GI in the Immunocompromised Host: GI in the Immunocompromised Host: Gut in Leukemia

0:00Welcome to Board Pearls. This is episode two of four of the GI in the Immunocompromised Host chapter, in the Special Populations and Acute or Supportive Care module. This episode is the gut in leukemia, from induction chemotherapy through stem cell transplant, followed in one woman. Her induction chemotherapy shows why a neutropenic cecum fails, why it's imaged and not scoped, which antibiotics cover what crosses its wall, and when antifungals and surgery come in. Her transplant then shows how the days since transplant narrow the cause of diarrhea, how gut graft-versus-host disease is staged and proven, why cytomegalovirus, CMV, is always excluded, and what comes after steroids fail.

0:42Here's the patient. A forty-seven-year-old woman with acute myeloid leukemia is in induction chemotherapy with cytarabine. On day twelve, her absolute neutrophil count is sixty, and she develops a fever of thirty-nine degrees, right lower quadrant pain, and loose stools.

0:58She has neutropenic enterocolitis, also called typhlitis, an injury of the cecum and right colon during profound neutropenia. It occurs with an absolute neutrophil count below five hundred, especially below one hundred, during cytotoxic chemotherapy, most often acute leukemia induction: cytarabine for acute myeloid leukemia, or intensive regimens for childhood acute lymphoblastic leukemia. Chemotherapy injures the mucosa, and bacteria or fungi then cross the damaged wall. The cecum is the most vulnerable segment because of its limited blood supply, its distensibility, and its bacterial load.

1:35Her presentation is the classic triad of fever, neutropenia, and right lower quadrant pain, during cytarabine induction. Some patients present instead with right upper quadrant pain, nausea, vomiting, and diarrhea, sometimes bloody, depending on how much of the right colon and terminal ileum is involved.

1:54Her diagnosis is confirmed with a scan, not a scope. Computed tomography, CT, of the abdomen and pelvis with intravenous contrast shows cecal and right colon wall thickening over four millimeters, fat stranding in the mesentery, sometimes pneumatosis intestinalis, gas in the bowel wall, and free air if the bowel has perforated. Colonoscopy is generally contraindicated, because the thinned, friable bowel can perforate. Her CT shows a nine-millimeter cecal wall with stranding and no free air, so no endoscopist is called.

2:28Her treatment is conservative, and the antibiotics are chosen for the organisms crossing her bowel wall. She gets bowel rest, intravenous fluids, electrolyte replacement, and broad intravenous antibiotics against gram-negatives, anaerobes, and Pseudomonas aeruginosa. Colonic flora, the gram-negatives and anaerobes, are what cross the damaged wall, and Pseudomonas colonizes the gut of heavily treated oncology patients on prior antibiotics. Piperacillin-tazobactam or a carbapenem, meropenem or imipenem, covers all of them in one drug, and she gets piperacillin-tazobactam.

3:05Other measures are added for specific problems. Vancomycin is added when gram-positive coverage is needed, because central venous lines bypass the skin barrier and are the main source of gram-positive bacteremia in these patients. Nasogastric decompression is added for ileus or persistent vomiting. Granulocyte colony-stimulating factor, filgrastim or pegfilgrastim, speeds neutrophil recovery when neutropenia is prolonged.

3:33If her fever persists, her coverage widens to fungi. Empiric antifungal therapy is added after seventy-two hours of persistent fever or sepsis despite optimal antibacterial coverage, because invasive fungal infection, most often Candida or Aspergillus, is the main superinfection in prolonged neutropenia. The options are an echinocandin, caspofungin or micafungin, or liposomal amphotericin B. The seventy-two hours count from her first antibacterial dose, and she's still febrile at three days, so she starts an echinocandin.

4:08Surgery is held for complications that medical care can't manage: perforation, hemorrhage that persists despite correction of clotting, full-thickness necrosis, sepsis that persists despite optimal therapy, or an abscess that fails percutaneous drainage. Mortality in severe cases approaches half. Free air on a repeat CT would end her conservative care. Instead, her neutrophils recover, her fever settles, and her pain resolves.

