Critical illness in children undergoing hematopoietic progenitor cell transplantation









  • Outcomes for allogeneic hematopoietic cell transplant (HCT) patients requiring intensive care unit care have improved over the past 2 decades.



  • Both acute and late cardiac complications occur in HCT. Etiologies for this cardiac dysfunction include previous cardiotoxic treatments and therapies such as anthracyclines, cyclophosphamide, irradiation, iron overload, hyperhydration therapies, blood product transfusions, impaired renal function, sepsis, acute graft-versus-host disease (GVHD), transplant-associated thrombotic microangiopathy, and genetic susceptibility.



  • HCT patients experiencing respiratory symptoms, including a new oxygen requirement, deserve prompt evaluation by the critical care team, as they are at risk for rapid development of respiratory failure.



  • Patients undergoing allogeneic HCT experience prolonged immune dysregulation and are at risk for both opportunistic infection and GVHD. Patients who develop GVHD are at high risk for developing other transplant-related toxicities.



  • Neurologic complications contribute significantly to the morbidity and mortality following HCT. Seizures are the most common neurologic complication; encephalopathy, motor function deficits, cranial nerve palsies, visual disturbances, and impaired coordination may also occur.



  • Leukoencephalopathy primarily occurs in HCT patients who receive cranial radiation and/or intrathecal chemotherapy. Peripheral nervous system neurotoxicity also occurs posttransplantation as an immune-mediated complication.



Hematopoietic progenitor cell transplantation has evolved as treatment for a variety of congenital and acquired malignant and nonmalignant disorders. Over the years, the name of this procedure has changed with attempts to be more accurate. Throughout the literature, it has been referred to as bone marrow transplant (BMT), hematopoietic progenitor cell transplant (HPCT), or hematopoietic stem cell transplant (HSCT). Most recently, it is referred to as hematopoietic cell transplant (HCT).


The first successful pediatric BMT occurred in a child with combined immunodeficiency. Reported in 1968, the patient received marrow from a human leukocyte antigen (HLA)-matched sibling. Presently, in adults and children, the majority of allogeneic transplants are performed for the treatment of malignant disorders such as leukemias and lymphomas, although the field continues to expand to include nonmalignant disorders such as autoimmune disorders, metabolic diseases, immunodeficiencies, and hemoglobinopathies. Since its inception, the field of pediatric HCT has demonstrated vast improvements in morbidity and mortality related to transplantation; however, there are still many hurdles to overcome. The major contributors to morbidity and mortality of allogeneic transplantation continue to be relapse of disease, transplant-related toxicity, infection, and graft-versus-host disease (GVHD).


Sources of hematopoietic progenitor cells and identification of donors


HCT involves transplanting hematopoietic progenitor cells from a donor source into a recipient. These stem cells are capable of self-renewal and terminal differentiation that ultimately give rise to myeloid cells, lymphocytes, erythrocytes, and platelets ( Fig. 93.1 ). The donor source of these stem cells can be from the patient/recipient (autologous) or from another individual (allogeneic). The source of the donor (autologous vs. allogeneic) is dependent on the indication for which the transplant is being performed. Traditionally, HCT has been performed using stem cells obtained from bone marrow. However, stem cells can be mobilized into the peripheral blood and harvested for transplant. These peripheral blood stem cells (PBSCs) allow for faster hematopoietic recovery and possibly less tumor contamination than bone marrow when used in autologous transplantation. However, there may be more side effects in the allogeneic setting, particularly increased incidence of GVHD.




• Fig. 93.1


As hematopoietic stem cells divide, they give rise to common lymphoid and common myeloid precursor cells that eventually generate all mature blood lineages of the body. GMP, Granulocyte-monocyte precursors; LT-HSC, long-term hematopoietic stem cells; MEP, megakaryocyte-erythrocyte precursors; NK, natural killer; ST-HSC, short-term hematopoietic stem cells.

(Modified from Leung AYH, Verfaillie CM. Stem cell model of hematopoiesis. In: Silberstein LE, Anastasi J, Hoffman R, et al, eds. Hematology: Basic Principles and Practice . 4th ed. Philadelphia: Elsevier; 2001.)


Umbilical cord blood has also been shown to contain large numbers of stem cells capable of reconstituting hematopoiesis. The first HCT using cord blood was performed in 1988 for a child with Fanconi anemia. Since then, unrelated cord blood stem cells have been used and numerous public cord blood banks have been established worldwide.


In circumstances in which there is no matched unrelated donor or cord blood found in a timely fashion, haploidentical transplantation can be performed using a parent or a sibling as donor. Histoincompatibility barriers of a mismatched transplantation are overcome by using mega-doses of stem cells. However, for this to be successful, a majority of the T cells have to be removed from the graft to prevent severe GVHD. Unfortunately, this increases the risk for severe infection and relapse of the patient’s original disease. , More recently, centers have been using several in vivo and ex vivo graft manipulation techniques to abrogate these risks.


HLAs are expressed on the surface of various cells, in particular white blood cells (WBCs). These antigens are also known as the major histocompatibility complex , with relevant genes on the short arm of chromosome 6. This genetic region has been divided into chromosomal regions, called classes. Classes I and II are important in transplantation. Class I is made up of HLA-A, HLA-B, and HLA-C. Class II is made up of HLA-DR, HLA-DP, and HLA-DQ, as well as variations on these genes. Traditionally, the loci critical for matching for a bone marrow donor are HLA-A, HLA-B, and HLA-DR. HLA-C and HLA-DQ have recently gained importance and are now considered in determining the best available donor. ,


Ideally, a matched sibling donor is the best donor for a patient. However, only 25% of patients with siblings are fortunate to have a matched sibling donor. If there is no sibling donor, an alternative donor is identified using the National Marrow Donor Program (NMDP), which has approximately 12.5 million potential donors and nearly 209,000 cord blood units available for patients who need an HCT. As the degree of mismatch between patient and donor increases, so do the risks of complications from transplantation, especially GVHD and graft failure.


Indications and outcomes


HCT has been used for a variety of diseases. Autologous transplantation has traditionally been used to treat nonhematologic malignant diseases by escalating the doses of chemotherapy to myeloablative doses in hopes of eradicating the cancer. Recently, successive (two or three) autologous transplants have been performed, particularly in brain tumors and neuroblastoma. The rationale of giving hematopoietic stem cells after the chemotherapy is completed is to minimize the period of neutropenia; it is hoped that this will reduce the number of infections and life-threatening complications.


Allogeneic HCT is performed for hematologic cancers. In children, these are most commonly acute lymphoblastic leukemia (ALL) and acute myelogenous leukemia (AML). It is also used to treat hematologic diseases, including sickle cell anemia, thalassemias, and severe aplastic anemia. A variety of immunodeficiencies and metabolic disorders are cured by allogeneic transplant, including severe combined immunodeficiency and hemophagocytic lymphohistiocytosis ( Box 93.1 ).



• BOX 93.1

Current Indications for Pediatric Hematopoietic Progenitor Cell Transplantation


Autologous transplantation





  • Malignant disorders




    • High-risk neuroblastoma



    • Relapsed non-Hodgkin lymphoma



    • Relapsed Hodgkin disease



    • Medulloblastoma



    • Germ cell tumors



    • Brain tumors



    • Relapsed Ewing sarcoma




  • Nonmalignant disorders



  • Autoimmune disorders



Allogeneic transplantation





  • Malignant disorders




    • Acute myelogenous leukemia



    • Acute lymphoblastic leukemia



    • Chronic myeloid leukemia



    • Myelodysplastic syndromes



    • Juvenile myelomonocytic leukemia




  • Nonmalignant disorders




    • Aplastic anemia



    • Fanconi anemia



    • Severe combined immunodeficiency



    • Thalassemia major



    • Diamond-Blackfan anemia



    • Sickle cell anemia



    • Wiskott-Aldrich syndrome



    • Osteopetrosis



    • Inborn errors of metabolism



    • Hemophagocytic lymphohistiocytosis



    • Shwachman-Diamond syndrome



    • Congenital immune deficiencies





Survival from HCT has improved in recent years. In autologous transplantation, the incidence of treatment-related mortality is less than 10%. However, the majority of treatment failures are due to recurrent disease. The event-free survival rate (EFS) for autologous HCT for high-risk neuroblastoma previously ranged from 33% to 66%, but a recent trial using tandem myeloablative autologous transplants demonstrated an improvement to 73.7% EFS. For recurrent or refractory non-Hodgkin lymphoma, the EFS in autologous HCT ranges from 27% to 59%. In relapsed or refractory Hodgkin disease, the EFS ranges from 20% to 62%. ,


Among children with ALL, allogeneic transplantation is generally reserved for patients with high-risk disease, including patients who fail to achieve remission or who relapse after chemotherapy. Among the 1494 patients younger than 18 years receiving an HLA-matched sibling transplant for ALL between 2006 to 2016, the 3-year survival rates range from 45% to 74% depending on their disease status going into transplantation. The corresponding survival rates among the 2827 recipients of an unrelated donor transplant range from 47% to 68%. For pediatric patients with AML transplanted with matched sibling donors between 2006 and 2016, the 3-year survival rates following transplant range from 30% to 70%.


