Upper Gastrointestinal Symptoms and Signs

The approach to SOT patients with esophageal or gastric symptoms is influenced by a high frequency of nonspecific symptoms as harbingers of serious infection (for example, CMV infection presenting as nausea and vomiting) and by the rapidity with which disease can progress. GERD is the most common cause of heartburn and midchest pain, particularly following lung transplantation (see lung transplant earlier), but viral and fungal esophagitis may underlie these symptoms, particularly after chemoprophylaxis has been discontinued. Candidal esophagitis is seen with particular frequency in those with diabetes; other risk factors include use of broad-spectrum antibiotics, high-dose immunosuppression, and the presence of a Roux-en-Y anastomosis in liver transplant recipients. Severe necrotizing fungal esophagitis can lead to perforation, which can have a fatal outcome in up to one third of patients. Odynophagia, dysphagia, or hematemesis should lead to consideration of an esophageal infection; herpesviruses (CMV, HSV) and fungal species (Candida) are responsible for the largest proportion, but unusual organisms can be seen.⁶³ Dysphagia secondary to pill esophagitis may develop in SOT recipients, caused by antibiotics, antivirals, potassium chloride, bisphosphonates, and NSAIDs. Esophageal strictures following severe esophageal infection have been reported and may present a long time after eradication of the organism.

Anorexia, nausea, and/or vomiting are common following SOT, particularly early in the post-transplant course.^15,47,48 These symptoms are often related to herpesvirus infections or to medications (including immunosuppressive drugs), and thus, endoscopic evaluation is necessary for diagnosis in most patients. Tacrolimus (Prograf) is a macrolide lactone that can cause nausea, abdominal pain, and diarrhea, often leading to anorexia, food aversion, and weight loss. These side effects are dose dependent and can be managed with dose reduction or, more rarely, drug discontinuation. Sirolimus (Rapamune), a newer macrolide immunosuppressant, has a GI side effect profile similar to tacrolimus. MMF (CellCept) is an inhibitor of nucleic acid synthesis with gastrointestinal side effects of nausea, vomiting, and diarrhea, often requiring dosing modifications. A formulation of mycophenolic acid delayed-release tablets (Myfortic) appears to have significantly fewer gastrointestinal side effects with similar therapeutic efficacy.⁶⁴ Less common causes of anorexia and nausea include pancreatitis, cholecystitis, or cystitis. Rarely following SOT, graft-versus-host disease (GVHD) presents with fever, skin rash, and gastrointestinal symptoms, particularly nausea, vomiting, and diarrhea.^65,66 Endoscopic evaluation with biopsy is essential if GVHD is suspected and skin lesions are absent, recognizing that other conditions such as viral infections and drug reactions can have a GHVD-like histologic pattern.⁶⁷ Symptomatic gastroparesis is frequently seen in the setting of lung transplant but is less often reported in the setting of other solid organ transplant.⁵² CMV and VZV may rarely involve intestinal neural plexuses, leading to intestinal dilation or gastroparesis. H. pylori infection may be associated with symptomatic dyspepsia, gastritis, and gastroduodenal ulceration, but there is no relationship between the use or degree of immunosuppression and H. pylori colonization; its incidence is similar to that seen in the nontransplant setting.²

