood and urine, and send a stool sample for at least C. difficile toxin assay; depending on the history, stool culture for enteric pathogens and stool microscopic ova and parasites exam also may be requested.

  3. Culture any wounds or surgical sites with purulent drainage.

  4. Plain film of the abdomen is important to rule out free air or bowel obstruction or megacolon (from C. difficile). CT scan is frequently more helpful in delineating processes such as abscesses, appendicitis, bilomas, lymphocoeles, urinomas, etc.

2. Emergency Management

  1. Establish IV access and hydration - patients are often dehydrated leading to acute kidney injury.

  2. In the neutropenic patient, after rapidly obtaining the relevant cultures, start broad-spectrum antimicrobial therapy including Pseudomonas coverage, with exact antibiotic choice according to local resistance patterns at that particular center.

  3. Plain film of the abdomen to rule out obstruction or free air, or megacolon (C. difficile).

  4. Emergent surgical consultation for suspected perforated viscus, megacolon, appendicitis. Recall that signs of peritonitis may be absent in neutropenic patients and severe pain with hypotension may be the major manifestation.

Other management points not to be missed

  • Cultures of blood, urine, wounds; stool sample for C. difficile PCR, norovirus PCR, (sometimes also culture for enteric pathogens, and ova and parasite exam).

  • Review previous culture data, transplant operative notes, and previous abdominal imaging when time permits for hints as to present processes.

  • Look up the CMV sero-status of the donor and recipient (D+/R- is the highest risk status in solid organ recipients; D-/R+ is highest risk in HSCT recipients).

  • Look up the patient's pre-transplant PPD status (negative? anergic? If positive was isoniazid prophylaxis administered?). Consider stool culture for mycobacteria; also Histoplasma urine antigen and blood fungal battery.

  • Obtain a history of recent or remote travel, pets, and other exposures (lake swimming, restaurant food, ill contacts, caring for small children etc.).

3. Diagnosis

Diagnostic criteria and tests

After obtaining blood, urine, and wound cultures as well as stool for C. difficile, culture for enteric pathogens (Salmonella, Shigella, Vibrio, Campylobacter, E. coli 0157:H7) and microscopic ova and parasites examination, consider also stool norovirus PCR, rotavirus Ag, Cyclospora and Microsporidia stains and stool acid-fast stain and mycobacterial culture

If LFTs are elevated or previous biliary tract manipulations have occurred, consider right upper quadrant ultrasound, or abdominal CT if the patient is stable enough. Ultrasound is preferred for assessing patency of hepatic vasculature and the diameter of the bile ducts. CT is preferred for visualizing lymphadenopathy, abscesses or collections outside the right upper quadrant, colonic thickening, typhlitis, etc.

Blood should also be send for quantitative CMV PCR; also consider quantitative EBV PCR and adenovirus PCR.

For suspected GVHD or CMV esophagitis/gastritis/colitis, endoscopy and/or colonoscopy with biopsy are essential to make the diagnosis. GVHD requires profound immunosuppression for treatment and thus should be documented by a tissue biopsy. CMV in the GI tract may be visualized directly on histopathology by CMV inclusions in cells, but even if these are not seen, CMV immunostain may be positive and should be requested in a transplant recipient with a compatible clinical syndrome. For an intestinal transplant recipient, scope and biopsy will also serve to rule out rejection.

Establishing a diagnosis

C. difficile assay results should be available within 24 hours, but in the meantime, suspect C. difficile-associated diarrhea in a patient with copious watery stools (may be as many as 15-20) with abdominal cramping and a history of recent antibiotics. If diarrhea is not present and progressive abdominal distention occurs, suspect C. difficile with ileus, which is an ominous presentation as it may be followed by megacolon and perforation.

Since 2013, with the rise of the GII.4 strain, norovirus has become the most common cause of foodborne infection, causing > 50% of foodborne infections in the US. While immunocompetent individuals may be ill for 24 – 72 hours, transplant recipients can develop a severe chronic norovirus diarrheal syndrome with waxing and waning of symptoms for months to years. This frequently goes undiagnosed unless an astute clinician sends a norovirus stool PCR. Dehydration, weight loss, and secondary bacterial infections are common.

