GI in the Immunocompromised Host: GI in the Immunocompromised Host: Organ Transplant

0:00Welcome to Board Pearls. This is episode one of four of the GI in the Immunocompromised Host chapter, in the Special Populations and Acute or Supportive Care module. This episode is the solid organ transplant recipient and the five causes weighed at every gastrointestinal, GI, symptom. The first patient is a kidney recipient with diarrhea. His case shows how time since transplant narrows the list, how cytomegalovirus, CMV, is prevented and why the lung needs the longest course, how CMV colitis is diagnosed and treated, how mycophenolate injury is told apart from CMV and managed, and why a simple antifungal makes tacrolimus toxic. The second patient is a liver recipient with a small bowel mass, and her case shows when a post-transplant lymphoma responds to less immunosuppression and when it needs chemotherapy.

0:54Here's the first patient. A fifty-two-year-old man received a deceased-donor kidney transplant five months ago and takes tacrolimus, mycophenolate mofetil, and prednisone. His mycophenolate was increased six weeks ago after a borderline rejection episode. For three weeks he's had five or six watery stools a day without blood or fever. He finished CMV prophylaxis two months ago.

1:17His watery diarrhea, starting weeks after his mycophenolate dose went up, most likely means mycophenolate enteropathy, a dose-related drug injury of the intestinal lining. That diagnosis is reached only after the other causes are weighed, because every GI symptom in a solid organ recipient is weighed against five: CMV, mycophenolate enteropathy, calcineurin inhibitor toxicity, post-transplant lymphoproliferative disorder driven by Epstein-Barr virus, and Clostridioides difficile. About forty thousand solid organ transplants are done in the United States each year, and roughly a fifth of recipients have a GI complication in the first year.

1:55Time since transplant is what narrows the five. The first month is dominated by surgical complications, line-related and hospital-acquired infections, primary graft non-function, hepatic artery thrombosis and bile leaks in liver recipients, and acute cellular rejection. Months one to twelve are the peak window for opportunistic problems, with CMV the most common pathogen, mycophenolate enteropathy the most common drug toxicity, and C. difficile the most common bacterial enteric infection.

2:25Beyond a year, the list shifts to the cumulative cost of immunosuppression: chronic calcineurin inhibitor nephrotoxicity and new cancers, including skin cancer and lymphoproliferative disorder, along with late community infections and recurrence of the original disease, such as primary sclerosing cholangitis, PSC, viral hepatitis, or autoimmune hepatitis, as chapter twenty-four covers. At five months, he's in the window where CMV, mycophenolate, and C. difficile all peak, so he's tested for all three.

3:00His CMV risk depends on his serostatus and on his prophylaxis. Donor-positive, recipient-negative, written D plus R minus, carries the highest risk, because the recipient has no prior cellular immunity to CMV. D plus R plus and D minus R plus are intermediate, and D minus R minus is lowest. Universal prophylaxis with valganciclovir, nine hundred milligrams daily, has cut symptomatic disease to under five percent.

3:30The duration of prophylaxis follows how intense the immunosuppression is and how much CMV the donor organ carries. Lung recipients need six to twelve months, because the risk of bronchiolitis obliterans demands intensive immunosuppression and the lung graft carries the most CMV-laden donor lymphoid tissue. Heart recipients need six months, liver recipients three to six, and kidney recipients three, because kidney recipients have the lightest immunosuppression and the smallest donor viral burden. D plus R minus recipients get the upper limit for every organ, and many programs extend to twelve months. Because CMV disease can appear after prophylaxis ends, many programs continue surveillance polymerase chain reaction, PCR. His prophylaxis ended two months ago, so late CMV is possible.

4:19Finished prophylaxis and a negative blood test don't exclude CMV colitis. CMV colitis causes fever, diarrhea that's often bloody, pain, and weight loss, with deep linear or punched-out ulcers mainly in the right colon and terminal ileum that mimic inflammatory bowel disease. Blood PCR is the right first test, but a positive result doesn't prove tissue invasion, and a negative one doesn't exclude colitis confined to the tissue. Diagnosis needs a biopsy from the ulcer base, where the inclusions concentrate, with CMV immunohistochemistry, which is more sensitive than standard staining. His blood CMV PCR is negative, so he still needs a colonoscopy with biopsies.

