Hematopoietic stem cell transplant-complications (bone marrow transplant complications; cord blood transplant complications; stem cell transplant complications)

Hematopoietic stem cell transplant complications

Also known as

Bone marrow transplant complications

Cord blood transplant complications

Stem cell transplant complications

Related conditions

Veno-occlusive disease, sinusoidal obstruction syndrome

Idiopathic pneumonia syndrome

Capillary leak syndrome

Septic shock

Immune compromise, immunodeficiency

Adrenal insufficiency

Hemorrhage

Mucositis

Airway obstruction

Altered mental status

Seizure

Graft versus host disease

Graft failure

1. Description of the problem

What every clinician needs to know

Pediatric hematopoietic stem cell transplant (HSCT) patients may require intensive care for a variety of conditions that may be otherwise be common to the ICU, such as respiratory distress or septic shock, but are often substantially more severe or complex for several reasons: (1) toxicity of the HSCT preparative regimen (chemotherapy, immuno/biotherapy +/- radiation); (2) pancytopenia and history of multiple transfusions; (3) immune compromise; (4) antineoplastic therapy prior to HSCT; (5) comorbidities occurring either pre- or peri-transplant; and (6) the presence of graft versus host disease (GVHD), caused by alloreactivity).

Indications

Indications for HSCT encompass a wide spectrum across pediatrics including malignancies (leukemias, lymphomas and solid tumors), conditions predisposing to cancer (paroxysmal nocturnal hemoglobinuria, myelodysplastic syndrome), bone marrow failure syndromes (idiopathic aplastic anemia as well as congenital marrow failure syndromes including Fanconi anemia, dyskeratosis congenita and Diamond-Blackfan anemia), hemoglobinopathies (sickle cell anemia, beta thalassemia major), primary immune deficiencies (Wiskott-Aldrich syndrome, and severe combined immunodeficiency syndrome or SCID, cartilage-hair hypoplasia, CD40 ligand deficiency, common variable immunodeficiency disease or CVID, and nucleoside phosphorylase deficiency), autoimmune diseases (inflammatory bowel disease, juvenille rheumatoid arthritis, systemic lupus erythematosus), macrophage and granulocyte disorders (severe congenital neutropenia or Kostmann’s syndrome, Swachman-Diamond, leukocyte adhesion, Chediak-Higashi syndrome and chronic granulomatous disease), hemophagocytoses (hemophagocytic lymphohistiocytosis or HLH, familial hemophagocytic lymphohistiocytosis or FEL, X-linked proliferative storage diseases (leukodystrophies, mucopolysaccharidoses such as Hurler’s, Maroteaux-Lamy and Sly’s syndromes) and bone diseases (osteogenesis imperfecta, osteopetrosis).

While the intent of HSCT in the vast majority of these diseases is cure, the HSCT process itself can be inherently destructive to the body. Intensive care, support and interventions stand to rescue the patient from otherwise fatal complications of therapy and require a high level of collaboration among intensive care and transplant providers.

Clinical features

There are two broad types of HSCT: (1) autologous (patient receives back their own previously collected bone marrow or peripheral blood stem cells, most commonly after high-dose chemotherapy given to consolidate remission of malignancy or eradicate residual disease, or to reset the immune system in the case of autoimmune disease); and (2) allogeneic (patient receives healthy donor bone marrow, peripheral blood stem cells or umbilical cord/placental blood to restore normal marrow/immune function where it is deficient, allow otherwise potentially lethal intensive anti-cancer treatment, and provide alloreactivity that may eliminate minimal residual malignant disease).

Key management points

HSCT practitioners are increasingly using reduced intensity or non-myeloablative preparative regimens to condition patients prior to receiving the HSC graft. This move toward reduced intensity regimens on the one hand may lead to decreased incidence of toxicity and thus lower frequency of ICU transfer. On the other hand, reduced intensity regimens have allowed for HSCT in patients not previously eligible for transplant due to poor overall functional status, uncontrolled infection or poor organ function. Thus many reduced intensity HSCT recipients may find their way to the ICU after all.

2. Emergency Management

In addition to the usual primary assessment conducted by the intensivist for all patients presenting to the ICU, there are several key features of the HSCT patient that must be swiftly ascertained to provide optimal care and anticipate new events. Primary patient features of the patient include:

• Autologous or allogeneic transplant, which will determine whether GVHD may occur.

• Graft source (cord blood, bone marrow or peripheral blood stem cells) which may impact on speed to marrow recovery.

• Underlying disease or indication for transplant, which will help indicate unique risks for the patient as well as potential prognosis for survival.

• Day post-transplant, which will impact on complications likely to occur, types of infections likely and expectation of timing for marrow recovery.