Diarrhea and Constipation

Colonic and small bowel complications (diverticulitis, ischemic colitis, malignancy, and infections) have been reported to occur following all types of SOT. Early in the post-transplant setting, infections predominate. Diarrhea is commonly infectious and may be accompanied by fever,⁶⁸ abdominal pain (46%), nausea (32%) and vomiting (22%).^69,70 The microbes usually responsible are CMV and Clostridium difficile, but the literature describes a wide range of organisms in SOT recipients, particularly when they are cared for in infection-endemic areas (for example, adenovirus, rotavirus, coxsackievirus, bacterial enteric pathogens, enterohemorrhagic Escherichia coli, Yersinia enterocolitica, Giardia lamblia, Candida species, cryptosporidium, Enterocytozoon bieneusi, Isospora belli, and Strongyloides stercoralis).⁷⁰ Diagnosis can be made by examination of stool specimens in nearly all cases; the exceptions are CMV, certain parasites, and EBV-LPD. Small intestinal involvement with CMV often causes profuse watery diarrhea with protein-losing enteropathy, particularly if the diagnosis is delayed.⁷¹ Colonic involvement may appear as an inflammatory colitis resulting in bloody diarrhea and is often associated with fever, abdominal distention, and pain.⁷² Diagnosis of CMV may require mucosal biopsy, particularly if blood specimens are negative for CMV DNA or antigen. C. difficile infection may present with a more severe course post SOT, and patients with fulminant colitis and toxic megacolon require prompt surgical intervention to prevent perforation and peritonitis.⁷⁰ Signs of colitis may be subtle due to concomitant immunosuppression. Only about 70% of patients respond to treatment with metronidazole; persistent and more severe cases require oral vancomycin. Recurrence may develop in up to 20% of cases.⁷³ The use of probiotics (e.g., Saccharomyces boulardii) in SOT recipients remains controversial because there have been reports of yeast dissemination and infection in the immunocompromised host.⁷⁴ Intestinal fungal infections can be seen in up to 25% of SOT recipients. In the absence of prophylaxis, intestinal fungal overgrowth and diarrhea can result from antibiotic use or intestinal dysmotility. Common parasitic infections also must be considered in an immunocompromised host, particularly in areas of high endemicity. The protozoa are a much less frequent cause of acute diarrhea post SOT. Microsporidia (E. bieneusi) is a more rarely reported cause of chronic diarrhea, perhaps reflecting the fact that it is often not sought out in the post-SOT setting. Clinically, patients with this infection experience fatigue, intermittent diarrhea, and weight loss. There are no clearly effective therapies for E. bieneusi. Symptoms of colitis or toxic megacolon are most often associated with infection, but in up to 20% of cases, no clear etiology can be found.^70,75 Early recognition, diagnosis, and treatment of colitis can decrease disease-associated mortality. Eosinophilic colitis with diarrhea has been reported with the use of tacrolimus and cyclosporine. Histologically this is characterized by eosinophilic colonic infiltrates and peripheral eosinophilia. Elevated serum immunoglobulin E may be present in some patients.

Drug-related diarrhea is seen in up to a third of SOT patients, most commonly with tacrolimus or sirolimus.^70,76 MMF causes watery diarrhea in up to 30% of patients, and may require dose reduction or discontinuation. The mechanism of MMF-induced diarrhea is unclear. There have also been reports of altered tacrolimus metabolism and absorption in patients suffering from MMF-induced or other causes of chronic diarrhea. Antithymocyte globulin (ATG) and anti–T cell antibody (OKT3) therapies are associated with diarrhea, which predictably lasts for three to four days and resolves spontaneously. Most cases of immunosuppressant-induced diarrhea can be managed with dose manipulation, but some are so severe that discontinuation of the immunosuppressant is required. Diarrhea also can be caused by magnesium-containing preparations prescribed to correct renal magnesium wasting and by antibiotics prescribed either prophylactically or therapeutically. Noninfectious diarrhea has been reported to increase the risk of graft loss and mortality.⁷⁶

Constipation is seen in less mobile recipients who are receiving certain medications (e.g., narcotics, calcium- and aluminum-containing antacids, anticholinergics). This is generally responsive to increased patient mobility, decreased use of narcotics, use of methylnaltrexone,⁷⁷ and therapy with laxatives and senna.

Abdominal Pain

Abdominal complications are common, affecting up to 30% of patients following SOT.⁷⁸ Symptoms may be mild despite the presence of life-threatening complications. All patients with abdominal pain should be aggressively evaluated, with particular attention to whether the patient requires urgent surgery or a specific medical treatment. Most recipients with abdominal pain will not need surgery.

The intra-abdominal conditions presenting with pain that require urgent surgery are abscess, perforation, severe colitis, appendicitis, intestinal obstruction, intestinal ischemia, and acute cholecystitis. These disorders may appear in the early post-transplant period. Immunosuppression may mask symptoms and suppress the host response, leading to a delay in diagnosis and increase in mortality. Most transplant patients with acute appendicitis have right lower quadrant pain. Overall, intestinal perforation occurs in less than 5% of SOT recipients, although the incidence may be slightly higher in the setting of lung transplant.^14,79 Perforation may occur spontaneously without clear etiology, but it is associated with colon diverticula in up to two thirds of cases (particularly renal transplant recipients) and ischemia in 15%. Perforation, especially of a diverticulum, carries a mortality of up to 55%.^30,72 Risk factors for the development of colonic perforation include diverticular disease, immunosuppression (particularly glucocorticoids), CMV infection, fungal infections (e.g., mucormycosis), unrecognized lymphoma (EBV-LPD), colon cancer, and ischemia.^2,72 Abdominal radiographs and helical computed tomography (CT) scans can confirm the presence of perforation, but may not reveal its source before surgery. Diverticular perforation is especially common after renal transplant, often leading to abscess formation and fistulization, sometimes without causing severe pain or findings of peritonitis. Pretransplant colonic screening for diverticulosis in patients less than 50 years of age has not been shown to predict post-transplant colonic perforations. SOT recipients also are at increased risk for the development of cholelithiasis.⁸⁰ Factors related to gallstones include cyclosporine, obesity, and cystic fibrosis as an underlying disorder. Abdominal pain is frequently associated with tissue-invasive CMV disease. Although generally producing a diffuse pattern of mucosal edema, CMV may also cause focal ulceration, perforation, high-grade stricture, and intestinal obstruction (see Fig. 34-1). The first manifestation of disseminated VZV infection is often severe abdominal pain related to intestinal pseudo-obstruction and visceral neuropathy. Early treatment of both CMV and VZV infection results in improved survival.

