Section 2: Common Infections
CMV infection is the most common viral infection following intestinal transplant.
Risk factors include :
CMV donor/recipient mismatch.
Administration of lymphocyte depleting antibodies as induction therapy.
Bacterial and fungal infection.
Infection with human herpesvirus-6 and -7.
Clinical manifestations of CMV can vary based upon the degree of involvement and viral replication, but may include:
- Nausea and/or vomiting
- Abdominal pain
- Increased stool output
- Fever and/or chills
- Myalgia and arthralgia
- Pneumonia (presenting with shortness of breath, hypoxia, non-productive cough)
CMV status should be continually monitored post-transplant via PCR in order to ensure early detection of infection and should be used after detection to monitor treatment efficacy. For definitive diagnosis of CMV tissue invasive disease, histology exam with monoclonal antibodies against CMV antibodies and in situ hybridization are the gold standard.
CMV enteritis can sometimes be associated with increased inflammatory infiltration and increased apoptosis, and thus confused with acute cellular rejection. The diagnosis is made by identification of characteristic nuclear or cytoplasmic viral inclusions with confirmatory immunohistochemical staining.
CMV prophylaxis is recommended for intestinal transplant patients with oral valganciclovir for the first 3-6 months post-transplant. If oral medication is not tolerated, then intravenous ganciclovir is utilized.
If a transplant patient becomes CMV positive, then ganciclovir and valganciclovir are considered first line antiviral treatments. If the CMV is ganciclovir-resistant, then foscarnet or cidofovir is utilized. One must be careful with the use of foscarnet and cidofovir because of the nephrotoxic effects, the imbalance in electrolytes, and the bone marrow suppression. In patients with hypogammaglobulinemia in the presence of CMV, immunoglobulin replacement therapy may also be beneficial in overall treatment.
For more information please refer to (14).
Epstein-Barr Virus (EBV)
Infection post-transplant that is most closely associated with risk of developing PTLD. For more information please see the section about PTLD above.
Varicella Zoster Virus
The varicella zoster virus is usually acquired via direct contact or airborne spread. Primary varicella presents with a centrifugal rash that usually spares the palms and soles, accompanied by crusting of older lesions and new popular lesions that appear for several days. Reactivation may include a poplar rash, which is usually preceded by pain or paresthesia.
If a patient has disseminated disease, clinical manifestations may include:
The median time for zoster reactivation is 9 months post-transplant.
Diagnosis can be made via direct fluorescence antibody (DFA) when skin lesions are present. In the presence of disseminated disease, PCR to detect VZV DNA in blood, spinal fluid, vesicle fluid, or tissues may be utilized.
Treatment with intravenous acyclovir should be used in patients with disseminated disease or ophthalmic involvement. It is recommended that at least four weeks prior to transplant that patients get vaccinated with the Oka vaccine if they are seronegative for VZV. If a second dose is planned, the vaccination doses should be at least three months apart.
It is not recommended to vaccinate post-transplant due to risk of disseminated disease. In the event of known exposure to VZV, seronegative patients should receive post-exposure prophylaxis of varicella immunoglobulin within 96 h of exposure.
Please refer to (4) for more information.
Herpes Simplex Virus (HSV)
HSV are a group of viruses usually acquired during childhood. Most seropositive recipients are at risk of viral reactivation within 2-3 weeks of transplantation.
Clinical manifestations include:
Blisters or ulcerative lesions in the orolabial, genital, or perianal regions
Disseminated visceral disease
If there is gastrointestinal involvement, it usually presents with esophagitis, while colitis is rare. (4)
Diagnosis is made with direct fluorescence antibody (DFA) testing of skin lesions, however, the use of HSV DNA by PCR may also be necessary to increase the diagnostic yield.
Treatment of localized disease is usually sufficient with oral acyclovir, valacyclovir, or famciclovirin in patients with reliable intestinal absorption.
For patients with unreliable absorption or disseminated disease, intravenous acyclovir should be used. In the case of acyclovir resistant infections, foscarnet or cidofovir should be utilized. Prompt treatment is crucial as mortality for disseminated disease is high.
The majority of ADV infections are diagnosed within the first six months post-transplant. Risk factors for development include: young age and high immunosuppression. Patients usually present first with small bowel involvement which may then progress to disseminated disease.
Treatment is mainly based on supportive care for the patient with a decrease in immunosuppression. Some transplant centers utilize cidofovir for treatment for ADV, however, it is not FDA approved for this purpose.
Enteric Viruses- Rotavirus and Norovirus
Both rotavirus and norovirus are common causes of prolonged bouts of diarrhea in immunocompromised transplant patients. Both of these viruses are of importance when considering transplant patients because of the possibility of leading to dehydration and electrolyte imbalances.
The viruses also have been shown to be associated with cellular rejection episodes, so close monitoring of patients during the time of viral infection is crucial.
Treatment for the viruses is supportive, particularly paying attention to hydration and nutritional status.