A second tier of information should be gathered, including:

• Current blood counts, status of engraftment and recent degree of transfusion dependence.

• Pre-transplant organ function, including renal, pulmonary and cardiac evaluations, as well as changes in those organ functions since admission.

• Details of the preparative regimen including use of total body irradiation, craniospinal boost radiation, either full or reduced intensity chemotherapy, and use of biologic agents such as antibodies (antithymocyte globulin, alemtuzumab and others) that may impact on organ toxicities and status of immune function.

• Estimated prognosis for survival of patient when they entered HSCT, which may guide discussions and decision making. For example, a sickle cell disease patient with a matched sibling donor may have upwards of 95% disease free survival, while estimates for a multiply recurrent acute lymphoblastic leukemia patient in third remission with an unrelated marrow donor may fall to the 20% range.

• Concomitant medications, including immunosuppressants (steroids, calcineurin inhibitors (tacrolimus, cyclosporine), low-dose methotrexate, mycophenolate, sirolimus, anticytokines), diuretics, antihypertensives, growth factors, symptomatic medications (analgesics, antiemetics) and antimicrobials (both for prophylaxis, specific treatment and empiric treatment).

• History of corticosteroid exposure and other factors predisposing to adrenal insufficiency.

• Isolation precautions. HSCT patients are by definition immune compromised to varying degrees and many have or are suspected to have active infections that may be transmissible within the ICU. Institutional precautions for HSCT patients should be discussed and followed as well as any additional precautions for infections or colonizations of the specific patient. In most instances, precautions for HSCT patients will differ from and be more stringent than standard universal precautions otherwise applicable in the hospital.

3. Diagnosis

VOD/SOS

Veno-occlusive disease of the liver (also known as sinusoidal obstruction syndrome), while not exclusive to HSCT (it may occur uncommonly after chemotherapy or exposure to other toxins outside of the HSCT setting) is a common HSCT complication. The diagnosis is a clinical one, characterized by the triad of tender hepatomegaly, hyperbilirubinemia and fluid retention/weight gain in the absence of other explanations for these findings. VOD/SOS is caused by injury from the myeloablative preparative regimen. It typically presents in the period after the preparative regimen until about 3 weeks after the regimen is complete, but is known to occur later more rarely. VOD/SOS incidence varies based on definitions of the disease as well as specific patient risk factors, but can be estimated to occur in 10% to 60% of patients receiving fully myeloablative regimens. Patient specific factors that raise the risk of VOD include use of busulfan, cyclophosphamide or total body irradiation as preparative regimen elements, prior use of gemtuzumab ozogamicin (Mylotarg, which is used to treat acute myelogenous leukemia by targeting CD33 expressing cells and thus may be toxic to liver sinusoids) and pre-HSCT liver disease irrespective of etiology.

The diagnosis of VOD/SOS is not typically made by liver biopsy, as the concomitant thrombocytopenia and often unstable clinical status makes for a less than ideal candidate for invasive procedures. If biopsy is necessary to exclude other conditions, transjugular rather than percutaneous approach can substantially decrease the risk of biopsy complications. In most patients, the diagnosis is made clinically according to the following factors: (1) weight gain of 5% above baseline; (2) tender hepatomegaly; and (3) bilirubin of 2.0 or greater. Common associated findings in the VOD/SOS patient include edema and ascites, thrombocytopenia with acute increase in platelet transfusion requirement, acute renal dysfunction and right-sided sympathetic pleural effusion.

Serum chemistry profile should include fractionated bilirubin, as the hyperbilirubinemia of VOD/SOS is predominantly direct. Transaminases are not typically elevated at onset but may elevate as VOD/SOS continues due to hepatocyte injury and necrosis from progressive sinusoidal fibrosis.

Meticulous attention to fluid status is standard of care for the HSCT patient throughout the hospital course, and should continue in the ICU. Serial weights in addition to strict monitoring of volume intake and output of all routes will help in the overall delineation of trends, contributing to both establishing/confirming diagnosis and assessing impact of therapeutic interventions.

Differential diagnosis should include cholestasis associated with cytokine effects of sepsis, post-shock from a period of decreased liver perfusion, medications or parenteral nutrition. However VOD/SOS may also coexist in these situations. Hyperbilirubinemia is common in the HSCT patient and is not specific to VOD/SOS, nor is weight gain and fluid retention, thus continual reassessment of differential diagnosis is warranted.

Abdominal ultrasound with attention to liver size and portal vessel flow may provide confirmation of the VOD/SOS diagnosis, but the absence of detectable portal flow disruptions does not rule out VOD/SOS. Classic ultrasound findings in VOD/SOS include hepatomegaly, attenuation or reversal of portal flow, ascites, elevated hepatic artery resistive indices, gall bladder wall edema and periportal edema. Periodic ultrasonography may be useful in reassessments during therapy.