Typhlitis has a characteristic appearance on imaging (phlegmon and necrotic appearance of the right colon) but suspect it in a patient with fever, neutropenia and right-sided abdominal pain if the patient is too unstable for a CT scan.

Bilomas, hepatic abscesses and other collections after abdominal transplantation are usually diagnosed on CT scan and microbiologically by aspiration and culture of the fluid.

CMV esophagitis, gastritis, enteritis and colitis generally require a biopsy with visualization of CMV inclusions or positive CMV immunostaining, but presumptive diagnosis of tissue-invasive CMV may be made in a patient with gastrointestinal symptoms and a high CMV PCR viral load. However, be aware that CMV in the GI tract may occasionally present with a blood CMV viral load that is low or even undetectable.

Other possible conditions

It is important to consider noninfectious causes of diarrhea, particularly GVHD (since therapy of GVHD usually requires high doses of immunosuppression). GVHD may also coexist with bacterial infections or CMV colitis, or may provide a portal for enteric bacteria to enter the bloodstream.

Medication-related diarrhea (such as that due to mycophenolate mofetil) will generally be more chronic and will parallel the time course of administration of the medication.

Chemotherapy-related diarrhea from intestinal mucositis will be suggested by the time frame of occurrence, but concomitant infection may also be present.

Post-transplant lymphoproliferative disease (PTLD) related to EBV may present in the GI tract and the presenting symptom may be a GI bleed or perforation. In a febrile patient with abdominal lymphadenopathy or masses, a quantitative EBV PCR in the blood is helpful but ultimately a biopsy diagnosis is necessary.

Confirmatory tests

In addition to the tests listed above, eosinophilia is suggestive of GVHD, parasitic infection or drug reaction. Elevated liver function tests may suggest rejection in a liver transplant recipient; biliary complications; viral infection such as CMV, HSV, or adenovirus hepatitis; GVHD in an HSCT recipient; or recurrence of underlying disease such as hepatitis C.

Current C. difficile assays are very sensitive (particularly the PCR) so it is generally not necessary to obtain 3 sequential assays as was done in past.

Wherever possible, tissue biopsy is helpful to rule out unusual pathogens and to obtain a microbiologic diagnosis, if non-invasive testing is unrevealing.

4. Specific Treatment

Suspected or proven C. difficile infection should be treated with oral metronidazole or oral vancomycin; for severe cases, many clinicians prefer starting with oral vancomycin. If ileus is present, intravenous metronidazole should be administered (IV vancomycin does not penetrate the colonic lumen). Vancomycin may also be administered via rectal enema or through a stoma.

For norovirus or rotavirus infection, there are no specific antivirals. Adequate hydration is essential. Reduction of immunosuppression may be helpful, as well as IVIg replacement if the patient is hypogammaglobulinemic. Off-label nitazoxanide has been used in severe cases of norovirus diarrhea.

For intra-abdominal abscesses, cholangitis or infected bilomas, broad-spectrum coverage should be instituted (pending cultures) that includes Gram-negative coverage and also preferably Enterococcus (which increasingly means VRE). Coverage for Candida is also reasonable in this setting. If previous culture data exists, take this into account in designing the initial antimicrobial regimen.

When culture and susceptibility results are received, the antibiotic regimen should be modified accordingly, but in a neutropenic patient should always retain broad-spectrum Gram-negative coverage.

In the presence of multiresistant Gram-negative bacteria, antimicrobial choices may be extremely limited and may confer high risk of toxicity. For example, carbapenemase-producing Klebsiella (KPC) and carbapenem-resistant Acinetobacter baumanii (CRAb) may be sensitive only to colistin, amikacin, and/or tigecycline (the latter is less effective for bacteremia and for the urinary tract, but IV colistin and amikacin are highly nephrotoxic). In the severely ill patient, particularly one known to be colonized previously with such organisms, the risks of toxicity of these agents must be weighed against the risk of overwhelming sepsis if the organism is not treated rapidly.

For tissue-invasive CMV in the GI tract, treatment is generally with intravenous ganciclovir (occasionally oral valganciclovir in the mildly ill patient) and many clinicians would add adjunctive CMVIg (CMV hyperimmune globulin) to enhance host defenses against CMV.