Abdominal pain may also be a manifestation of transplant-related complications that do not usually have a dire outcome. Pain has been reported with oral tacrolimus, sirolimus, and MMF. Abdominal pain is seen in up to 19% of patients taking MMF and can significantly limit its use.⁸¹ The etiology of MMF-induced pain been postulated to involve local irritant and inflammatory effects as well as interference with rapidly dividing intestinal cells, a hypothesis supported by a study showing fewer gastrointestinal complications with delayed-release mycophenolic acid (Myfortic), than with MMF.⁶⁴ Narcotic-induced ileus is common after surgery. Care must be taken to rule out an infectious etiology such as CMV or VZV, both of which can involve the intestinal nerve plexuses.² Noninfectious pseudo-obstruction often can be managed conservatively with nasogastric decompression, vigorous correction of electrolyte imbalance, and withdrawal of opiates. Opioid-related gut symptoms can also be blocked with the use of methylnaltrexone while not interfering with central pain relief.⁷⁷ Neostigmine can be safely used for treatment of intestinal pseudo-obstruction in the transplant setting.⁷² Surgical intervention may be required in the setting of massive colon dilation. Acute pancreatitis has been reported in 1% to 2% of renal transplant recipients, up to 6% of liver transplant recipients, and up to 18% of heart transplant recipients; it may have a fatal outcome.⁸² Acute pancreatitis is associated with CMV infection, hypercalcemia, cholelithiasis, biliary manipulation, malignancy, recent alcohol ingestion, and medications such as azathioprine, cyclosporine, tacrolimus, and glucocorticoids. Treatment of pancreatitis in the post-transplant setting is identical to that in the non-transplant setting, except for the need to exclude viral infection and some immune suppressive medications.

Pneumatosis intestinalis may be discovered during abdominal imaging after SOT as an incidental finding, but can also be a manifestation of life-threatening intestinal ischemia or infection with a gas-forming organism. Pneumatosis intestinalis is associated with CMV infection, C. difficile colitis, and sepsis and can be seen in patients receiving glucocorticoid therapy. The majority of patients require no specific intervention, and the gas collections resolve spontaneously unless caused by ischemia or an infection with a clostridial organism

Gastrointestinal Bleeding

When gastrointestinal bleeding occurs, it is often secondary to infectious ulcers. Noninfectious causes of hemorrhage include NSAID gastroduodenal ulcers, diverticular bleeding, anastomotic bleeding, and ischemic colitis. The current incidence of gastroduodenal ulcer disease in the transplant population is about 5%, with perforation rates of less than 1%.³ Prophylaxis with histamine (H₂)-receptor antagonists or proton pump inhibitors decreases the occurrence of ulcer disease in this population; both therapies are equally effective.³ Patients infected with H. pylori prior to transplantation are more likely to develop peptic ulcer disease following transplant.⁸³ In the absence of effective antiviral prophylaxis, viral ulcerations are the most common cause of intestinal bleeding. HSV-associated esophageal ulcers may present with severe bleeding even in the absence of esophageal symptoms. CMV can lead to ulceration throughout the entire intestinal tract. Although CMV esophageal ulcers are usually shallow (see Fig. 34-1A), ulcers elsewhere can be deep, erode into vessels, and lead to severe bleeding. CMV can also cause diffuse inflammation similar to that seen in idiopathic inflammatory bowel disease (see Fig. 34-1C and D). VZV and EBV are much less often associated with gastrointestinal (GI) bleeding. Although EBV itself does not cause mucosal ulceration, EBV-LPD can form mucosal tumors that can ulcerate and bleed (see Fig. 34-2). Massive bleeding has been reported in the setting of invasive fungal infection.