4. Specific Treatment

The mainstay of VOD/SOS treatment is supportive, with aggressive management of fluid overload to prevent the cascade of clinical deterioration that may ensue should VOD/SOS progress. Commonly patients have been fluid restricted and receiving intermittent loop diuretics on the BMT unit prior to ICU transfer, but require an increase in dose and/or frequency, or transition to continuous infusion. Furosemide is the most commonly employed loop diuretic.

Where aggressive diuresis fails, renal replacement therapies can be effective in managing fluid overload. Use of continuous venovenous hemofiltration is preferred over intermittent hemodialysis, since CVVH allows more finely titratable volume shifts than HD, which is often not tolerated in the acutely ill HSCT patient.

Where the capability exists to perform CVVH, this intervention should be considered earlier rather than later in the course of the critically ill HSCT patient with VOD/SOS, as very severe VOD/SOS is uniformly fatal and thus CVVH is unlikely to yield meaningful benefit if it is reserved as a last resort.

Acute renal dysfunction is common in VOD/SOS and may be exacerbated by the intravascular volume depletion necessary to stabilize the disease. Efforts to preserve renal blood flow may include titration of intravascular volume status and use of inotropic support. Hyper- and hyponatremia are common. Comprehensive review of potentially nephrotoxic agents must be undertaken on at least a daily basis, and dose adjustments made in consultation with a clinical pharmacist.

Thrombocytopenia, already existing in the HSCT patient due to the preparative regimen, commonly becomes acutely more severe due to consumption/destruction in the liver vasculature. Platelet counts should be checked more frequently (e.g. 3 to 4 times per day) rather than daily, with transfusion as necessary.

Other coagulopathy may coexist, thus basic coagulation (“DIC” or at minimum PT/PTT) profile should be monitored regularly and supplementation given as needed to correct coagulopathy. It may also be helpful to screen for deficiency of vitamin K dependent clotting factors, again with replacement as indicated.

The hepatomegaly of VOD/SOS is painful, and along with third spacing of fluids often leads to pleural effusion, pulmonary infiltrates, and respiratory insufficiency or even failure. Patients with even early VOD/SOS should exercise aggressive pulmonary toilet measures and close clinical monitoring for hypoxemia, tachypnea and other signs of respiratory distress.

Therapies directed at the underlying pathogenesis of VOD/SOS have been employed for both prevention and treatment of VOD/SOS, but none are consistently found to provide significant benefit. Interventions have included use of drugs directed at the coagulation cascade such as unfractionated or low molecular weight heparin, tissue plasminogen activator (tPA, associated with significant bleeding), prostaglandin E1, and activated protein C; agents directed at hepatocyte/sinusoidal preservation such as vitamin E, glutamine, and N-acetylcysteine; and mechanical shunts to reduce portal pressure.

Defibrotide, which has antithrombotic and fibrinolytic effects, has been employed more recently with a more favorable bleeding risk profile, though definitive role remains unclear, and clincial trials are ongoing.

5. Disease monitoring, follow-up and disposition

Serial assessment of laboratory parameters to include coagulation profile, complete blood count, serum electrolytes, and serum hepatic profile should occur at least daily, with some tests conducted more frequently as necessary to treat and monitor anemia, thrombocytopenia, renal function and electrolyte disturbance.

Stabilization and ultimately improvement of VOD/SOS is characterized by improvement in severity of thrombocytopenia, and slowing of rise then decline in serum bilirubin. Serum creatinine may not improve until the patient is able to liberalize hydration status. Respiratory compromise associated with VOD/SOS typically results from pleural effusion and may take longer to improve and resolve.

Prognosis

VOD/SOS may range from mild to severe disease. Mild VOD/SOS will spontaneously resolve in the majority of patients, with no expectation of permanent organ injury. In the ICU setting, patients with mild VOD/SOS may require intensive care for other, coexisting complications, in which case the VOD/SOS component should be seen as reversible and not expected to be fatal. Moderate VOD/SOS characterizes the more likely pediatric ICU candidate, and with aggressive management of fluid disturbance and associated renal and pulmonary disfunction should be considered a very salvagable situation with an “all hands on deck” approach. Patients with very severe VOD/SOS are not likely curable, and can be recognized by a very steep upward climb in the serum bilirubin, peaking well above 15 g/dL, that does not reverse with aggressive supportive measures. Such patients are at very high risk for multisystem organ failure and death.

What's the evidence?

Strasser, SI, McDonald, GB, Applebaum, Forman, Negrin, Blume. “Gastrointestinal and hepatic complications”. Thomas' Hematopoietic Cell Transplantation. 2004.

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