Allogeneic HCT is the treatment of choice for young patients with severe aplastic anemia and an available HLA-matched sibling donor. These patients have had excellent outcomes in recent years, with survival rates ranging from 79% for unrelated donor transplants to 92% for matched sibling transplants. Transplant outcomes for other nonmalignant diseases have also improved, with Fanconi anemia patients having a 5-year overall survival of 60% to 94%, Wiskott-Aldrich disease at 90%, and severe combined immunodeficiency at 71% to 94%. , For inherited metabolic disorders, the overall survival of pediatric patients with adrenoleukodystrophy/metachromatic leukodystrophy is approximately 60% to 89% depending on the degree of neurologic dysfunction prior to HCT. For Hurler syndrome, the overall survival is approximately 95%.


Transplant procedure


Conditioning regimen, stem cell harvesting/collection/cryopreservation, and reinfusion are detailed in this section.


Conditioning regimen


Patients undergoing HCT are subjected to a treatment regimen referred to as a conditioning regimen or preparative regimen prior to infusion of the hematopoietic progenitor cells. The purpose of this preparative regimen is multifold. In cases of malignant disorders, it provides eradication of disease. In addition, the preparative regimen must be immunosuppressive in allogeneic transplantation to allow the donor cells infused to establish themselves in the marrow cavity and overcome host rejection. The precise conditioning regimens can include chemotherapy alone or in combination with radiation. Numerous regimens have been explored and are dependent on the disease for which the transplant is required and the research interests of the institution performing the transplant.


Stem cell harvesting/collection/cryopreservation


Stem cells can be collected or harvested from either bone marrow or peripheral blood. For patients or donors undergoing bone marrow harvest, general anesthesia or regional anesthesia is given. Bone marrow is generally aspirated using special bone marrow harvest needles percutaneously from the posterior iliac crests through numerous passes. The amount of marrow taken is based on the size of the recipient. If there is a significant size discrepancy between the donor and recipient (recipient larger than donor), the donor may lose a significant amount of blood. Donors can be placed on iron therapy after harvest or they can electively store autologous blood ahead of time. A newer technique allows for the collected marrow to be processed with removal of red blood cells (RBCs; particularly necessary in cases of major ABO incompatibility between donor and recipient). These RBCs can be transfused to the donor postoperatively.


PBSCs can be mobilized in patients recovering from chemotherapy (autologous) or by giving allogeneic donors cytokines, such as granulocyte colony-stimulating factor (G-CSF). Their stem cells then can be collected using an apheresis machine in an outpatient setting. Collection of sufficient cells for transplantation may require several apheresis procedures. Stem cells for allogeneic transplantation usually are collected on the day they are anticipated to be reinfused into the patient. Autologous collection of stem cells requires cryopreservation of the cells until the day of reinfusion. Dimethyl sulfoxide (DMSO) is added to the collection product to ensure cell viability, and the cells are frozen in liquid nitrogen until needed.


Stem cells can be collected from umbilical cord blood. After delivery of the infant, sterile umbilical venous access is obtained, and the blood is collected into anticoagulated tubes. This can be done either before or after delivery of the placenta. A sample of this cord blood is used for HLA typing and infectious disease testing; the remainder is cryopreserved.


Reinfusion


The day of stem cell reinfusion is referred to as day 0 for the transplant period. Cryopreserved stem cells are thawed in a water bath under sterile conditions and may be washed to remove the DMSO cryopreservant. Stem cells are then infused into the patient though the indwelling central venous catheter. These cells can migrate into the bone marrow on their own. Blood transfusion–like complications can occur with reinfusion of stem cells; patients are generally placed on cardiac monitors with emergency medications available at the bedside during the infusion. The infusion procedure is generally short, lasting anywhere from approximately 10 minutes to 4 hours, depending on the volume of cells infusing.


Recovery period


After the reinfusion of stem cells, patients wait for count recovery to occur and receive treatment for any toxicities. Allogeneic transplant patients receive immunosuppressive medicines to prevent GVHD. Most patients are hospitalized for the entire transplant procedure, starting with the conditioning regimen. However, there is a trend toward outpatient HCT, particularly in the autologous setting. A typical hospitalization for HCT is 4 to 6 weeks, but it may be prolonged if umbilical cord blood is used or shortened for autologous transplants.


Complications


Patients undergoing HCT are at high risk for complications that may require a stay in the pediatric intensive care unit (PICU). In one series, 19% of pediatric HCT patients required a PICU admission. In other published series, 6% to 25% of pediatric HCT patients required mechanical ventilation. , Because of the high use of critical care services by HCT patients, it is beneficial for the pediatric intensivist to be familiar with their complications.


The reasons for these patients being at high risk for critical illness are multifactorial. Many of these patients are undergoing HCT for an underlying disease that places them at risk for critical illness, such as malignancies, severe immunodeficiencies, and metabolic disorders. To make room for the new hematopoietic progenitor cells, patients are given conditioning regimens with high doses of toxic chemotherapy and/or radiation. This makes them severely immunocompromised, placing them at high risk for opportunistic infections. The conditioning agents themselves cause significant oxidative stress and may be the common denominator behind many of these complications.


While mortality rates for HCT patients requiring ICU care are quite high in comparison with the general ICU population, they appear to be improving. Data from the 1980s showed mortality rates for mechanically ventilated pediatric HCT patients to be near 90%. , However, more recent data indicate that the mortality rates continue to improve, with a report using the Virtual PICU Systems Database demonstrating a mortality rate of 42.5% for HCT patients requiring invasive positive-pressure ventilation. Some of the improvements seen in outcomes over the years may be due to differing characteristics of the patients, as very few studies reported severity of illness scores. In any case, no series reporting on mortality of pediatric HCT patients was able to predict with 100% certainty that a given patient would not survive. Therefore, the critical care and transplant teams must work together and use their best judgment when making recommendations to families regarding appropriateness and duration of critical care services for this complex patient population.


Cardiac complications


Cardiac complications following HCT can occur during the immediate transplant period or can be late sequelae in survivors. The heart may be injured during the transplant process from a variety of pathophysiologic etiologies. First, previous cardiotoxic treatments and therapies, such as anthracyclines and iron overload from frequent RBC transfusions, may predispose the heart to subsequent injury during transplantation. In addition, cardiotoxic therapies, such as cyclophosphamide and irradiation used as part of the preparative regimen, may further injure the recipient heart. Moreover, hyperhydration therapies, blood product transfusions, and impaired renal function may place further stress on the heart. Sepsis, which commonly affects the HCT patient, has also been found to decrease cardiac contractility. More specific to the HCT patient, there are rare reports of acute GVHD affecting the heart and cardiovascular system. Further, transplant-associated thrombotic microangiopathy has been associated with cardiovascular complications such as pericardial effusions and pulmonary arterial hypertension. , Additionally, in a small series of children treated for a primary immunodeficiency with HCT (n = 10), cardiac chamber hypertrophy was reported to occur in those transplanted at less than 1 year of age and who received high-dose corticosteroids for acute GVHD. Finally, there is evidence to suggest that genetic susceptibility may also play a role in HCT-related heart failure. For example, using a nested case-control study design, it was noted that polymorphisms in the NAD(P)H oxidase subunit RAC2 as well as carbonyl reductase CBR1 were associated with a significant increase in the risk of acute heart failure among HCT recipients. These findings suggest that acute heart failure occurs as a result of oxidative stress or metabolic derangements induced by cardiotoxic alcohol metabolites of anthracyclines and that variants of RAC2 and CBR1 modulate this risk.


An analysis of 2821 adult and pediatric patients found that only 26 (0.9%) experienced a major or fatal cardiac complication in the first 100 days after transplant. Seven of the 26 cardiac complications occurred in children. Among the 26 patients with significant cardiac complications, 11 had evidence of heart failure, 5 had pericardial tamponade, and 10 had dysrhythmias. All 11 patients with heart failure died compared with only one each with tamponade or a dysrhythmia. All cases of heart failure occurred between day −6 and day +35. Four of the seven pediatric patients had heart failure. Electrocardiographic abnormalities have been reported in as many as 11% of pediatric HCT recipients.