5:04Had his biopsies shown CMV colitis, he'd have been treated with intravenous ganciclovir, five milligrams per kilogram every twelve hours adjusted for kidney function, until the viremia cleared, then oral valganciclovir, with immunosuppression reduced as far as his graft allowed. Resistance and the salvage drugs, maribavir, foscarnet, and cidofovir, are covered in chapter thirty-three. Letermovir, a terminase inhibitor, is used only for prophylaxis, in hematopoietic cell transplant and, since twenty twenty-three, in high-risk D plus R minus kidney recipients, never for treatment.

5:42His colonoscopy shows patchy segmental colitis with skip areas, a picture like Crohn disease. His biopsies show dilated, atrophic crypts, eosinophilic crypt abscesses, and prominent crypt apoptosis, with negative CMV immunohistochemistry, and his C. difficile test is negative.

5:59Those findings, with his recent dose increase, confirm mycophenolate enteropathy. Mycophenolate mofetil and enteric-coated mycophenolic acid cause a dose-dependent enteropathy in about a fifth of solid organ recipients. It mimics Crohn disease, with segmental colitis and skip lesions, and its histology, crypt distortion, dilated atrophic crypts, eosinophilic crypt abscesses, and apoptosis, overlaps with graft-versus-host disease. It's told apart from CMV by negative immunohistochemistry and blood PCR, together with a recent dose increase, formulation switch, or interacting drug. It's told apart from graft-versus-host disease by the host, because mycophenolate enteropathy occurs after solid organ transplant, while gut graft-versus-host disease follows hematopoietic cell transplant, except in rare liver recipients, and by the absence of skin or liver involvement.

6:54His treatment follows from the mechanism, direct dose-dependent toxicity to the crypt epithelium from drug in the colon. The first step is reducing the dose by twenty-five to fifty percent. Switching from mycophenolate mofetil to enteric-coated mycophenolic acid resolves symptoms in a substantial subset, by moving absorption further along and reducing colonic exposure while keeping systemic immunosuppression. Azathioprine is substituted only in refractory cases, because its purine-analog mechanism lacks this colonic toxicity.

7:26His dose is reduced with his transplant team, and he's told to expect improvement over two to four weeks, the time the crypt epithelium needs to renew itself. Treating his colitis as Crohn disease with a biologic would have added immunosuppression on top of a drug injury.

7:42Two months later his diarrhea has resolved, but a new drug causes a new problem. He develops oral thrush and starts fluconazole, and two weeks later he has tremor, headache, and a sharply risen creatinine. His tacrolimus level is high.

7:47He has calcineurin inhibitor toxicity from a drug interaction. Tacrolimus and cyclosporine are extensively metabolized by hepatic CYP3A4, and interactions cause most toxic levels in stable patients. His case is the classic one: a new azole for thrush or Candida vaginitis inhibits CYP3A4 and drives tacrolimus into the toxic range. So tremor with a rising creatinine in a transplant recipient sends the eye first to anything new on the medication list.

8:28The drugs that raise calcineurin inhibitor levels are worth knowing as a group. They include the azole antifungals, fluconazole, itraconazole, ketoconazole, voriconazole, and posaconazole; erythromycin and clarithromycin, with azithromycin the safer macrolide; verapamil and diltiazem; the hepatitis C protease inhibitors voxilaprevir and glecaprevir; grapefruit juice; and imipenem, ceftazidime, metoclopramide, and cimetidine. Amiodarone with sofosbuvir is a separate danger, severe bradycardia, and the combination is avoided. The inducers that lower levels are rifampin, phenytoin, phenobarbital, carbamazepine, and St. John's wort. Isoniazid inhibits CYP3A4, but in a regimen with rifampin, rifampin's effect wins.

9:20Over the long term, he's watched for the toxicity of calcineurin inhibitors themselves. Tacrolimus causes chronic nephrotoxicity, neurotoxicity with tremor, headache, and occasionally seizures, hypertension, post-transplant diabetes, and rarely thrombotic microangiopathy, and cyclosporine adds hirsutism and gingival hyperplasia. Both constrict the renal arterioles, afferent more than efferent, causing chronic ischemic nephropathy. Tacrolimus-associated thrombotic microangiopathy is managed by switching the calcineurin inhibitor, not by plasma exchange alone.