4:35She reaches remission and receives an allogeneic hematopoietic cell transplant from a human leukocyte antigen, HLA, mismatched unrelated donor, using peripheral blood stem cells after myeloablative conditioning. On day thirty-two she develops a maculopapular rash on her palms and trunk, a rising bilirubin, and diarrhea of about one point six liters a day.

4:56Her rash, rising bilirubin, and diarrhea at day thirty-two point to acute graft-versus-host disease, in which donor T cells attack the recipient's skin, liver, and gut. The day after transplant narrows the cause of diarrhea, so her timing is checked first. About twenty thousand allogeneic transplants are done in the United States each year, and their GI complications follow a calendar. The first twenty-one days are dominated by conditioning toxicity, with mucositis, nausea, vomiting, and diarrhea that can mimic graft-versus-host disease but doesn't need its treatment. Engraftment syndrome comes around neutrophil recovery, about days seven to thirty, with fever, rash, non-cardiogenic pulmonary edema, and diarrhea, and responds to a short course of steroids.

5:46Classical acute graft-versus-host disease presents from day fifteen to one hundred, and late-onset acute disease beyond day one hundred is now formally recognized. Sinusoidal obstruction syndrome, also called hepatic veno-occlusive disease, presents within twenty-one days of myeloablative conditioning with weight gain, painful hepatomegaly, and hyperbilirubinemia. Day thirty-two, with skin, liver, and gut involved, fits acute graft-versus-host disease.

6:19Her transplant carried every major risk factor, and her gut involvement is the most dangerous kind. Acute graft-versus-host disease occurs in about forty percent of allogeneic recipients despite prophylaxis with a calcineurin inhibitor plus methotrexate or post-transplant cyclophosphamide. It targets the skin, with a maculopapular rash; the liver, with cholestatic hyperbilirubinemia; and the gut, with anorexia, nausea, vomiting, diarrhea, hematochezia, ileus, and pain. Gut involvement carries the worst prognosis, and steroid-refractory gut disease has a mortality above half. Risk rises with HLA mismatch, with peripheral blood stem cells more than marrow and marrow more than cord blood, and with myeloablative rather than reduced-intensity conditioning, and she has all three.

7:09Her gut disease is staged by daily stool volume, under the Glucksberg-Seattle system. Stage one is five hundred to nine hundred ninety-nine milliliters a day, or persistent nausea with upper-gut disease on biopsy. Stage two is one thousand to one thousand four hundred ninety-nine milliliters. Stage three is one thousand five hundred to two thousand milliliters. Stage four is over two thousand milliliters, or severe pain, ileus, or hematochezia. The overall grade combines the gut, skin, and liver stages, and grade three to four is the group in which steroid-refractory disease is deadliest. At one point six liters a day she's stage three, and her stool is measured every day, because the volume sets her stage.

7:52Serum biomarkers refine her prognosis. Under the Mount Sinai Acute Graft-versus-Host Disease International Consortium, MAGIC, criteria, REG3-alpha and ST2 are combined into an Ann Arbor score at diagnosis, and a higher score predicts higher non-relapse mortality and guides trial enrollment and how intensively she's treated. TIM3 has emerged as a third marker in late presentations.

8:18Her diagnosis needs tissue proof, and the biopsy is also how CMV is excluded. A rectosigmoid biopsy is preferred, because it has a high yield with low procedural risk in a patient with low platelets. The key finding is crypt apoptosis, bright eosinophilic apoptotic bodies in the crypt epithelium, sometimes called popcorn lesions. The Lerner system grades the biopsy from scattered apoptotic bodies, through crypt destruction and crypt dropout, to total loss of the mucosa.

8:46CMV colitis also causes crypt apoptosis, mimicking graft-versus-host disease, and the two coexist often enough that every workup includes CMV polymerase chain reaction, PCR, and immunohistochemistry on tissue. Starting high-dose steroids over an unrecognized viral colitis would deepen her immunosuppression against the virus.