Adenovirus infection is usually treated with reduction of immunosuppression and (in highly symptomatic cases) cidofovir, although the nephrotoxicity of cidofovir may limit therapy.

Cryptosporidiosis is usually treated with reduction of immunosuppression, hydration and sometimes nitazoxanide.

Drugs and dosages

Dosages of antimicrobials should be maximal within the indicated range (especially for neutropenic or septic patients), but should be adjusted for renal dysfunction according to the manufacturers' instructions. The following list includes some commonly used antibiotics in this setting, though it is not comprehensive; doses given are for normal renal function and should be adjusted for renal dysfunction according to the manufacturer's nomogram.

  • Acyclovir 5 mg/kg IV Q8h (mucosal HSV in an immunocompromised patient); 10 mg/kg IV Q8h (for disseminated zoster in an immunocompromised patient or one unable to take oral medications) ; acyclovir 400 mg po BID (e.g.) for prophylaxis.

  • Amphotericin B Lipid Complex (ABLC) or Liposomal Amphotericin B - prophylaxis 3 mg/kg/day, treatment 5 mg/kg/day (premedication generally with acetaminophen, diphenhydramine, +/- hydrocortisone, normal saline).

  • Amikacin - regimens vary depending on traditional or extended interval dosing (use manufacturer's nomogram) and adjust to maintain trough level at less than 8 and peak 28-35 mcg/ml (for pneumonia or sepsis).

  • Anidulafungin 200 mg IV loading dose followed by 100 mg IV once daily.

  • Azithromycin 500 mg daily.

  • Aztreonam 1-2 g IV Q6-8h.

  • Caspofungin 70 mg IV x 1 dose then 50 mg IV Q12h.

  • Cefazolin g IV Q8h.

  • Cefepime 2 g IV Q8 h.

  • Ceftazidime 1-2 g IV Q8h.

  • Ceftriaxone 1 g IV Q24h (higher for endocarditis or meningitis).

  • Ciprofloxacin 400 mg IV Q12h.

  • Clindamycin 600-900 mg IV Q8h.

  • Colistimethate 100-125 mg IV Q6-12h (generally reserved for MDR organisms - especially important to adjust for renal dysfunction - watch for nephrotoxicity).

  • Cytomegalovirus immune globulin (CMVIg) 100 mg/kg-150 mg/kg IV (premedication generally with acetaminophen, diphenhydramine, +/- hydrocortisone; dosing schedules vary; used for hypogammaglobulinemia or adjunctive therapy for tissue-invasive CMV disease such as CMV pneumonitis).

  • Daptomycin 6 mg/kg IV Q24h.

  • Filgrastim (G-CSF) 300 mcg SQ or 480 mcg SQ can be administered daily as needed for neutropenia in the solid organ transplant recipient (it does not appear to precipitate rejection in this setting). Filgrastim should be used under the guidance of a hematologist in the HSCT recipient. When filgrastim is stopped, the WBC count may fall by up to 50%.

  • Fluconazole 100-400 mg IV Q24h.

  • Foscarnet - follow manufacturer's nomogram.

  • Ganciclovir 5 mg/kg IV Q12h (therapy) or 5 mg/kg IV Q24h (prophylaxis).

  • Gentamicin - regimens vary depending on traditional or extended interval dosing (use manufacturer's nomogram) and adjust to maintain trough level at less than 2 and peak 7-10 mcg/ml (for pneumonia or sepsis).

  • Imipenem 500-1000 mg Iv Q6h.

  • Intravenous immunoglobulin (IVIg) 400 mg/kg IV per dose; number and timing of doses varies; with acetaminophen/diphenhydramine (and sometimes hydrocortisone) premedication - used for hypogammaglobulinemia or adjunctive therapy for tissue-invasive CMV disease such as CMV pneumonitis.

  • Itraconazole 200 mg Q12h.

  • Isavuconazole 372 mg po/IV Q8h for 6 doses, then 372 mg po/IV Q24h.

  • Levofloxacin 500 mg-750 mg IV Q24h.

  • Linezolid 600 mg IV Q12h.

  • Meropenem 500 mg IV Q6h-1 gram IV Q8h.

  • Metronidazole 250-500 mg po 3-4 times per day, or 500 mg Q6-8h IV.

  • Micafungin 100-150 mg IV Q24h.

