Transplant Related Complications

When evaluating patients for potential complications of transplantation, it is critical to have a full understanding of the entire treatment course to assemble a reasonable differential diagnosis. Factors that must be taken into account include donor source (allogeneic or autologous), interval post-transplant (early versus late), type of GVHD prophylaxis, infectious prophylaxis, current use of immunosuppressive medications, ablative regimen, and duration of granulocy-topenia. The three major categories of transplant-related toxicities are (1) treatment-related organ damage, (2) infectious complications, and (3) graft-versus-host disease.

Organ Damage

Damage can be manifested early or late after transplantation. Some of the more commonly recognized organ toxicities that are not clearly attributable to infection or GVHD are discussed next.

Idiopathic Pneumonia Syndrome (IPS)/Diffuse Alveolar

Hemorrhage (DAH)/Engraftment Syndrome These processes usually occur during the transplant hospi-talization around the time of neutrophil recovery, more commonly after allogeneic HSCT.109-111 These terms may represent slightly different manifestations of the same poorly understood entity. By definition, they have no clearly identified infectious etiology. Onset can be insidious, but decompensation can be sudden. Radiographic findings can be nonspecific. Mortality is extremely high in patients who require mechanical ventilation. Elevated circulating and bronchoalveolar lavage (BAL) levels of tumor necrosis factor (TNF) and other cytokines have been observed.112,113 Early intervention with high-dose steroids (1g IV solumedrol) even before diagnostic studies are performed may be lifesaving.114 New agents, including TNF blockers such as etanercept (Enbrel), are being studied in clinical trials.115

Interstitial Pneumonitis (IP) Interstitial pneumonitis (IP) often occurs 2 to 6 months after transplant. IP may present as a delayed inflammatory response to a conditioning agent, such as BCNU. In these circumstances, complete responses can be obtained with a steroid dose of 1 mg/kg. IP can be steadily progressive and fatal, particularly after allo-HSCT. IP must be distinguished from infectious pneumonitis.

Hepatic Veno-occlusive Disease (VOD) VOD is a clinical syndrome characterized by painful hepatomegaly, jaundice, ascites, fluid retention, and weight gain.116,117 The onset is usually before day + 35 after stem cell reinfusion, and other causes of these symptoms and signs are absent. VOD develops in 2% to 40% of patients after SCT and ranges in severity from mild, reversible disease to a severe syndrome associated with multiorgan failure and death, with established severe VOD shown to have a mortality rate approaching 100% by day + 100 post-SCT. VOD is believed to be caused by primary conditioning regimen-induced injury to sinusoidal endothelial cells and hepatocytes with subsequent damage to the central veins in zone 3 of the hepatic acinus.118 Early changes include deposition of fibrinogen, factor VIII, and fibrin within venular walls and sinusoids. As the process of venular microthrombosis, fibrin deposition, ischemia, and fibrogenesis advances, widespread zonal disruption leads to portal hypertension, hepatorenal syndrome, multiorgan failure, and death. Despite therapeutic interven tions, including the use of antithrombotic and thrombolytic agents such as prostaglandin Ei and tissue-plasminogen activator (t-PA) with or without concurrent heparin, little success has been achieved in the treatment of severe VOD. Recently, the use of defibrotide (DF), a single-stranded polydeoxyri-bonucleotide that has specific aptameric-binding sites on vascular endothelium, has shown promise in the treatment of VOD.119,120 DF upregulates the release of prostacyclin (PGI2), prostaglandin E2, thrombomodulin (TM), and t-PA both in vitro and in vivo. Moreover, it has been shown to decrease thrombin generation, tissue factor expression, plasminogen activator inhibitor (PAI)-i release, and endothelin activity.

Hemolytic-uremic Syndrome (HUS)/

ThromboticThrombocytopenic Purpura (TTP) Both HUS and, less commonly, TTP can occur after either allo- or autotransplant. HUS/TTP presents 2 to 12 months posttransplant. HUS is manifest by nonimmune-mediated hemolytic anemia characterized by schistocytes on smear, mild azotemia, and mild hypertension.121,122 It is likely precipitated by endothelial damage caused by the ablative regimen or by medications such as cyclosporine, tacrolimus, or siroloimus. HUS is usually self-limited, and treatment is supportive. Plasmapheresis is generally not indicated but isolated reports have indicated some benefit.