In another report, the Associazione Italiana Ematologia Oncologia Pediatrica-BMT Group described their transplant-related toxicities in 636 pediatric patients transplanted for acute leukemia. In their experience, the incidence of moderate or severe cardiac toxicity in the first 90 days posttransplant varied by the type of transplant, with autologous recipients experiencing an incidence of 1.9% (4 in 216, 2 deaths) and allogeneic recipients of a compatible related donor experiencing a comparable incidence of 2.4% (7 in 294, 4 deaths). However, recipients of an allogeneic alternative donor experienced a 6.4% rate of these cardiac complications (8 in 126) with all 8 experiencing an early death. In that study, the presence of moderate or severe cardiac toxicity increased the relative risk of an early posttransplant death more than ninefold (relative risk [RR], 9.1; 95% confidence interval [CI], 2.8–29.6) and more so than toxicity to any other organ system. The manifestations of the cardiac disease are varied; they include myocardial ischemia and pericarditis in addition to dysrhythmias, pericardial effusion, and progressive congestive heart failure. One further cardiovascular complication that merits special attention in the pediatric HCT patient is the occurrence of pulmonary hypertension.


Pulmonary arterial hypertension in the setting of pediatric HCT has been reported with increased frequency once it was identified as a potential concern and assessed for with routine screening. In one report, a routine day +7 echocardiogram detected elevated right ventricular pressures in 13% of the patients. In that report and others, pulmonary arterial hypertension was found to be associated with transplant-associated thrombotic microangiopathy. , Additionally, pulmonary arterial hypertension is reported to occur in the setting of patients undergoing transplant for malignant infantile osteopetrosis. Pulmonary venoocclusive disease may also account for episodes of pulmonary arterial hypertension. The incidence of pulmonary venoocclusive disease in HCT patients is speculative given the limited available data. Pulmonary arterial hypertension is reported to be the proximate cause of death in pediatric patients undergoing HCT for hemophagocytic lymphohistiocytosis and idiopathic myelofibrosis. , Independent of the cause, pulmonary arterial hypertension should always be suspected in the pediatric HCT patient with unexplained cardiopulmonary dysfunction, as emergent therapy may be life-saving.


Late cardiovascular toxicity occurring a year or more after HCT has also been reported. Late cardiovascular complications following HCT include heart failure, dysrhythmias, hypertension, and cerebrovascular accidents. Duncan et al. recently reported on late cardiovascular complications among 661 pediatric allogeneic HCT patients. Cardiovascular complications assessed accounted for approximately 4% of survivors, including cardiomyopathy (3%), cerebrovascular accident (0.6%), coronary artery disease (0.2%), and cardiac-related death (0.5%). Several pathologic mechanisms of late congestive heart failure have been offered, including the same mechanisms causing acute heart failure, such as previous cardiotoxic agents (anthracyclines, alkylating agents, thoracic irradiation) in conjunction with cyclophosphamide and total body irradiation during conditioning regimens.


Despite the relatively low incidence of overt cardiac dysfunction, subclinical cardiac dysfunction appears relatively common in pediatric HCT recipients and may portend a poor outcome. For example, in a case control study of 40 consecutive pediatric HCT patients, HCT patients were found to have similar left ventricular ejection fractions as controls. However, the HCT recipients were found to have significantly decreased rate-corrected velocity of circumferential fiber shortening, mitral inflow E velocity, and mitral septal annular E′ velocity. Using speckle tracking echocardiography, HCT patients were also noted to have decreased left ventricular global circumferential systolic strain, circumferential systolic strain rate, circumferential diastolic strain rate, and longitudinal diastolic strain rate. Strain echocardiography has also been used to assess changes in cardiac function among pediatric patients undergoing HCT for sickle cell disease and severe aplastic anemia. This technology has demonstrated initial decrease in function following transplant and subsequent improvement over time.


In another report, 100 pediatric HCT patients underwent a routine scheduled echocardiogram at day +7. At least one abnormality was noted in 30% of the children—most commonly, a pericardial effusion or an elevated estimated right ventricular pressure. Survival was decreased in those children with any abnormality detected. Pericardial effusion has been reported to occur in approximately 17% of pediatric HCT recipients. It is asymptomatic in approximately half of the cases and is rarely the proximal cause of death. Despite that observation, HCT patients with a pericardial effusion have a significantly increased risk of mortality. Additionally, a pericardial effusion may be anticipated in patients with a pretransplant prolonged corrected QT dispersion. , ,


In another assessment, the group at Cincinnati Children’s Hospital began performing screening echocardiograms on all HCT patients admitted to the PICU. They observed abnormalities that required follow-up or intervention in 50% of patients. The most common abnormalities noted were elevated right ventricular pressures, left ventricular systolic dysfunction, pulmonary hypertension, and pericardial effusions. Two-thirds of the pericardial effusions found required pericardiocentesis, and all patients with pulmonary hypertension required treatment with pulmonary vasodilators. In addition to echocardiography and electrocardiography, biomarkers may also identify patients at risk for cardiac dysfunction. Elevations in N-terminal pro B-type natriuretic peptide concentrations at day 14 after stem cell transplant can identify patients at risk of developing cardiac events during the first 6 months after HCT. ,


In summary, cardiac toxicity may present as an acute finding in the immediate posttransplant period with evidence of progressive heart failure, dysrhythmias, and pericardial effusions with tamponade. Late cardiovascular complications are also being studied. Although clinically evident late cardiac complications are being reported, there appear to be several subclinical findings detected by use of more involved testing. The importance of these subclinical findings requires more study and is likely to be better understood as these children age further.


Pulmonary complications


The incidence of HCT-related pulmonary complications in children is reported to be between 12% and 25%. , The need for mechanical ventilation support is the most frequent reason for admission of HCT patients to the PICU. , , Pulmonary complications can be divided into early and late complications ( Table 93.1 ). Early complications occur within the first 100 days after transplant. The division into early and late complications is not absolute but may help the clinician in developing a differential diagnosis. Early complications include infection, periengraftment respiratory distress syndrome (PERDS), pulmonary cytolytic thrombi (PCT), diffuse alveolar hemorrhage (DAH), and idiopathic pneumonia syndrome (IPS). Late-onset complications occur beyond 3 months after HCT and include bronchiolitis obliterans syndrome (BOS), bronchiolitis obliterans organizing pneumonia (BOOP), and IPS.



TABLE 93.1

Pulmonary Complications of Hematopoietic Progenitor Cell Transplantation












































Complications Characteristics Treatment
Early-Onset Pulmonary Complications
Infection Positive test for infection Antimicrobials
Diffuse alveolar hemorrhage Progressive bloody return on BAL Corticosteroids, FFP, plasmapheresis
Idiopathic pneumonia syndrome Diffuse noninfectious lung injury Etanercept
Engraftment syndrome Periengraftment pulmonary edema Corticosteroids
Late-Onset Pulmonary Complications
Bronchiolitis obliterans Obstructive lung disease Corticosteroids, macrolides
Bronchiolitis obliterans organizing pneumonitis Restrictive lung disease Corticosteroids
Idiopathic pneumonia syndrome Diffuse noninfectious lung injury Etanercept
Pulmonary venoocclusive disease Pulmonary hypertension Sildenafil, prostacyclin, defibrotide

BAL, Bronchoalveolar lavage; FFP, fresh frozen plasma.


Early pulmonary complications


Periengraftment respiratory distress syndrome


PERDS occurs just as patients begin to show signs of neutrophil recovery. This syndrome is likely caused by pulmonary leukoagglutination and inflammatory cytokines. Patients may develop fever, rash, fluid retention, capillary leak, and pulmonary edema. In severe cases, patients can develop multiorgan involvement. Engraftment syndrome may be related to a graft-versus-host response or, in some cases, a host-versus-graft response. In mild cases, no treatment is necessary. In more severe cases, particularly if there is lung involvement, corticosteroids may be beneficial. Survival from PERDS is quite good in comparison with other pulmonary complications of HCT, in excess of 90%.


Pulmonary cytolytic thrombi


PCT is a rare pulmonary complication of HCT. It was first described in a small case series of 13 patients published in 2000. Patients in this series presented with fever at a median of 72 days after HCT (range, 8–343 days). Two of the 13 patients also had a cough at presentation. Chest computed tomography (CT) performed on these patients revealed pulmonary nodules. Pathologic exam revealed necrosis and basophilic thromboemboli in the nodules. Immunohistochemical staining demonstrated that the nodules contained entrapped leukocytes and disrupted endothelium.