  • Moxifloxacin 400 mg IV Q24h.

  • Oxacillin 1-2 g IV Q4-6h.

  • Piperacillin-tazobactam 3.375 grams IV Q6h-4.5 grams IV Q6h.

  • Posaconazole Extended – release formulation preferred: 300 mg po Q12 x 2 doses, then 300 mg po daily. If necessary to administer via tube, use the liquid formulation, 200 mg po four times daily (treatment dose) or 200 mg po three times daily (prophylaxis) – which must be given with food containing fat.

  • Tigecycline 100 mg IV x 1 dose followed by 50 mg IV Q12h.

  • Tobramycin - regimens vary depending on traditional or extended interval dosing (use manufacturer's nomogram) and adjust to maintain trough level at less than 2 and peak 7-10 mcg/ml (for pneumonia or sepsis).

  • Trimethoprim-sulfamethoxazole one double-strength po daily or thrice weekly for Pneumocystis prophylaxis; 15-20 mg/kg/day of the trimethoprim component (divided Q6h) for treatment of Pneumocystis pneumonia.

  • Vancomycin 1-1.5 grams IV Q12h with subsequent pre-dose levels and appropriate adjustment.

  • Vancomycin (oral): 125-250 mg po 4 times per day.

  • Valganciclovir 900 mg po BID for treatment, and 450 mg po BID (or 900 mg po daily) for prophylaxis.

  • Voriconazole 6 mg/kg po/IV Q12h x 2 doses then 4 mg/kg IV Q12h, with a level on Day 5 (aiming for level 2 – 5).

Note that azole antifungals and some macrolides (erythromycin, clarithromycin) raise the levels of cyclosporine, tacrolimus, sirolimus, and everolimus, and require close monitoring and adjustment of levels and doses of those agents. Also note that aminoglycosides may have enhanced nephrotoxicity in patients receiving cyclosporine or tacrolimus, and alternative agents should be considered if appropriate microbiologically. Assistance of a pharmacist familiar with transplant-related issues is very helpful.

Refractory cases

For severe C. difficile infection, combination therapy (such as IV metronidazole plus oral vancomycin +/- rectal vancomycin enemas) may be used. Case reports support the idea of IVIg for severe C. difficile infection. Investigational monoclonal antibody preparations are under study. Patients with worsening manifestations such as progressive colonic dilatation on a KUB should undergo consultation with a colorectal surgeon. Fecal microbiota transplants are increasingly used in the general population, with some case reports in immunocompromised patients, but larger studies are needed to definitively establish the safety and efficacy of this therapy in transplant recipients.

For refractory diarrhea without a diagnosis, colonoscopy with biopsy and also small bowel biopsy are important in ruling out treatable pathogens. If all else is negative, reduction of immunosuppression may be helpful.

For abdominal fluid collections (known or suspected abscesses) and manifestations of sepsis despite CT-guided drainage, relaparatomy and operative drainage may be needed.

For typhlitis, most patients will improve following neutrophil recovery. In the absence of this, patients may respond to broad-spectrum antibiotics, bowel rest and hydration. However in a subset of cases, clinical deterioration will lead to surgery. Surgical consultation in severely ill patients is a good idea.

5. Disease monitoring, follow-up and disposition

Monitoring

C. difficile-associated diarrhea generally responds rather gradually to therapy, often taking several days for significant reduction of stool number and volume to occur. However, if manifestations are worsening, then additional therapies should be considered.

Other causes of diarrhea, such as norovirus, may also take much longer to resolve than in the normal host.

Abdominal abscess may take weeks or months to resolve, especially intrahepatic abscesses. Protracted or repeated courses of IV antibiotics may be necessary, as well as repeat drainage for cultures (organisms may periodically change, particularly in patients with biliary anastomotic complications or leaks). Serial imaging is helpful in determining length of therapy.

Tissue-invasive CMV in the GI tract generally takes at least 4-6 weeks to resolve. Although the blood CMV PCR viral load should be followed weekly during treatment, it may become undetectable before tissue-invasive CMV has resolved. It is a good idea to treat at least 4-6 weeks, longer if symptoms are only partially resolved.