Cardiomyopathy Cardiac dysfunction can occasionally be observed after HSCT. It usually presents shortly after completion of conditioning and has been linked with cyclophosphamide.123 It can present as myopericarditis. If patients can be managed through the acute episodes, there may not be permanent dysfunction. Long-term cardiac complications are uncommon and usually can be related to previous anthracycline exposure.

Neurologic Dysfunction Neurologic dysfunction can be an unrecognized problem after HSCT. Potential issues include memory disturbance and learning disability secondary to irradiation, Guillain-Barre syndrome, limbic encephalitis, cyclosporine/tacrolimus-associated hypertensive encephalopathy and seizures, and peripheral neuropathies.124


Cataracts often develop in patients 1 to 5 years after transplant.125 The incidence is increased in patients who received TBI and those on prolonged steroid therapy for GVHD.


Infection is a major cause of morbidity and mortality after transplantation. There are numerous predisposing factors that increase the risk of infection after HSCT, including the following:

• Prolonged granulocytopenia

• Disruption of mucosal barriers

• Extensive use of antibiotics

• Prolonged placement of indwelling venous access

• Delayed recovery of cellular immunity

• Impaired antibody production

• Use of immunosuppressive medications to treat or prevent GVHD

• Immune defects associated with underlying malignancy

• Suppression of immune responses by GVHD itself

It is important to have an understanding of the typical time course associated with risk of developing specific infections after HSCT.126 It is critical to anticipate the development of infection, and considerable attention has been paid to prophylaxis and preemptive therapy. Examples are detailed here:

1. Bacterial: During the transplant hospitalization, gut decontamination with oral nonabsorbable antibiotics is often employed along with systemic agents such as a quinalone. If patients become febrile while neutropenic, typical broad-spectrum coverage is employed. For outpatients with chronic GVHD on steroids, oral antibiotics targeting encapsulated organisms are frequently prescribed on a chronic basis for suppression. Although routine immunoglobulin (IgG) administration is not recommended after transplant, it is recommended that patients whose IgG levels are consistently very low should receive replacement therapy.

2. Fungal: There are data indicating that prophylactic flu-conazole can prevent Candida infections and may improve long-term survival after transplant.127,128 Amphotericin B or a liposomal derivative has been routinely administered for fever and neutropenia unresponsive to antibacterial antibiotics. The newly available voriconazole may ultimately be substituted for amphotericin in this setting.129,130 Moreover, its oral administration and activity against Aspergillus may lead to it being more widely adopted as fungal prophylaxis after discharge for patients on steroids for GVHD.

3. Pneumocystis carinii: Pneumocystis carinii pneumonia (PCP) can develop as early as 1 month after transplant. Prophylaxis should be instituted no later than 30 days post-HSCT and be continued for approximately a year or longer if the patient remains on steroids for GVHD. Trimethoprim-sulfamethoxazole is the most efficacious agent. For patients with allergies or cytopenias, atovoquone or other agents (dapsone, pentamidine) may be substituted, but coverage should never be omitted. Practitioners should be aware of development of PCP in the months after discontinuation of prophylaxis.

4. Viral: Herpesviruses (HSV, VZV, EBV, HHV-6, and, most importantly, CMV) present the largest viral problem after transplant. HSV-induced mucositis can be completely prevented with acyclovir administration during the transplant hospital stay. Many centers will continue acyclovir for 1 year to prevent varicella-zoster virus (VZV) infections, which occur in 30% to 40% of patients not receiving prophylaxis.131 CMV usually occurs 2 to 6 months after transplant and is more common in allotransplant recipients. Patients at highest risk are those who are CMV seropositive and receive cells from a seronegative donor.132 In this circumstance, no anti-CMV immunity is transferred. CMV-filtered, or better still, CMV-negative blood products are essential to prevent nosocomial transmission. Data exist that demonstrate that treatment of patients preemptively with gancyclovir when CMV reactivation can be detected in blood or BAL fluid (before actual development of invasive infection) will reduce the risk of subsequent CMV pneumonitis and improve survival.133-136

Vaccinations are routinely administered to patients 1 and 2 years after HSCT. Diptheria tetanus, inactivated polio, MMR (measles-mumps-rubella), hepatitis B, pneumococcal, and Hemophilus influenzae vaccine are often given.137 The ability to make antibody is impaired post-HSCT and vaccinations are therefore usually delayed until the 1-year anniversary. Recent data suggest that vaccination of the donor before transplant may allow earlier transfer of immunity to the patient.138

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