Subsequent publications containing studies involving PCT describe the pulmonary nodules seen on CT as being bilateral and located primarily in the periphery, subpleural, and basilar areas of the lungs. Further investigation of pathologic samples discovered the leukocytes to be monocytes and described the lung parenchyma adjacent to the nodules to be infarcted, likely secondary to entrapped debris in surrounding vessels. PCT seems to be responsive to treatment with cyclosporine and corticosteroids. Both radiologic and clinical improvement may be observed within 1 to 2 weeks of beginning treatment. , Development of PCT in leukemia patients undergoing HCT may be associated with decreased risk of relapse.


Diffuse alveolar hemorrhage


Alveolar hemorrhage may be infectious or noninfectious in etiology. However, the term DAH in an HCT patient generally refers to a noninfectious etiology. The reported incidence ranges from 1% to 21% of HCT patients, with the highest incidence in patients with mucopolysaccharide storage diseases. , It usually occurs in the early posttransplant period and is characterized by widespread alveolar injury, absence of infection, and progressively bloodier return of bronchoalveolar lavage fluid during bronchoscopy. Patients commonly present with respiratory distress and fever, and less commonly with hemoptysis. It can occur in both autologous and allogeneic transplants. The exact etiology of DAH is unknown, although it is associated with GVHD and engraftment. Endothelial injuries from chemotherapy and radiation, inflammation, undiagnosed infections, and immune-mediated damage related to GVHD have all been postulated as the cause. ,


Conventional critical care practice uses invasive mechanical ventilation with high positive end-expiratory pressure (PEEP) to tamponade bleeding as a first-line therapy in DAH. In addition, successful use of high-dose corticosteroids has been described in case reports of DAH. , However, no prospective studies have proven the benefit of this therapy. , Despite this, corticosteroids remain the standard of care for DAH. Fresh frozen plasma transfusions and plasmapheresis have been tried but are of uncertain benefit. Recombinant intravenous factor VIIa has also been used for refractory bleeding in DAH but has not been found to have an impact on survival. , Intrapulmonary instillation of recombinant factor VIIa and tranexamic acid have been used in both adult and pediatric patients with pulmonary hemorrhage with promising results for hemorrhage control. The use of aminocaproic acid initially appeared promising in a small series of eight patients, but a much larger study failed to demonstrate any benefit.


Idiopathic pneumonia syndrome


The incidence of IPS in pediatric HCT patients has been reported to be between 2% and 15%. , , IPS is usually considered an early complication of transplant, but it has also been described as a late complication. The diagnosis is established using the diagnostic criteria set by an expert panel convened by the National Institutes of Health (NIH) in 1993. Patients must exhibit widespread lung injury as evidenced radiographically by bilateral lung disease, signs and symptoms of pneumonia (cough, dyspnea, or rales), abnormal lung function (increased alveolar to arterial oxygen gradient, pulmonary function testing with restrictive lung disease findings), and absence of an infectious etiology.


The term IPS is often used interchangeably with idiopathic pneumonitis and interstitial pneumonitis in the literature. However, interstitial pneumonitis is the histopathologic description in some cases of IPS. Other cases of IPS will demonstrate histopathologic findings consistent with DAH or BOOP. IPS, interstitial pneumonitis, DAH, BOOP, and BOS are all considered noninfectious pulmonary complications of transplantation. As prevention and treatment of infectious pulmonary complications have improved, these noninfectious complications are now the more troublesome.


Inflammation plays a significant role in the development of IPS. GVHD is known to be associated with high levels of inflammatory cytokines. GVHD has consistently been found to be associated with IPS. , , Because of this association, there is debate in the literature as to whether IPS represents GVHD of the lung. However, the histopathology of IPS often does not resemble that of acute GVHD, which typically involves epithelial cell apoptosis.


Some cases of IPS may be caused by an unidentified infection. A retrospective study of stored bronchoalveolar lavage (BAL) samples from HCT patients with pulmonary complications detected human metapneumovirus in 5 (3%) of 163 patients. Newer metagenomic techniques are being studied to more accurately find respiratory tract pathogens. With improved detection of microbes, a more complete understanding of the pulmonary microbiome is essential in order to understand the role that various microbes play in causing disease.


Because of the role of inflammation in IPS, corticosteroids have been used as therapy but have not been found to be universally efficacious. , Therefore, since tumor necrosis factor-alpha (TNF-α) has been found to be an important mediator in mouse models of IPS, the soluble TNF-α-binding protein, etanercept, has been used in recent years. Etanercept showed promise in an early phase I/II trial when given with systemic corticosteroids to patients with IPS. Ten of 15 patients treated on the protocol were able to be weaned from supplemental oxygen. A retrospective study comparing etanercept and corticosteroids versus corticosteroids alone also demonstrated improved survival in the patients receiving etanercept. These promising results lead to a phase II trial of etanercept in pediatric IPS patients. The phase II results were also encouraging, with a response rate of 71%, 28-day survival of 89%, and 1-year survival of 63%. The results were in contrast, however, to the parallel adult study, in which the 1-year survival was less than 25%. There were significant transplant-related differences between the adult and pediatric patients that could explain the differences in outcomes. The adult patients were also much less compliant with the etanercept dosing in comparison with the pediatric patients.


Late pulmonary complications


Bronchiolitis obliterans syndrome/bronchiolitis obliterans organizing pneumonia


BOS and BOOP are late-onset noninfectious pulmonary complications of HCT. Both complications are associated with chronic GVHD and are much more commonly observed after allogeneic transplant as opposed to autologous transplant. The NIH developed consensus criteria for BOS in 2005, with a proposed amendment in 2009, in order to facilitate communication in the literature. The amended criteria include (1) absence of an infectious etiology, (2) evidence of chronic GVHD at another site, (3) forced expiratory volume less than 75% predicted or a decline of more than 10% from previous, and (4) forced expiratory volume in 1 s/forced expiratory vital capacity less than 0.7 or residual volume/total lung capacity greater than 120% and CT findings of air trapping or bronchiectasis.


The pathophysiology of BOS likely involves donor T cells causing an immune-mediated injury to lung epithelial cells. This injury then causes the release of inflammatory mediators, leading to fibroblast migration, smooth muscle cell proliferation, and eventual deposition of collagen and fibrin in the airway lumens. Risk factors for the development of BOS include busulfan conditioning, allogeneic transplant, recurrent pulmonary infections, and chronic GVHD.


Patients with BOS typically present 6 to 12 months after HCT, are afebrile, and have nonspecific symptoms, such as a nonproductive cough and exertional dyspnea. They may have a history of recurrent respiratory infections and GVHD. Radiographic findings, pulmonary function testing (PFT), and pathology results from lung biopsy are used to make the diagnosis. Patients with BOS have an obstructive pattern on PFT. On high-resolution chest CT, both high- and low-attenuation areas are noted, as are bronchial dilation, bronchial thickening, vascular attenuation, and expiratory air trapping. Biopsy specimens demonstrate submucosal bronchiolar fibrosis and luminal narrowing and obliteration.


BOOP is also known as cryptogenic organizing pneumonia (COP). Patients with BOOP may present 2 to 6 months after HCT, which is earlier than BOS. They also tend to present more acutely than patients with BOS, presenting with fever, cough, dyspnea, and rales. Patients with BOOP have patchy air space disease on chest radiograph. High-resolution chest CT demonstrates ground-glass opacifications, areas of consolidation, and pulmonary nodules. As opposed to patients with BOS, pulmonary function testing in BOOP reveals a restrictive lung disease pattern. Biopsy specimens of BOOP contain granulation tissue in the distal airways, alveolar ducts, and peribronchial alveolar space. , Like BOS, the pathophysiology seems to involve T cells and inflammatory cytokines leading to alveolar epithelial cell injury.


For both BOS and BOOP, it is recommended that patients undergo BAL to rule out infection. BOS may be diagnosed on clinical grounds to avoid open-lung biopsy and its associated risks. The diagnosis of BOOP generally requires biopsy; however, a transbronchial specimen is often sufficient.


The number of patients with BOS or BOOP reported in the literature is small. Therefore, it is difficult to make firm recommendations regarding treatment or prognosis. BOOP seems to have a better prognosis than BOS and may be reversible, while the goal of therapy in BOS is stabilization of disease. It is believed that establishing the diagnosis early in order to begin therapy when the disease is less severe may be of benefit. Therefore, serial PFTs are currently recommended in HCT patients at risk for pulmonary complications. BOS and BOOP may respond better to corticosteroids than other noninfectious pulmonary complications of HCT. , First-line therapy for these complications remains a systemic corticosteroid burst with a prolonged taper over several months. A recent trial of inhaled fluticasone, azithromycin, and montelukast (FAM) showed promise at halting the progression of BOS and enabled use of a shorter course of steroids. However, the use of azithromycin in patients transplanted for hematologic malignancies must be weighed against the newly identified risk of relapse when azithromycin was given early in the transplant course. Other therapies—such as inhaled cyclosporine, etanercept, infliximab, and extracorporeal photochemotherapy—have been described in case reports for BOS and require further study.