Wrong diagnosis

Even though one pathogen may be addressed by the current therapy, some patients have more than one etiology for ongoing diarrhea, abdominal pain, fever and sepsis. If these manifestations continue despite appropriate antimicrobials, consider resistant organisms, fungal, viral or other opportunistic infection such as disseminated histoplasmosis or CMV colitis, loculated undrained collections, or noninfectious causes such as GVHD.

Follow-up

Patients with C. difficile-associated diarrhea are at risk for relapse, particularly if they are treated again with antibacterials for other infections, and should be closely monitored for recurrences of symptoms. Although over-the-counter probiotic preparations have become popular in the general population, their efficacy and safety in the immunocompromised host is not yet known. Saccharomyces is a live yeast and should not be given as a probiotic to immunocompromised patients.

Followup for patients with intra-abdominal abscesses generally relies on repeat imaging to determine the size of the residual collection as well as clinical followup and measuring drain output.

Followup for patients with CMV tissue-invasive disease, as above, is with weekly CMV PCR in blood and also monitoring of symptoms. In some but not all patients, repeat colonoscopy or endoscopy with biopsy may be necessary particularly if symptoms continue despite protracted treatment.

Pathophysiology

Diarrhea in the immunocompromised host may be caused either by direct mucosal invasion (i.e. by a pathogen), chemical damage to the mucosal lining (e.g. GVHD or chemotherapy-induced mucositis) or by alterations in the secretory mechanism without mucosal damage.

Any process that damages the mucosal intestinal lining also predisposes to entry of enteric flora into the bloodstream; thus GVHD may be followed by bacteremia or candidemia.

Biliary tract colonization with organisms such as Enterococcus, Gram-negative bacilli and yeast, may become invasive infection (cholangitis and/or bacteremia) in the setting of obstruction, stricture, bile leak or procedural manipulation of the biliary tree (e.g. through change of an internal/external biliary drainage catheter). Although colonization per se does not need to trigger pathogen-directed antimicrobial therapy, development of fever and elevated LFTs in the setting of previously known colonization should help to determine antimicrobial choice, particularly in the setting of multiresistant organisms.

Extensive use of broad-spectrum antibiotics pre- and post-transplant, including quinolone prophylaxis for subacute bacterial peritonitis prior to liver transplantation, may "select out" for more resistant organisms including VRE, multi-resistant Gram-negatives, and sometimes Candida. Alterations in the normal intestinal flora and skin flora of the groin and abdominal wall can predispose to challenging infections after the transplant operation.

Neutropenia in the HSCT recipient also predisposes to translocation of enteric organisms into the bloodstream.

Epidemiology

Diarrhea in the transplant recipient may have implications for graft function, particularly in kidney recipients whose allografts are sensitive to hydration status. A study by Bunnapradist et al, which included 41,442 patients who received kidney transplants between 1995-2002 in the US, showed that the 3-year cumulative incidence of diarrhea was 22%. Risk factors included female sex, type 1 diabetes and regimens containing tacrolimus and mycophenolate mofetil. Unspecified noninfectious diarrhea was associated with a nearly 2-fold increased risk of graft loss and death.

C. difficile infection increased in the second half of the 1990s with the advent of an epidemic strain associated with enhanced spread and severity. Transplant recipients are at particular risk owing to their immunosuppression and often extensive prior antibiotic therapy.

Intriguing recent data from a case-control study by Dubberke et al suggest an association between CDAD and subsequent new onset GI-GVHD in HSCT recipients. It is possible that the inflammation created by C. difficile as well as perhaps unmasking of gut antigens may underlie this association.

Regarding intra-abdominal infection, a number of studies have addressed the risk factors, microbiology and incidence after different types of organ transplantation. Any anatomical or technical complication may predispose to infection. Troppmann et al described reasons for early relaparotomy in pancreas transplantation, finding an overall relaparotomy rate of 32% (in 1998), with the most common causes being intra-abdominal infection and graft pancreatitis (38%), pancreas graft thrombosis (27%) and anastomotic leak (15%). Pancreas graft loss and recipient mortality were higher when relaparotomy was required.