Gastrointestinal Malignancy

Post-transplant lymphoproliferative disorders (PTLDs), lymphoid proliferations, or lymphomas associated with EBV infection (EBV-LPD) occur in 1% to 20% of transplant recipients.⁸⁴ Although most PTLDs are of B cell origin, T cell lymphoma has been reported. EBV reactivation generally presents in the early post-transplant setting as a mononucleosis-like syndrome with diffuse adenopathy and fever; detection of EBV DNA in the bloodstream may allow preemptive therapy, with lower doses of immune suppression or treatment with rituximab.⁸⁵ PTLD manifesting later than a year after transplant is more insidious, often presenting with extranodal disease or visceral involvement. Gastrointestinal PTLD can present with diarrhea, intestinal obstruction (see Fig. 34-2B), bleeding, or perforation. Mucosa-associated lymphoid tissue-type (MALT) lymphomas have also been reported in the post-transplant setting.⁸⁶ Fortunately, they often respond to reduction in immunosuppression, antibiotics (if associated with H. pylori), surgery, or chemotherapy.

The risk of cancer in long-lived transplant recipients is higher than in the general population, particularly for lymphomas, skin cancers, colorectal and anal cancers, and Kaposi’s sarcoma.⁸⁷ Patients who underwent liver transplant for cirrhosis secondary to primary sclerosing cholangitis are at high risk for the development of colonic dysplasia and diffuse colon cancer related to underlying ulcerative colitis.⁸⁸ If severe colonic dysplasia is discovered, colectomy can be performed safely as early as 10 to 12 weeks following transplant.

Hepatobiliary Complications

Drug-induced hepatotoxicity can be problematic after a transplant because this diagnosis is often one of exclusion. Azathioprine hepatotoxicity presents as an elevation in serum aminotransferases in up to 10% of recipients; injury is generally cholestatic, with centrilobular hepatocyte damage. Azathioprine is being used less often following organ transplantation. A less common presentation is the slow insidious development of sinusoidal obstruction syndrome (veno-occlusive disease), which often manifests as portal hypertension, usually regressing following withdrawal of the drug. Cyclosporine- or tacrolimus-induced cholestasis can occur when blood levels are high. Sirolimus has been reported to cause dose-dependent elevations in serum aminotransferases. Transplant recipients are exposed to numerous other pharmacologic agents that alone, or in combination, can produce cholestasis, fatty liver, hepatitis, or a mixed histologic picture.

Bacterial sepsis can have profound effects on liver function, with severe cholestasis the most common finding (a syndrome called cholangitis lenta).⁸⁹ CMV infection may lead to elevations in hepatic enzymes with either a cholestatic or hepatocellular picture. CMV hepatitis is more frequent and severe in liver transplant recipients, compared with recipients of other organs.⁶ VZV and HSV infection can lead to hepatitis and fulminant liver failure.²⁶ EBV hepatitis is seen in 2% to 3% of patients after SOT but is generally mild. Primary or recurrent disease with either HCV or HBV can lead to liver disease in the post-transplant setting. These viruses may be transmitted to the recipient by any solid organ from the donor. Immunosuppression leads to a marked increase in HCV titers and in some cases, to aggressive hepatic disease post-transplant, with progression to cirrhosis within 3 to 10 years.⁹⁰ The results of treatment of hepatitis C in the post-transplant setting with interferon-α (INF-α)–based regimens are disappointing. Sustained virologic clearance can be achieved in 10% to 30% of post-LT recipients, but use of interferon-based therapies is limited because of side effects.⁹¹ HCV can be successfully treated in renal transplant recipients, but because the rate of renal graft failure related to INF-α is unacceptable, treatment should not be attempted. It is unknown whether interferon alpha therapy for HCV in HT or LT recipients carries an increased risk of graft failure and its use is not recommended.⁹² Chronic HBV carriers (hepatitis B surface antigen-positive recipients) may develop a hepatitis flare following transplant, but disease often responds to antiviral agents.

Vascular injury associated with liver transplantation may lead to liver dysfunction. Nodular regenerative hyperplasia (with subsequent portal hypertension) and peliosis hepatis have both been reported following renal transplantation.