Pulmonary venoocclusive disease


Case reports of pulmonary venoocclusive disease (PVOD) in HCT patients have been infrequently described. Patients have presented both early and late after HCT with increasing dyspnea and signs of right heart failure. Cardiomegaly and pulmonary edema are noted on chest radiograph. Evidence of pulmonary hypertension is detected on echocardiogram. In patients who have undergone cardiac catheterization, high right atrial pressure, right ventricular pressure, and pulmonary artery pressures are observed, whereas the pulmonary artery wedge pressure is frequently normal. Pathologic specimens demonstrate fibrosis of the venules and small pulmonary veins, whereas the larger pulmonary veins are typically normal. Because the resistance to flow in the pulmonary veins is typically normal in PVOD, the pulmonary artery wedge pressure appears normal despite having increased resistance through pulmonary venules and small pulmonary veins. Pulmonary arterial intimal fibrosis and hypertrophy may also be observed. , PFT is normal for forced expiratory lung volume, functional vital capacity, and total lung capacity, but carbon monoxide diffusing capacity is typically less than 50%.


Lung biopsy has historically been the gold standard for the diagnosis of PVOD. However, this procedure carries a high risk of complication. Mineo et al. reported that the presence of two of three characteristic CT findings (ground-glass appearance, septal thickening, and mediastinal lymphadenopathy) was able to diagnose PVOD with 95.5% sensitivity and 89% specificity. Therefore clinical suspicion, PFT, and CT findings may be sufficient to make the diagnosis. There may be a genetic predisposition to PVOD, as abnormalities in the bone morphogenetic receptor type II are reported in both PVOD and pulmonary hypertension patients. Corticosteroids, other immunosuppressive agents, and anticoagulation have been used without notable benefit. Sildenafil and prostacyclin have been reported to be of some benefit in treating pulmonary hypertension. However, these medications should be used with caution as they may worsen some patients by causing an increase in pulmonary edema. Theoretically, defibrotide may be beneficial given its efficacy in hepatic VOD. Its use has been described in a case series of eight patients with osteopetrosis and pulmonary hypertension, in which four of the patients were believed to have VOD. Two of the four patients had a favorable response to defibrotide. However, these numbers are much too small to form any definitive conclusions.


Critical care for pulmonary complications


Mechanical ventilatory support


The majority of patients with pulmonary complications in the ICU are admitted for positive-pressure ventilation. Debate continues over which patients may benefit from noninvasive ventilation (NIV) versus invasive mechanical ventilation (IMV) and which ventilatory strategies should be used once IMV is needed. Data from immunocompromised adults suggest that a trial of NIV is warranted. In a meta-analysis, Wang et al. found that immunocompromised patients treated with NIV had a lower mortality rate, shorter hospital stay and shorter duration of mechanical ventilatory support when compared with patients treated with IMV. They also found that approximately half of the patients were successfully managed with NIV and avoided intubation. The outlook may not be as promising for NIV in the pediatric HCT population. Duncan et al. found in a retrospective multicenter study of pediatric HCT patients requiring ICU care that only 24% were able to be successfully managed with NIV. Rowan et al. found in their multicenter retrospective study of ventilatory management of pediatric HCT patients with respiratory failure that 41% of patients who required IMV failed an initial trial of NIV. Moreover, patients who received NIV prior to intubation had a significantly higher mortality rate (70.3% vs. 53.4%) than patients who were intubated at the outset (odds ratio [OR], 2.1; P = .01). A practical approach may be to allow a brief trial of NIV support in select pediatric HCT patients and to follow closely for signs of improvement in respiratory status. If no improvement is observed in work of breathing and/or oxygen requirement within a few hours of aggressive titration of NIV support, IMV should be strongly considered.


Rowan et al. reviewed multicenter mechanical ventilation practices in pediatric HCT patients. Although they were not able to find evidence to support any particular mode of ventilation being superior to another, their results provide useful insight. Patients treated with high-frequency oscillatory ventilation (HFOV) had a higher mortality rate than those treated with conventional mechanical ventilation. However, when HFOV was started within the first 48 hours, there was a trend toward improved survival when compared with conventional mechanical ventilation (CMV) or later transition to HFOV. There were no survivors in the group of patients transitioned to HFOV after 7 days of CMV. Therefore, HFOV may be more effectively used if initiated early in the course of mechanical ventilation. Further analysis of the data revealed that patients receiving traditional lung-protective ventilatory management with peak inspiratory pressure of 31 cmH 2 O or less and PEEP/fraction of inspired oxygen (Fi o 2 ) titration per the ARDSNet protocol had improved survival. Interestingly, for every day that patients received an Fi o 2 greater than 0.6, they had a significant increase in their mortality risk (OR, 4.6; P < .0001). Oxygen toxicity may be of particular concern in HCT patients given the extreme oxidative stress that they experience during conditioning.


Adjunctive therapies


A post-hoc analysis of a multicenter trial of calfactant (calf lung–derived surfactant) in mechanically ventilated pediatric patients with acute lung injury suggested possible benefit in the subgroup of immunocompromised patients. However, a subsequent trial of calfactant in pediatric patients with acute lung injury with leukemia, lymphoma, or a history of HCT was stopped early due to futility, making this therapy unlikely to be beneficial.


Extracorporeal membrane oxygenation (ECMO) has infrequently been used as a heroic measure for HCT patients with severe lung injury. A recently published review of the Extracorporeal Life Support Organization database reported three survivors to hospital discharge of the 29 pediatric HCT patients who received ECMO support after HCT. The authors concluded that while outcomes of ECMO in HCT patients are very poor, it should be considered in select patients who received HCT for a nonmalignant condition or a malignancy with a low risk of relapse.


Lung transplantation has been reported in children who have developed chronic respiratory failure as a complication of HCT in multiple case series in the literature. Of the patients reported, survival appears to be comparable to lung transplantation in the general population. Therefore, this may be an appropriate option in select patients.


Conclusion


The literature continues to be confusing regarding the nomenclature of these noninfectious pulmonary complications of transplantation. It is important for the critical care physician at the bedside to treat the patient appropriately without becoming anxious over the particular name of the disease. Although corticosteroids and etanercept, a TNF-α receptor antagonist, may prove to be beneficial in some cases (i.e., IPS), at the present time, there is no definitive treatment for critically ill children with any of the noninfectious pulmonary complications. The NIH recently hosted a workshop to identify knowledge gaps and research priorities in the understanding of pulmonary complications of pediatric HCT. The executive summary identified three main priorities: (1) build, characterize, and study prospective observational cohorts; (2) improve mechanistic understanding of pulmonary disease in HCT recipients and translate it to potential therapies; and (3) improve clinical outcomes. It is hoped that this workshop will encourage investigators to continue the work needed to improve outcomes in this fragile population. With our current understanding, the best care we can offer is excellent supportive care, paying close attention to fluid balance, preventing hospital-acquired infections, and using lung-protective strategies during mechanical ventilation.


Dilemmas in the diagnosis of pulmonary complications


As HCT patients with pulmonary complications are frequently tenuous, placing these patients at risk for complications from diagnostic procedures is a difficult decision. Although it is difficult to treat these critically ill patients without a firm diagnosis, it is also disconcerting to expose these patients to an invasive diagnostic procedure that may worsen their condition and still not result in a diagnosis. Therefore, the debate continues in the literature and at the bedside regarding the risk/benefit ratio of invasive diagnostic procedures such as BAL and lung biopsy.


St. Jude Children’s Hospital published data regarding the diagnostic yield of BAL at their institution. BAL identified the cause of respiratory symptoms in 53 (67.9%) of 78 of their allogeneic HCT recipients and 7 (63%) of 11 autologous transplant patients. The most common finding diagnosed on BAL was bacterial infection (52%). The patients tolerated the procedure well, with complications noted in less than 20%. In their series, transbronchial biopsy contributed additional information, which might have changed management, in only 2 of 7 patients. They also noted that 14 of 16 patients who underwent open-lung biopsy already had a positive BAL. The authors concluded that BAL had a beneficial risk/benefit profile and was useful in identifying patients who had an infectious etiology to their lung injury. However, biopsy did not add significantly more information and carried an unacceptable morbidity rate of 47%.