Everett et al found that 33% of pancreas recipients (in 1994) developed wound infections, particularly with Staphylococcus epidermidis and Candida species. Deep wound infections were associated with poorer outcomes. In more recent years, however, changing microbial epidemiology has seen the rise of MRSA, VRE and multiresistant Gram-negative bacilli. In a study by Loinaz et al (2006), intestinal and multivisceral transplant recipients were at high risk for infection; bacterial infections occurred in 92.7%, and in 80% within the first 2 months after transplant. Risk factors were pretransplant hospitalization, and therapy with mycophenolate mofetil or daclizumab (an IL2 receptor inhibitor).

Risk factors for development of infection with multiresistant Gram-negative bacteria in renal transplantation (particularly extended-spectrum and AmpC beta-lactamase producing E. coli and Klebsiella) were described by Linares et al, and included kidney-pancreas transplantation, prior antibiotics, post-transplant dialysis and post-transplant urinary obstruction.

In addition to increasing resistance in bacteria, Candida species are also showing increasing resistance to fluconazole, and species such as Candida glabrata (mostly R to fluconazole) and C. krusei (always R to fluconazole) are on the rise. With invasive candidal intra-abdominal infection and/or candidemia, obtaining yeast identification to the species level with antifungal susceptibility testing is important in guiding or modifying therapy.

Norovirus infection (a common community-acquired and foodborne gastroenteritis) has been described as having caused viral shedding and intermittent diarrhea for up to 898 days in kidney recipients (Schorn et al). Similarly, Roddie et al described norovirus as a cause of diarrhea lasting up to 6 months in HSCT patients.

Rotavirus, a common cause of diarrhea in healthy infants and children, was found by Liakopoulou et al to be the etiology of diarrhea in 21 allogeneic HSCT patients, in whom it was difficult to distinguish from GVHD. As GVHD requires intense immunosuppression, it is important to rule out these other infectious causes of diarrhea and assess for GVHD with a tissue biopsy before starting GVHD therapy.

Prognosis

In general, prognosis of transplant recipients with diarrhea and/or intra-abdominal infection is affected by their overall degree of immunosuppression; the presence of neutropenia; presence of GVHD or organ rejection; multiorgan dysfunction including need for renal replacement therapy; need for mechanical ventilation; hemodynamic instability; and many other factors.

Prognosis for fulminant C. difficile infection may be improved by emergent colectomy, although mortality is still high.

Presence of multiresistant organisms such as carbapenemase-producing Klebsiella (KPC) and carbapenem-resistant Acinetobacter baumanii (CRAb) severely limits the available antibiotics (often only colistin, amikacin, tigecycline or a subset of those are effective in vitro). Intravenous colistin and amikacin are nephrotoxic, and tigecycline has poor penetration into the urinary tract and is less effective when bacteremia is present.

Preliminary evidence suggests high mortality in pre- or post-transplant patients with invasive infection with these organisms, although long-term colonization without invasive infection has been noted. Better treatment strategies are urgently needed.

Special considerations for nursing and allied health professionals.

NA

<b>What's the evidence?</b><b>Diarrhea in transplant recipients</b>AlhyrabaMGrimSABenedettiEClarkNM. Unusual presentation of cytomegalovirus enteritis after liver and kidney transplantation. Transpl Infect Dis2007;9:343-6.

(Presentation with severe watery diarrhea, shock and acute kidney injury).

BaldwinAKingmanHDarvilleM et al. Outcome and clinical course of 100 patients with adenovirus infection following bone marrow transplantation. Bone Marrow Transplant2000;26:1333-8.

(Large retrospective single-center review that elucidates risk factors and outcomes of adenovirus infection in this population.)

BunnapradistSNeriLWongW et al. Incidence and risk factors for diarrhea following kidney transplantation and association with graft loss and mortality. Am J Kidney Dis2008;51:478-86.

(Epidemiologic study of over 40,000 transplant recipients from the US Renal Data System.)

CoxGJMatsuiSMLoRS et al. Etiology and outcome of diarrhea after marrow transplantation: a prospective study. Gastroenterology1994;107:1398-407.

(Investigation of 150 diarrheal episodes, and detection of a variety of viral and bacterial causes as well as graft-vs-host disease.)

DubberkeERReskeKASrivastavaA et al. Clostridium difficile-associated disease in allogeneic hematopoietic stem-cell transplant recipients: risk associations, protective associations, and outcomes. Clin Transplant2010;24:192-8.