Organ transplant recipients, particularly following LT, are at high risk for biliary tract disease. Presentation includes acalculous cholecystitis, gallbladder sludge, thickened gallbladder wall, dilated bile ducts, or cholelithiasis.⁸⁰ Gallbladder and biliary disease necessitating cholecystectomy occurs in about 1% to 6% of transplant recipients. Emergent cholecystectomy in the post-transplant setting carries a high mortality (29%).⁸⁰ However, pretransplant screening for gallstones and prophylactic cholecystectomy remain controversial. The etiology of biliary tract disease is multifactorial, including obesity, use of total parenteral nutrition, fasting, biliary strictures, and medications. Cyclosporine is excreted in the bile, where it may precipitate and has been implicated in an increased incidence of cholelithiasis and cholangitis.^27,93 Some centers recommend that biliary calculi be removed prior to transplantation or immediately on discovery after transplantation, but this recommendation is not universal.

Patients who have undergone liver transplantation for hepatocellular carcinoma are at risk for tumor recurrence in the graft, particularly if the lesions were multiple or large prior to transplant. PTLD may also involve the liver.

Ulcers and Tumors in the Gastrointestinal Tract

Mucosal ulcerations may bleed profusely when platelet counts drop after HCT, and in immunocompromised patients, ulcers may have an infectious etiology (e.g., CMV, HSV or fungal infection) that requires specific antimicrobial treatment.⁹⁵ Intestinal ulcerations should be healed before the start of conditioning therapy. CMV, Entamoeba histolytica and C. difficile are causes of colonic ulceration that may mimic idiopathic inflammatory bowel disease. Selected patients with ulcerative colitis and Crohn’s disease have undergone allogeneic and autologous HCT without complications of bleeding, perforation, or dissemination of microorganisms.^96,97 The presence of fecal occult blood should prompt colonoscopy and upper endoscopy before HCT, especially in patients older than 50 years. Endoscopic biopsy may be required for staging some forms of lymphoma with a predilection for gut involvement, such as mantle cell lymphoma.

Diarrhea

Patients with diarrhea should be investigated for organisms that may cause morbidity during the period of immunosuppression after HCT (e.g., E. histolytica, strongyloides, G. lamblia, cryptosporidia, clostridial infections, CMV, rotavirus, adenovirus).⁹⁸ Cryptosporidiosis may be resistant to therapy in an immunosuppressed patient,⁹⁹ but restoration of normal immunity after allogeneic HCT can result in clearance of Cryptosporidia.¹⁰⁰ Similarly, protracted diarrhea related to immune dysregulation can be treated with allogeneic HCT, for example, by restoration of T regulatory cells in children with immundysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome.¹⁰¹ Typhlitis is a syndrome of cecal edema, mucosal friability, and ulceration in neutropenic patients, often associated with polymicrobial sepsis; its cause is usually an intestinal clostridial infection, particularly with Clostridium septicum.¹⁰² After treatment, the risk of post-HCT typhlitis is no different than that of other patients.

Perianal Pain

Pain near the anal canal in a granulocytopenic patient is assumed due to bacterial infection until proved otherwise. Extensive supralevator and intersphincteric abscesses may be present without being apparent on external examination. CMV infection of anal glands may lead to fistula formation. Perineal HSV infection causes painful skin ulcerations. Perianal infections must be treated before HCT.

Fungal Liver Infections

Diagnosis depends on liver imaging (using high-resolution CT or magnetic resonance imaging [MRI]) in conjunction with circulating fungal biomarkers (galactomannan and glucan assays),^103,104 polymerase chain reaction (PCR), or culture of liver biopsy material. Therapy with newer antifungal drugs (caspofungin or azole drugs) should be continued through HCT until engraftment is established, which can effect resolution of intractable fungal liver abscesses.^105–107

Viral Hepatitis in Allogeneic Hematopoietic Cell Transplant Donors

Donors who are viremic with HBV or HCV will transmit virus to their recipients.¹⁰⁸ When two equally HLA-matched donors are available, the uninfected donor is preferred. If the more suitable donor has chronic hepatitis B, it may be possible to prevent passage of virus by treating that donor.^109,110 HBV persisting in donor peripheral blood stem cells may have to be eliminated to prevent passage.^110,111 HBsAg negative/anti-HBc–positive donors can be used if their serum and peripheral blood stem cells are HBV DNA negative. A donor who is naturally anti-HBs positive may be the preferred donor if the recipient is HBsAg positive or anti-HBc positive because adoptive transfer of immunity can lead to clearance of virus.¹¹² If a donor is infected by HCV and if time permits, treatment of the donor prior to harvest of donor cells may render them nonviremic, and much less likely to transmit infection.¹¹³ If HCV is transmitted, the acute phase of HCV infection may cause elevated liver enzymes at two to three months post HCT, after recovery of T cell function; after 10 years the outcome is no different than in transplant recipients without hepatitis C infection.¹¹⁴ In the long term, HCV-infected transplant recipients are at risk for development of cirrhosis and hepatocellular carcinoma.¹¹⁵