A meta-analysis including 72 BAL studies and 31 studies of lung biopsy in both pediatric and adult patients found that BAL was superior to lung biopsy for diagnosing an infectious etiology of lung injury while lung biopsy was superior for diagnosing noninfectious lung injury. Either technique lead to a diagnosis in over 50% of the procedures. Complications were reported in 8% of BAL procedures and 15% of the biopsies. Complications of lung biopsy were higher in children than adults ( P = .003). It was also noted that the addition of BAL galactomannan testing significantly improved the ability to detect invasive fungal infections. The authors concluded that a reasonable approach was to begin the diagnostic workup with BAL, particularly if infection was suspected, and proceed to biopsy if a noninfectious etiology became more suspect.


Hepatic complications


Hepatic complications of HCT have been a common cause of morbidity and mortality since the inception of the procedure. The complications include hepatic infections (viral, fungal, and bacterial); cholestasis; drug toxicity; sinusoidal obstruction syndrome (SOS), which is more commonly known as venoocclusive disease (VOD); and GVHD. HCT patients may also have an underlying liver disease going into HCT such as, but not limited to, tumor infiltration, chronic hepatitis, iron overload, or extramedullary hematopoiesis. ,


Viral hepatitis can be caused by any viral pathogen, including hepatitis B, hepatitis C, cytomegalovirus (CMV), Epstein-Barr virus (EBV), adenovirus, herpes simplex virus (HSV), and varicella zoster virus (VZV). The diagnosis of these pathogens is based on clinical manifestations, with identification of the virus determined (1) histologically, (2) by culture of blood or tissue, or (3) by the presence of viral antigen or nucleic acid within serum or liver tissue. Treatment is dependent on the identification of the viral pathogen. HSV and VZV are treated with acyclovir, whereas CMV is treated with ganciclovir or foscarnet. Unirradiated leukocytes from the marrow donor have been used to treat EBV-associated lymphoproliferative disorders after allogeneic bone marrow transplantation.


Fungal involvement of the liver is often seen in conjunction with widespread dissemination. There may be granulomas, abscesses, cysts, fungus in biliary ducts, or infarcts from vascular occlusion. Typically, Candida species are noted; however, any fungal pathogen can be involved. Fungal infection often presents with right upper quadrant abdominal pain. The diagnostic workup discovers positive serum tests for fungal antigens or DNA, radiologic findings of fungal infection and, if necessary, histologic evidence (including special stains). , If there is a suspicion of active infection in the liver, liposomal amphotericin, voriconazole, or caspofungin should be given until engraftment is established. , Bacterial infections of the liver occur less commonly but present similarly.


Gallbladder stones from poor oral intake, cytoreductive therapy causing exfoliation of gallbladder mucus-containing cells, and increased biliary excretion of precipitable material (cyclosporine A [CSA], antibiotics) all contribute to a 70% incidence of gallbladder sludge in this patient population. , Sepsis can also lead to cholestasis and hyperbilirubinemia. This is mediated by endotoxins, interleukin-6 (IL-6), and TNF-α. , Rarely, persistent biliary obstruction can be caused by lymphoproliferation from EBV- or CMV-related biliary disease, duodenal hematoma as a complication of endoscopy, inspissated biliary sludge, or leukemic relapse in the head of the pancreas. , Numerous medications required for HCT can have direct toxicity on the liver, including antibiotics, fluconazole, and CSA. Histologically, drug effect should be suspected when there is significant hepatocellular necrosis and minimal inflammation.


VOD after allogeneic HCT was first reported in 1979 and now is recognized as a major cause of morbidity and mortality in the first 100 days of transplant. The disease process begins in the sinusoids due to endothelial injury and affects venules only late in the course of the disease. The pathogenesis is believed to result from hepatic venule and sinusoidal endothelial injury. Histologically, subendothelial edema, endothelial cell damage with microthrombosis, fibrin deposition, and expression of factor VIII and von Willebrand factor within venular walls is observed. Hepatic necrosis occurs, and collagen deposition in the sinusoids, venular wall sclerosis, and collagen deposition in the venular lumen is seen as the disease progresses. Risk factors may include elevated transaminases before the conditioning regimen, , age younger than 6 to 7 years, use of methotrexate for GVHD prophylaxis, presence of oral mucositis, interstitial pneumonitis, and/or RBC transfusion iron overload. Certain preparative regimens have also been found to have a higher incidence of VOD, including those with high doses of total body irradiation, cyclophosphamide, or the combination of busulfan and cyclophosphamide, or etoposide and carboplatin. , , , A trial of adults undergoing HCT using everolimus and sirolimus for GVHD prophylaxis was terminated prematurely because of an unacceptably high rate of severe VOD and thrombotic microangiopathy. The authors believed that busulfan use in conditioning may have been a contributing factor.


Clinically, VOD presents with hyperbilirubinemia, painful hepatomegaly, and fluid retention. The incidence varies based on risk factors and the criteria used but reportedly are as high as 55%, with mortality rates ranging from 3% to 67%. Significant variability in mortality results from differing conditioning regimens and definitions of VOD. Two sets of criteria have been used for VOD. Jones et al. first described VOD and modified this criterion as hyperbilirubinemia greater than 2 mg/dL within 21 days of transplantation with at least two of three other findings: hepatomegaly, ascites, or 5% or greater weight gain. McDonald et al. in Seattle defined VOD in their series as two of the following criteria occurring within 20 days of transplantation: hyperbilirubinemia greater than 2 mg/dL, hepatomegaly or right upper quadrant pain, or sudden weight gain of more than 2% body weight. Clinically, most patients with VOD develop symptoms between days 6 and 7 after transplantation, peaking around 10 days after onset, and returning to baseline 10 days later if they are going to recover. Multiorgan failure is seen frequently in patients with VOD. , Severe VOD (S-VOD) is associated with the development of multiorgan failure, including renal failure, pulmonary insufficiency, cardiac failure, and changes in mental status. Liver ultrasound with Doppler study demonstrating reversal of portal flow is a late finding in VOD but is not part of the diagnostic criteria. Liver biopsy can be performed to diagnose VOD, but it is recommended that it be reserved for patients in whom the diagnosis is uncertain and other diagnoses must be excluded, such as hepatic GVHD. Transvenous liver biopsy and hepatic venous pressure gradient measurements can be performed safely and have been found, in a limited study, to have predictive value, with hepatic venous pressure gradient greater than 30 mm Hg associated with poor outcome. Hepatic venous pressure gradient levels greater than 10 mm Hg have been found to be highly specific for diagnosis of VOD. ,


Given that the pathogenesis of VOD is thought to involve endothelial injury and coagulation factor deposition, attempts have been made to reduce the hypercoagulable state with several agents, including heparin, prostaglandin, and bile salts. The Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) and Pediatric Blood and Marrow Transplantation Consortium Joint Working Committees used the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) criteria to develop consensus guidelines for the management of patients with VOD. , , Ursodeoxycholic acid is recommended for prophylaxis in patients at risk for VOD. , Defibrotide is not approved for prophylaxis for VOD. Due to the lack of evidence, the use of heparin, fresh frozen plasma, antithrombin III, glutamine, and prostaglandin E1 are also not recommended for prophylaxis. Early treatment with defibrotide is indicated for patients with S-VOD for 21 days or until resolution of multiorgan failure and/or signs of VOD, whichever comes later. , Supportive treatment for fluid retention and multiorgan failure is an important part of management of these patients. It is recommended to avoid acute fluid overload and restrict fluid in patients exhibiting evidence of fluid overload. Continuous renal replacement therapy is recommended if there is progressive fluid overload despite fluid restriction and diuresis and electrolyte disturbances that are refractory to medical management. Paracentesis (in the setting of intraabdominal hypertension/abdominal compartment syndrome or pulmonary dysfunction due to tense ascites) and/or thoracentesis (in the setting of pulmonary dysfunction) should be considered. Screening and empiric management for fevers or clinical instability should follow the standard of care HCT guidelines.


Colitis and other gastrointestinal complications


Gastrointestinal (GI) complications that arise after transplantation often result from mucosal damage secondary to radiotherapy and chemotherapy regimens, together with immunosuppression following transplantation. Upper GI complications include diffuse mucositis, nausea, vomiting, and nonspecific abdominal pain. Barker et al. reported a 90.1% incidence of mucositis and 85.2% incidence of posttransplant vomiting in a retrospective study of 142 patients who underwent HCT. Lower GI/intestinal acute complications include C. difficile colitis, viral and other gastroenteritis, typhlitis, intestinal GVHD, and intestinal thrombotic microangiopathy. In one case series, C. difficile colitis was reported in 8.5% of patients, viral enteritis in 7.0%, typhlitis in 3.5%, and intestinal GVHD in 27.4%. The incidence of typhlitis in this series was much lower than the 32% incidence previously reported in the literature for AML patients.


Viruses such as CMV, adenoviruses, and rotaviruses can cause diarrhea in the immediate posttransplant period. Imaging findings include nonspecific bowel wall thickening, ascites, and adjacent inflammatory changes, especially in the ileocecal region.