(Updated, rigorously performed study of C. difficile infection in HSCT recipients in the modern era.)

LiakopoulouEMuttonKCarringtonD et al. Rotavirus as a significant cause of prolonged diarrhoeal illness and morbidity following allogeneic bone marrow transplantation. Bone Marrow Transplant2005;36:691-4.

(Unexpected finding of protracted courses for rotavirus diarrhea in HSCT recipients.)

RiddleDJDubberkeER. Clostridium difficile infection in solid organ transplant recipients. Curr Opin Organ Transplant2008;13:592-600.

(Updated, comprehensive review of C. difficile infection in SOT recipients.)

RoddieCPaulJPBenjaminR et al. Allogeneic hematopoietic stem cell transplantation and norovirus gastroenteritis: a previously unrecognized cause of morbidity. Clin Infect Dis2009; 49:1061-8.

(As with rotavirus, increasingly norovirus is being identified as a cause of protracted diarrhea in immunocompromised patients.)

SchornRHohneMMeerbachA et al. Chronic norovirus infection after kidney transplantation: molecular evidence for immune-driven viral evolution. Clin Infect Dis2010;51:307-14.

(More about chronic norovirus infection in transplant recipients.)

WestMPirenneJChaversB et al. Clostridium difficile colitis after kidney and kidney-pancreas transplantation. Clin Transplant1999;13:318-23.

(More on C. difficile in SOT recipients, particularly pediatric kidney and kidney-pancreas recipients.)

<b>Intra-abdominal infection and abscesses in transplant recipients</b>EghtesadBKadryZFungJ. Technical considerations in liver transplantation: what a hepatologist needs to know (and every surgeon should practice). Liver Transpl2005;11:861-71.

(Excellent and highly readable discussion of liver transplant anatomy, making post-transplant complications more understandable.)

EverettJEWahoffDCStatzC et al. Characterization and impact of wound infection after pancreas transplantation. Arch Surg1994;129:1310-6, discussion 1316-7.

(Identification of coagulase-negative staphylococci and Candida as important pathogens in this setting.)

LoinazCKatoTNishidaS et al. Bacterial infections after intestine and multivisceral transplantation. The experience of the University of Miami (1994-2001). Hepatogastroenterology2006;53:234-42.

(Helpful review of a common but difficult complication, and correlations with the use of particular immunosuppressive agents.)

McCarvilleMBAdelmanCSLiC et al. Typhlitis in childhood cancer. Cancer2005;104:380-7.

(Retrospective review of 78 children with typhlitis from St. Jude Children's Research Hospital.)

PayaCVHermansPE. Bacterial infections after liver transplantation. Eur J Clin Microbiol Infect Dis1989;8:499-504.

(Timing, location and microbiology of post-transplant infections.)

SinghNPatersonDLChangFY et al. Methicillin-resistant Staphylococcus aureus: the other emerging resistant gram-positive coccus among liver transplant recipients. Clin Infect Dis2000;30:322-7.

(Exploration of risk factors and prevention for MRSA infection in liver recipients.)

TachopoulouOAVogtDPHendersonJMBakerMKeysTF. Hepatic abscess after liver transplantation: 1990-2000. Transplantation2003; 75:79-83.

(Microbiology and risk factors for this important complication.)

TroppmannCGruessnerACDunnCLSutherlandDEGruessnerRW. Surgical complications requiring early relaparotomy after pancreas transplantation: a multivariate risk factor and economic impact analysis of the cyclosporine era. Ann Surg1998;227:255-68.

(Discussion of both infectious and noninfectious complications of pancreas transplantation, and implications for graft survival or loss.)

<b>Other gastrointestinal infection-related issues in transplant recipients</b>LinaresLCerveraCCofanF et al. Risk factors for infection with extended-spectrum and AmpC beta-lactamase-producing gram-negative rods in renal transplantation. Am J Transplant2008;8:1000-5.

(Timely report of increasing antimicrobial resistance in Gram-negative bacilli in this population.)

SinghNGayowskiTRihsJD et al. Evolving trends in multiple-antibiotic-resistant bacteria in liver transplant recipients: a longitudinal study of antimicrobial susceptibility patterns. Liver Transpl2001;7:22-6.

(Documentation of the rise of MRSA and VRE over the decade of the 1990s.)

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