Chronic Liver Disease in Candidates for Hematopoietic Cell Transplantation

The risks faced by patients with fibroinflammatory liver disease include fatal sinusoidal obstruction syndrome following some myeloablative regimens and fulminant hepatitis B. In the absence of antiviral prophylaxis, fatal fulminant hepatitis B develops in approximately 15% of hepatitis B-infected HCT recipients.¹⁰⁸ There is a 35% risk of post-HCT reactivation of HBV in patients with isolated anti-HBc antibodies, usually during treatment for acute GVHD.¹¹⁶ Severe hepatitis B has been seen in anti–HBc/anti–HBs-positive patients and in a patient with occult hepatitis B.¹¹⁷ Prior to HCT, liver biopsy should be considered if there is a clinical suspicion of cirrhosis or extensive fibrosis, as these are relative contraindications to transplant even with reduced intensity conditioning regimens.¹¹⁸ A reduced intensity conditioning regimen may allow congenitally immunodeficient children with chronic liver disease to be transplanted successfully, with resolution of liver disease.¹¹⁹

Recent Liver Dysfunction in Candidates for Hematopoietic Cell Transplantation

Patients who come to HCT following recent chemotherapy or radiation therapy that damaged the liver may be at significant risk from additional liver insults after HCT.¹²⁰ These patients must be carefully evaluated with regard to the risk posed by liver-toxic conditioning regimens, particularly those containing cyclophosphamide (CY) or total body irradiation.^121–123 Imatinib (Gleevec) and gemtuzumab ozogamicin (Mylotarg) deserve special mention in this context. Iminatib mesylate (and similar drugs) may cause acute hepatocellular necrosis and multiacinar collapse, with eventual healing by focal fibrosis^124,125; we have successfully given CY-based myeloablative conditioning to patients who recovered from the acute injury but who had patchy fibrosis on biopsy. Gemtuzumab ozogamicin causes sinusoidal liver injury in 3% to 15% of patients¹²⁶ and is a risk factor for fatal sinusoidal obstruction syndrome (SOS) if given in proximity to a liver-toxic myeloablative regimen.^126,127

Gallbladder and Bile Duct Stones

HCT candidates with asymptomatic gallstones (incidentally discovered during CT or ultrasonography) do not require operative intervention.¹²⁸ Patients with symptomatic cholelithiasis or stones in the common duct are at risk for biliary sepsis after HCT.

Iron Overload

HCT candidates with diseases such as thalassemia, aplastic anemia, and chronic leukemia or lymphoma may come to HCT with marked hepatic siderosis. The amount of liver iron can be accurately determined by iron-specific MRI (FerriScan or T2*).¹²⁹ In patients with extreme iron overload, effective pre-HCT iron chelation therapy improves post-HCT survival.¹³⁰ Although some studies suggest an association between excess tissue iron stores and regimen-related toxicity, others have failed to demonstrate this. In most patients the quantitation of tissue iron stores and a decision about iron mobilization can be deferred until after recovery from HCT.

Anorexia, Nausea, and Vomiting

Myeloablative conditioning therapy makes most patients nauseated and anorexic,¹³¹ findings associated with delayed gastric emptying.¹³² Serotonin-antagonist drugs are very effective in relieving symptoms during chemotherapy. Mucositis caused by myeloablative conditioning therapy may lead to oral mucosal swelling, pain, and in severe cases sloughing of pharyngeal and esophageal epithelium, intense gagging, an inability to swallow, vomiting, retrosternal pain, and airway obstruction. Opioid therapy is effective in relieving pain but can lead to gastric stasis and intestinal ileus with worse anorexia and vomiting. Methylnaltrexone, a peripheral mu-opioid receptor antagonist, can block gut opioid symptoms while allowing pain relief.⁷⁷ Appetite and food intake may remain poor for up to three weeks after myeloablative therapy, an effect that is mediated by cytokines that affect appetite (interleukin [IL]-2, IL-6, tumor necrosis factor-α [TNF-α]).¹³¹ Some regimens, notably those that contain very high-dose melphalan or multiple alkylating agents, may cause unusually severe intestinal mucosal necrosis and anorexia.