9:56If his kidney function declines, the mTOR inhibitors sirolimus and everolimus are the substitution of choice, because they block T-cell proliferation downstream of interleukin-2 signaling without constricting renal vessels. Their own toxicities, hypertriglyceridemia, fluid retention, mouth ulcers, and impaired wound healing, reflect mTOR's roles in lipid metabolism, sodium handling, mucosal turnover, and tissue repair.

10:24As a kidney recipient, he's also at risk of BK virus, which causes interstitial nephritis and ureteric stenosis, with a rising creatinine and BK viremia, and which only rarely involves the gut. It's managed by reducing immunosuppression, because immune recovery is what clears BK, with cidofovir or leflunomide considered for refractory disease in selected centers.

10:46The fourth of the five causes is lymphoma. A sixty-one-year-old woman had a liver transplant eight months ago as an Epstein-Barr virus, EBV, seronegative recipient of a seropositive donor. She has fever, weight loss, abdominal pain, and a small bowel wall mass on computed tomography, CT.

11:05She most likely has post-transplant lymphoproliferative disorder, PTLD, an EBV-driven lymphoid proliferation that occurs in one to twenty percent of solid organ recipients. It's most common after intestinal and multivisceral transplants and least common after kidney transplants, and the risk is greatest in seronegative recipients of seropositive donors, especially children, whose first EBV exposure comes after transplant, under heavy immunosuppression. That describes her serostatus.

11:37PTLD is often extranodal, involving the GI tract, the lungs, the central nervous system, or the liver graft. The World Health Organization, WHO, divides it into four categories: early lesions, polymorphic disease, monomorphic disease, most often diffuse large B-cell lymphoma, and classical Hodgkin-like disease. Her biopsy shows a CD20-positive monomorphic lesion.

12:01Her treatment is staged, and each response decides the next step. Immunosuppression is reduced first, to the lowest tolerable level and often by half, with her transplant team, because EBV-driven proliferation partly reverses when immune surveillance returns. CD20-positive disease, most cases, then gets rituximab, three hundred seventy-five milligrams per square meter weekly for four doses.

12:27Her response to rituximab is itself prognostic. Complete responders continue with four more rituximab cycles, because their clones are still under immune control. Incomplete responders get four cycles of R-CHOP, rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone, because their clones have escaped it. That approach spares responders chemotherapy they don't need. CD20-negative PTLD, of T-cell, plasmacytic, or natural killer cell type, gets chemotherapy specific to its histology, because rituximab has no target.

13:04Her plan is reduced immunosuppression and four weekly doses of rituximab, then reassessment. In high-risk recipients like her, serial EBV DNA measurements allow action before disease appears, and the trend is more reliable than any single value.

13:20Here are the traps the boards set in these patients. Ignoring time since transplant. Undertreating D plus R minus recipients, or forgetting late CMV after prophylaxis ends. Excluding CMV colitis on a negative blood PCR. Calling mycophenolate enteropathy Crohn disease or graft-versus-host disease, or escalating immunosuppression for it. Missing a new azole or macrolide behind tacrolimus toxicity, or forgetting that rifampin lowers levels. Giving R-CHOP before reducing immunosuppression and trying rituximab. And giving rituximab for CD20-negative disease.

13:56So, start to finish. Every GI symptom after solid organ transplant is weighed against CMV, mycophenolate, calcineurin inhibitors, PTLD, and C. difficile, with time since transplant narrowing the list. CMV is prevented by serostatus with valganciclovir, for three months in kidney, three to six in liver, six in heart, and six to twelve in lung, longest for D plus R minus recipients. CMV colitis is diagnosed from the ulcer base with immunohistochemistry and treated with ganciclovir and less immunosuppression.

14:31Mycophenolate enteropathy is treated by reducing the dose or switching to the enteric-coated form. Tacrolimus toxicity sends the search to a new azole or macrolide, and an mTOR inhibitor replaces the calcineurin inhibitor when kidney disease progresses. PTLD is treated by reducing immunosuppression and giving rituximab, adding chemotherapy when the response is incomplete.

14:52Episode two is the stem cell transplant patient: neutropenic enterocolitis and graft-versus-host disease.

15:00For the full chapter, the practice vignettes, and the topic-tagged question bank, head to board pearls dot com. You'll find the rest of the series on Apple Podcasts, Spotify, or wherever you listen to podcasts. That brings us to the end of episode one of four of chapter thirty-four, and I'll see you in the next one.