Transplant recipients are at higher risk for severe infections and complications and may also shed respiratory viruses for longer periods of time, even with the use of antiviral therapy.
Influenza and other respiratory viruses have also been associated with allograft rejection. In the early post-operative period, respiratory tract infections account for roughly 15% of the bacterial infections that occur. (4)
Additionally, the majority of lower respiratory infections that occur in this population are caused by RSV, influenza, parainfluenza, adenovirus, and rhinovirus. Due to this, prompt diagnosis and treatment of respiratory viruses is critical to optimal patient care in the post-transplant period.
For specific on respiratory viruses and treatment please refer to this article.
What are commmon infections post-intestinal transplant?
What are common prophylactic (preventative) medications given post-intestinal transplant for infection?
Trimethoprim-sulfamethoxazole (Bactrim) is given for Pneumocystis jiroveci infection.
Nystatin swish and swallow or clotrimazole troche four times daily is given for fungal prophylaxis.
Intravenous ganciclovir or oral valganciclovir is given for CMV prophylaxis.
Section 1: Post-Transplant Complications
Acute Cellular Rejection (ACR)
Acute rejection is one of the most substantial hurdles in intestinal and multivisceral transplant.
Factors that influence the high rate of acute rejection include the:
- Inferior tolerogenecity of the intestine.
- Dynamic interaction between innate and adaptive immunity.
- Development of harmful alloantibodies.
In the first few weeks following transplant, the donor’s graft associated lymphoid tissue (GALT) is infiltrated by recipient lymphocytes.(2) The infiltrated GALT areas are sites of intense immune stimulation and areas where acute rejection is likely to occur. Acute cellular rejection is the leading cause of graft loss in the first two months post-transplant.(2)
If you wish to learn more about the immunological processes behind rejection, please visit the following article.
Clinical symptoms of acute cellular rejection may include:
- Nausea and/or vomiting
- Abdominal pain and/or distention
- Change in stoma output
Diagnosis of acute cellular rejection is made via endoscopic biopsy of the allograft usually in the form of ileoscopy. Adequate tissue sampling is necessary for accurate histological diagnosis. Since the distribution of acute rejection can be patchy, multiple biopsies are needed.
Surveillance biopsies are usually performed on post-transplant patients once per week for the first three months to check for rejection, and then spaced to once every three to six months, or when clinically indicated.
Patients in rejection may or may not present with clinical symptoms.
Histologic features include:
- Mixed but mostly mononuclear infiltrate with activated lymphocytes.
- Crypt injury.
- Increased crypt cell apoptosis.
Depending upon the degree of the apoptosis, inflammatory injury, and mucosal injury determines whether the rejection is considered to be indeterminate, mild, moderate, or severe. Earlier diagnosis provides a better treatment prognosis and outcome. If you wish to review the diagnostic features of acute cellular rejection further please refer to this website.
Treatment for acute rejection is based on the severity. Mild rejection is treated with high doses of corticosteroids and adjustments in levels of tacrolimus. Moderate and severe rejection episodes are treated with anti-lymphocyte antibodies, such as Thymoglobulin or Campath, and/ or alternative immunotherapies, such as anti-CD3 antibodies.
For intestinal transplants, unlike other solid organ transplants, antibody-mediated rejection is poorly defined, and the frequency and clinical significance remains uncertain.
For what is known, antibody-mediated rejection usually develops within the first two weeks after intestinal transplant in the presence of circulating immunoglobulins (IgG). In this post-transplant period, there is development of donor-specific antibodies (DSAs), which have been shown to contribute to both acute and chronic rejection.
Monitoring of DSA levels along with biopsies and clinical correlation can help with diagnosis of antibody mediated rejection.
For more information refer to (2,6).
This type of rejection develops months to years after the transplant has been completed, and after acute rejection episodes have subsided. It appears to be a combination of both antibody and cell mediated rejection.
Pathologically, there is myointimal hyperplasia with intraluminal narrowing of the mesenteric, serosal, and submucosal vasculature. The medium to larger sized arteries are more likely to show the signs of chronic rejection. The luminal narrowing of the vessels in chronic rejection lead to ischemic injury and lack of perfusion to the mucosa, thus causing sloughing of the epithelial cells. Overall, there is fibrosis and scarring of the transplanted organs. The only way to definitively diagnose chronic rejection is through a full thickness biopsy of the graft to look at the histology.
Risks for chronic rejection include:
- Acute rejection within the first month of transplant.
- Isolated small bowel graft.
- In many reports it has been shown that including the liver in the graft has an immunoprotective effect in preventing rejection.
- Greater number of acute rejection episodes.
- Older recipient age.
Symptoms of chronic rejection include:
- Abdominal pain and/or distention.
- Increased output from ostomy.
- Poor oral intake and/or decreased appetite.
- Weight loss.
For more information refer to (8).
Graft vs. Host Disease (GVHD)
GVHD occurs in all types of transplant, however, it is of major concern to intestinal transplant due to the large amount of lymphoid tissue in the intestine.