Neutropenic enterocolitis or typhlitis is a necrotizing inflammation of the colon in an immunocompromised patient. There is a predilection for the cecum, thought to be due to the marked distensibility of the cecum, along with lower vascularity. The clinical manifestations are a triad of abdominal pain/tenderness, fever, and neutropenia. The incidence of typhlitis can vary depending on the aggressiveness of chemotherapy and prophylactic antibiotics used. The typical time frame to be diagnosed with typhlitis after HCT appears to be 15.5 ± 7 days. Plain radiographs or ultrasounds of the abdomen appear to be good initial imaging modalities. CT scan can be used if the diagnosis is questionable with initial imaging. Plain radiographs of the abdomen will likely demonstrate dilation of small-bowel loops with a paucity of gas in the right side of the abdomen. In advanced cases with perforation, free intraabdominal air may be detected. Ultrasound of the abdomen will likely reveal asymmetric, echogenic wall thickening of the cecum and terminal ileum. CT will demonstrate luminal narrowing and stranding in the pericecal fat. Management includes bowel rest, antibiotic coverage to include Gram-negative organisms, G-CSF to treat neutropenia, and optimal parenteral nutrition. Antifungal therapy should be considered if there is no clinical improvement on initiation of antibiotics. Persistent GI bleeding despite resolution of neutropenia and coagulopathy, evidence of perforation with peritonitis, and uncontrolled sepsis are potential surgical indications.


Pneumatosis intestinalis can be noted in typhlitis, in which case it implies imminent bowel perforation. Corticosteroid therapy appears to be a significant risk factor for pneumatosis intestinalis, inducing atrophy of the Peyer patches in the intestine with resultant mucosal defects and dissection of intraluminal air into the submucosal or subserosal regions. If detected in an asymptomatic patient, it will most often be resolved with conservative management. , ,


Intestinal acute GVHD usually develops after 3 to 5 weeks and can be accompanied by skin and hepatic GVHD. Chronic GVHD occurs several months after transplantation. , Symptoms include secretory diarrhea, fever, nausea, vomiting, abdominal pain, and intestinal hemorrhage. In addition to nonspecific findings, CT imaging may reveal bowel wall enhancement correlating with mucosal destruction and replacement with granulation tissue.


Thrombotic microangiopathy (TMA) of the intestines can occur after HCT and is caused by intimal injury to the microvasculature followed by formation of microthrombi. The injury is presumed to be due to chemotherapy, total body irradiation, or the pretransplant conditioning regimen as well as the use of drugs known to be associated with TMA, such as tacrolimus and cyclosporine A. This is a rare complication but can mimic GVHD by presenting with fever and refractory diarrhea. Laboratory findings include elevated lactic acid dehydrogenase (LDH) and fragmented erythrocytes on a peripheral blood smear. The treatment is challenging and often requires removal of the possible offending immunosuppressant medication. Jodele et al. reported that early identification of TMA using a revised criterion and complement-blocking therapy such as eculizumab may improve outcomes.


Pancreatitis may also occur in HCT patients. Barker et al. reported a 4.9% incidence of pancreatitis that was not associated with any specific induction chemotherapy regimen. Werlin et al. also reported a similar 3.5% incidence of pancreatitis and recommended testing for pancreatitis prior to attributing GI symptoms to mucositis.


Myelosuppression and hematologic complications


Myelosuppression and immune dysregulation


Stem cell transplant conditioning results in an extended period of neutropenia, anemia, and thrombocytopenia. Neutrophil engraftment is defined as an absolute neutrophil count (ANC) of ≥0.5 × 10 3 /μL on 3 consecutive days following the postconditioning nadir. Neutrophil engraftment typically occurs 2 to 4 weeks following stem cell infusion. The duration of time from stem cell infusion to engraftment depends on numerous transplant-related factors. When peripheral blood progenitor cells are used, engraftment typically occurs 1 to 6 days sooner than when bone marrow is used as the stem cell source. Engraftment occurs slower when umbilical cord blood is used compared with PBSCs and bone marrow. Granulocyte-stimulating factors are commonly used following autologous HCT and umbilical cord blood transplant to reduce the time to neutrophil engraftment. Platelet engraftment generally occurs 1 to 2 weeks following neutrophil engraftment but can take weeks to months. A platelet count less than 100,000 on day 100 following transplantation is associated with poor outcome.


Neutrophil engraftment does not signify the reconstitution of a fully functional immune system. It is crucial to remember that engrafted post-HCT patients remain significantly immunocompromised and are at risk for life-threatening opportunistic infections. The restoration of normal immune function can take as long as 1 year in patients without significant post-HCT complications and longer in patients with chronic GVHD. Typically, natural killer cell recovery takes approximately 1 month, and T-lymphocyte recovery takes 6 to 12 months. Restoration of normal B-cell function takes approximately 3 to 6 months in the absence of GVHD.


Infectious complications


Patients undergoing HCT have increased susceptibility to infection because of a combination of (1) neutropenia, (2) breakdown of physical barriers (mucositis, indwelling venous catheters, skin lesions), and (3) defects in cellular and humoral immunity as a result of the conditioning regimen and immunosuppressive therapy given. The susceptibility to any particular organism varies according to the stem cell source (e.g., umbilical cord blood recipients are at increased risk for viral infection) and over the course of the transplant period. During the first 2 to 4 weeks of the posttransplant period, while the patient is neutropenic, bacterial infections account for approximately 90% of the infections. Enteric gram-negative bacilli (e.g., Escherichia coli , Klebsiella , Enterobacter , and Pseudomonas aeruginosa ) can cause rapid hemodynamic instability. The gram-positive infections ( Staphylococcus and Streptococcus ) are frequent causes of infections when central venous catheters are present. Therefore, empiric antibiotic coverage for fevers during this time must be broad spectrum and provide adequate coverage for these organisms.


Fungal infections are increasing in frequency with better treatment and prophylaxis of bacterial and viral infections, particularly after allogeneic transplantation. Fungal pathogens in HCT patients include the yeasts (e.g., Candida spp. and Cryptococcus neoformans ), molds (e.g., Aspergillus , Fusarium , and Mucormycosis ), and dimorphic fungi (e.g., Coccidioides , Histoplasma , and Blastomyces ). Of these, Candida and Aspergillus are the most common. Candida spp. colonize the gastrointestinal tract in more than half of healthy people, but they become opportunistic infections in HCT patients.


Candidal infections can occur as superficial mucosal infections (e.g., thrush) or deeply invasive processes (hepatosplenic candidiasis). Esophageal candidiasis is associated with dysphagia and retrosternal pain. This may be difficult to distinguish from chemotherapy or radiation-induced mucositis or herpetic mucositis. Endoscopy may be necessary to diagnose and appropriately treat. Candidemia may present with fever and systemic symptoms and is frequently not associated with tissue involvement. Because many HCT patients receive fluconazole prophylaxis, candidemia should be treated with amphotericin B. Traditionally, patients with documented candidemia or persistent/recurrent fevers underwent evaluation for multiorgan involvement, including CT or magnetic resonance imaging (MRI) of the brain, chest, and abdomen, and an ophthalmologic examination. However, given that more attention is being focused on the radiation risk of CT for the development of future cancers and the improvement in antifungal prophylaxis, the use of abdominal and pelvic CT scans as screening tools (not in cases of documented fungemia) for invasive fungal disease is now being questioned. A recent quality improvement project from St. Jude Children’s Research Hospital found a very low yield of abdominal CT in detecting undiagnosed fungal infections in patients with prolonged fever and neutropenia. The authors recommend that routine abdominal CT as a screening tool for invasive fungal disease no longer be performed. Instead, they recommend ultrasound or limited MRI in patients with clinical suspicion for invasive fungal disease in the abdomen.


Aspergillus spores are routinely inhaled; in immunocompromised or HCT patients, they can cause invasive infections. Neutropenia and GVHD with immunosuppressive treatment are risk factors for these infections. Outbreaks of aspergillus can occur in areas of construction or with contaminated ventilation. Invasive aspergillosis occurs most commonly in the lungs, with fever, cough, dyspnea, and, ultimately, hemoptysis as the disease progresses. The characteristic radiographic appearance is a cavitary lesion, but nodular infiltrates and bronchopneumonia are also reported. BAL should be performed initially. However, up to 50% of patients have a negative BAL. Open-lung biopsy should be considered if suspicion remains after a negative BAL.