9:09Other causes are excluded before treatment is escalated: mycophenolate injury, conditioning toxicity before day twenty-one, cord colitis after a cord blood transplant, Clostridioides difficile, and viral enteritis from rotavirus, norovirus, adenovirus, or BK virus. Adenovirus can cause a hemorrhagic, ulcerating colitis in these patients, because without T-cell control it reactivates and invades the gut wall, and cidofovir or brincidofovir treats documented systemic disease. BK virus more often causes hemorrhagic cystitis but can cause GI disease by the same failure of T-cell containment. Her biopsy shows crypt apoptosis with crypt destruction, and her CMV and C. difficile tests are negative.

9:56Her treatment starts with high-dose steroids. First-line is intravenous methylprednisolone, two milligrams per kilogram per day, with her calcineurin inhibitor continued, to suppress the donor T-cell attack in every tissue involved. Budesonide, which has high first-pass metabolism and so gives high local exposure with little systemic effect, can be added, or used alone for mild disease limited to the upper gut, but it can't treat skin, liver, or lower-gut disease. With stage three lower-gut disease plus skin and liver involvement, she needs methylprednisolone.

10:29About half of patients respond to steroids, and the rest are called steroid-refractory at day five to seven, or sooner if the disease progresses. By day six, her stool volume hasn't fallen, so she's steroid-refractory.

10:45Steroid-refractory acute graft-versus-host disease is treated with ruxolitinib, a JAK1 and JAK2 inhibitor, five to ten milligrams twice daily. It was approved by the Food and Drug Administration in twenty nineteen after a randomized trial showed a higher day-twenty-eight response than the best available therapy, and it works by interrupting the Th1 and Th17 cytokine signaling that drives effector T-cell injury. She starts ruxolitinib at the five-to-seven-day point, because steroid-refractory gut disease is too lethal to wait on a drug that has already failed.

11:20If ruxolitinib fails, later options each target a different pathway, chosen by which tissues are involved. Extracorporeal photopheresis induces regulatory T cells and works best in skin-predominant disease. Anti-tumor necrosis factor, TNF, agents, etanercept or infliximab, block the donor T-cell TNF that drives gut epithelial apoptosis. Mycophenolate broadly suppresses lymphocyte proliferation. Vedolizumab blocks alpha-four-beta-seven integrin from binding MAdCAM-1, keeping donor T cells out of the gut specifically. Tocilizumab blocks interleukin-6, the main cytokine in late or refractory disease. And mesenchymal stromal cells are used in trials.

12:05Graft-versus-host disease after day one hundred can also become chronic, with a different picture: esophageal strictures and webs, sicca syndrome, and obstructive lung disease, managed with long-term immunosuppression, corticosteroids, and steroid-sparing agents.

12:21Here are the traps the boards set in these patients. Scoping a neutropenic patient with typhlitis. Forgetting Pseudomonas coverage, or antifungals after seventy-two hours of fever. Treating conditioning toxicity before day twenty-one as graft-versus-host disease. Staging gut disease without measuring stool volume. Starting steroids without excluding CMV and C. difficile. Using budesonide alone for lower-gut disease. Waiting too long to call disease steroid-refractory. And missing ruxolitinib as the next step.

12:51So, start to finish. Fever, neutropenia, and right lower quadrant pain during chemotherapy is typhlitis. It's confirmed with CT, colonoscopy is avoided, and treatment is bowel rest with antibiotics covering gram-negatives, anaerobes, and Pseudomonas, adding antifungals for fever beyond seventy-two hours and granulocyte colony-stimulating factor for prolonged neutropenia. Surgery is for perforation, bleeding, necrosis, or uncontrolled sepsis.

13:22After allogeneic transplant, diarrhea from day fifteen onward, often with rash or cholestasis, suggests gut graft-versus-host disease, staged by daily stool volume. It's confirmed by rectosigmoid biopsy showing crypt apoptosis, always with CMV and C. difficile excluded. Treatment is methylprednisolone two milligrams per kilogram, with budesonide alone only for mild upper-gut disease, and ruxolitinib if there's no response in five to seven days.

13:50Episode three is the patient with human immunodeficiency virus, HIV.

13:55For 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 two of four of chapter thirty-four, and I'll see you in the next one.