Risk factors include:
- Young age.
- Transplant of multivisceral organs.
- Immunodeficiency disorders.
- History of splenectomy.
Clinical presentation varies based on the epithelial damage to the target organ (skin, liver, or intestine):
- Mild pruritis, initial skin eruption presenting as a macular erythematous rash present on the upper trunk, neck and feet;
- Blisters may occur on the palms, soles, and abdominal skin;
- Widespread erythema may indicate a toxic epidermal necrolysis;
- Mouth or tongue lesions;
- Perianal rash or eczema;
- Native GI tract ulceration,
- Native liver dysfunction;
- Bone marrow suppression.
Diagnosis is based on a skin biopsy for histopathologic diagnosis and evaluation and detection of donor chimerism. Further evidence of GVHD include high clinical suspicion, and a high proportion of donor cells detected by FISH, Y chromosome PCR, or HLA staining in affected recipient tissue or peripheral blood.
If a patient is exhibiting clinical symptoms of abdominal pain, nausea, emesis, and/or diarrhea, then endoscopic evaluation of the native GI tract to evaluate for histologic evidence of GVHD may be warranted. One should also do bloodwork to assess the function of the liver.
It is important to note that the morphologic characteristics of intestinal GVHD and acute cellular rejection are similar. Diagnosis of intestinal GVHD can only be made in the biopsies obtained from the native intestine, due to similarities between acute cellular rejection and GVHD.
In self-limited, mild skin cases of GVHD, no treatment may be necessary. In disseminated disease, steroid therapy is the treatment of choice, along with adjustments in immunosuppression.
Please refer to (1,3) for more information.
Intestinal transplant patients require high levels of immunosuppression which proves detrimental when it comes to the kidneys due to the nephrotoxicity of tacrolimus-based immunosuppression. For most intestinal transplant patients on tacrolimus-based immunosuppression, creatinine clearance decreases significantly from pretransplant value.
Since many patients develop poor kidney function, it is critical that general practitioners monitor post-transplant patient renal function closely, and refer to subspecialists early on if indicated.
Malignancy rates are higher in all transplant recipients. The risk of cancers such as Kaposi sarcoma, non-Hodgkin lymphoma, nonmelanomatous skin cancers, and cancers related to viral infections, are significantly increased.
Nonmelanomatous squamous cell and basal cell skin cancers are the most common malignancies in transplant recipients.
Squamous cell cancers tend to develop at a younger age, are typically more aggressive, and metastasize more often.
- Because of this, yearly skin checks with a dermatologist is recommended for all intestinal transplant recipients.
- If a transplant patient has the presence of a suspicious lesion, there should be a low threshold for biopsy and more aggressive treatment for precancerous lesions, such as actinic keratosis.
- Patients with repeated precancerous lesions may benefit from switching immunosuppression to an mTOR inhibitor, such as rapamycin (sirolimus), as it has been shown to reduce the risk of new squamous cell lesions.
- In addition to this, an overall lowering of immunosuppression is recommended to allow control of the malignancy by the patient’s own immune system.
Patients should be encouraged to wear sunscreen, avoid direct sunlight, and cover up when going outside to reduce their risk.
Risk factors for developing skin cancer include:
- History of skin cancer prior to transplant.
- Presence of premalignant skin lesions (warts or keratosis).
- History of exposure to UV rays.
- Older age.
- Male gender.
- Fair skin phenotype.
- Immunosuppression: duration and type.
- Infection related: keratinocytes of transplant recipients are more likely to be infected with HPV than nontransplant individuals.
For other cancers, such as prostate, cervical, breast, and colon, transplant patients are at least at a two-fold increase in risk. All transplant patients should receive appropriate screenings for each of these cancers or as their transplant team sees fit based on his or her history and individual needs, existing co-morbidities, overall life expectancy, and preference for screening. Most transplant centers require annual mammography and pap smear for female intestinal transplant patients as well as annual prostate exam for male patients.
For more information please refer to (10,11).
Avascular Necrosis (AVN
The most common reason for AVN is chronic steroid use.
Generally, transplant patients are on high doses of steroids during transplant and in the immediate post-operative period, and remain on some level of steroids for the remainder of his or her life.
Because of this, many intestinal and multivisceral transplant patients will develop some extent of AVN in one or more of his or her joints.
The most common joints for AVN to arise include hips, knees, and ankles; however, it can occur in any joint of the body including the jaw, wrists, hands, elbows, and shoulders.
It is a very painful condition, causing a deep, throbbing, aching bone pain that is usually made worse by activity.
In the early stages, treatment is based on symptom relief. If a patient's status allows, NSAIDs may be recommended.
Topical anti-inflammatory agents, such as Diclofenac, may be prescribed to help alleviate some of the joints' pain.
Other modalities, such as ice, may help to relieve swelling.
Assistive devices, like crutches or walkers, may help alleviate the stress placed on the joints and reduce pain.
In advanced disease, and when joints have collapsed, joint replacement or fusion may be recommended.