CMV is one of the most problematic viral infections for HCT patients. CMV may emerge in the allogeneic patient between 1 to 3 months posttransplantation if either the patient or donor was CMV positive before transplant. CMV lies dormant after the initial clinical infection. However, in immunosuppressed patients, this virus can reactivate and result in interstitial pneumonitis, enteritis, encephalitis, retinitis, or bone marrow suppression. CMV infection is defined as the identification of CMV from any site or the seroconversion to CMV positivity on polymerase chain reaction (PCR) or antigenemia testing. CMV disease is defined as the clinical manifestations seen in the presence of CMV infection. The use of CMV-negative blood products and leukofiltration of blood products along with routine screening during the first 100 days posttransplant with PCR or antigen testing has helped reduce the risk of CMV infections in patients undergoing transplant. Monitoring of CMV with antigenemia and/or PCR testing is the standard of care for 100 days posttransplant and allows for preemptive therapy if results of these tests become positive (even before the onset of clinically apparent disease). Ganciclovir, valganciclovir, or foscarnet treatment is then given for 7 to 14 days followed by prophylaxis and/or screening through 100 days posttransplantation. Interstitial pneumonitis from CMV presents with hypoxia and fever and an interstitial pattern on chest radiograph. Untreated, there is an 80% mortality rate. Ganciclovir and intravenous (IV) immunoglobin is the recommended treatment for CMV interstitial pneumonitis. For patients resistant to ganciclovir or with unacceptable medication toxicity, foscarnet may be used. , Ganciclovir can cause neutropenia, and administration of growth factor (e.g., G-CSF, granulocyte macrophage–CSF) should be considered if the ANC falls below 1000/μL. If the ANC falls below 500/μL, holding the drug should be considered. In addition, renal adjustment may be necessary as both ganciclovir and foscarnet can be nephrotoxic. CMV prophylaxis with ganciclovir is prohibited by its marrow-suppressive effects.


CMV enteropathy presents with dysphagia, abdominal pain, nausea, vomiting, diarrhea, and/or gastrointestinal bleeding. These symptoms can be seen with GVHD as well; endoscopy should be performed to aid in the diagnosis. Treatment is similar to that of CMV pneumonia.


EBV, human herpesvirus 6, HSV, adenovirus, VZV, human metapneumovirus, and BK virus infections are all common posttransplantation that cause a range of clinic findings, including hemorrhagic cystitis, colitis, retinitis, encephalitis, and pneumonitis. The diagnostic and treatment options for each of these viruses and clinical presentations is beyond the scope of this chapter. The reader is referred to multiple published reviews of this topic.


Recent study has focused on the role of adoptive transfer of virus-specific T cells from seropositive donors. Translational and clinical research has focused on the role of this immunotherapeutic approach to the treatment of CMV, EBV, and adenovirus. Broad application of this biotechnology is evolving.


Graft failure


Graft failure is an uncommon, potentially lethal complication of HCT. Primary graft failure is defined as failure of the stem cell graft to recover hematopoietic function by day 30, although some patients successfully engraft later than day 30. Secondary graft failure is the loss of the donor stem cell graft after initial engraftment. The risk of graft failure is increased with HLA disparity between donor and host, when reduced intensity conditioning regimens are used, with the use of umbilical cord blood stem cells, and when transplant is performed for a nonmalignant hematologic condition. It is rare in HLA-matched sibling donor transplants. Graft failure is treated with the infusion of hematopoietic cells either alone or in combination with growth factors, chemotherapy, or immunosuppression. , Graft failure is an emergency, as the risk of death increases with the duration of neutropenia and because there are few effective therapies.


Hematologic complications


HCT recipients commonly require blood product transfusions during the acute transplant phase due to conditioning-associated myeloablation and potentially increased consumption of platelets and RBCs. For most patients, the need for blood product transfusions declines rapidly following engraftment and hospital discharge. However, patients may require transfusion support for months after transplant. All blood products should be gamma-irradiated to rid the product of competent donor T cells that can cause transfusion associated-GVHD. Additionally, blood products must be CMV negative to prevent transmission of the virus to nonimmune patients. This can be achieved by using blood from CMV-seronegative donors or with leukofiltration.


Donors and recipients who are HLA matched are not necessarily ABO matched. ABO matching is not required for successful transplant and is a secondary consideration when choosing a donor. However, ABO mismatching puts the recipient at risk for immune-mediated hemolytic anemia. The risk for, and severity of, potential hemolytic anemia depends on the degree of compatibility and is divided into four groups: (1) ABO matched; (2) minor ABO mismatch, in which there is potential for hemolysis of the recipient RBCs by donor isoagglutinins (e.g., donor blood type O+ and recipient A+); (3) major ABO mismatch, in which case the recipient isoagglutinins are directed against donor RBCs after engraftment (e.g., donor blood type A+ and recipient O+); and (4) bidirectional mismatch, which combines minor and major ABO mismatch (e.g., donor blood type A+ and recipient blood type B+). When there is a major or bidirectional mismatch, the stem cell product must be RBC depleted or the patient must have the offending isoagglutinins removed by pheresis prior to infusion to prevent a hemolytic reaction. Minor incompatibility, in which the recipient’s RBCs are incompatible with components of the donor’s plasma, puts the recipient at risk for an immune-mediated transfusion reaction. Plasma depletion of the product prior to infusion reduces the risk. Even when plasma depletion is used, mild hemolysis can exist for weeks to months due to antibody production from the newly produced B lymphocytes against residual recipient RBCs.


There are many described late hemolytic complications of transplant, most of which are uncommon. Autoimmune hemolytic anemias, thrombocytopenia, and neutropenias from post-HCT immune dysregulation can occur months to years after transplantation and are typically managed with immunosuppression, immunomodulation, or IV immunoglobin.


Transplant-associated thrombotic microangiopathy (TA-TMA) is increasingly recognized as an important complication of HCT. The diagnosis should be suspected in patients who present with hypertension, evidence of hemolytic anemia, thrombocytopenia, proteinuria, and multisystem involvement, such as renal failure, pleural effusions, neurologic changes, ascites, and/or pericardial effusions. The diagnosis is made by biopsy with evidence of microangiopathy on the specimen or by meeting clinical criteria, including elevated LDH, proteinuria, thrombocytopenia, anemia, microangiopathy, and/or elevated sC5b-9 levels. , Patients at particularly high risk for severe disease are those with proteinuria and elevated sC5b-9 levels. The underlying pathophysiology is thought to involve abnormalities in complement activation . Treatment with eculizumab, a monoclonal antibody that prevents the formation of sC5b-9, is promising.


Hemolytic uremic syndrome (HUS) is a potentially life-threatening, uncommon post-HCT complication. It presents with hemolysis and mild to moderate renal dysfunction at a median time of 5 months post-HCT. Patients may also have seizures and hypertension. Many cases of post-HCT HUS gradually self-resolve, although patients may be left with residual renal dysfunction. Post-HCT thrombotic thrombocytopenic purpura (TTP) classically presents earlier than HUS with thrombocytopenia, schistocytes on the peripheral blood smear, and elevated LDH. Endothelial damage from transplant conditioning, GVHD, and calcineurin inhibitors are believed to contribute to the development of post-HCT TTP. It differs from classic TTP of childhood in that ADAMTS13 deficiency is not present. , Additionally, standard therapies for idiopathic TTP, such as plasma exchange, do not appear to be effective for the treatment of post-HCT TTP.


Iron overload


Iron overload has been recognized as an important transplant complication as well as a risk factor for the development of other transplant-related toxicities. HCT patients are at risk for increased iron burden due to repeated blood transfusions pre- and post-HCT and disturbed iron metabolism in the setting of chronic inflammation. , Adverse effects from iron overload may include increased susceptibility to infection, VOD, chronic liver disease, endocrine abnormalities, and cardiac dysfunction. , , Studies suggest that iron overload has an adverse impact on survival in patients undergoing HCT for beta-thalassemia major and hematologic malignancies. , , However, the impact of iron overload on transplant-related toxicities in patients transplanted for other reasons is less well established.


There are multiple ways to diagnose iron overload. Liver biopsy remains the gold standard, but frequently the diagnosis is made with imaging and laboratory studies. Elevated ferritin is a nonspecific marker of inflammation, rendering this a sensitive—but not specific—indicator of iron overload. Serum iron studies are useful adjuncts for diagnosis and are often used for monitoring the efficacy of therapy. MRI can provide a quantification of organ-specific iron burden. Phlebotomy is a standard treatment for iron overload. , However, it may have limited utility given that many patients may be anemic after HCT. Iron chelation is effective but may be limited by the practical considerations in the case of deferoxamine infusion and potential toxicities of the treatments.


Graft-versus-host disease


GVHD is the most common complication of allogeneic HCT. GVHD develops when donor T lymphocytes respond to proteins on recipient cells. Activated donor T lymphocytes, monocytes, and macrophages trigger a self-propagating cycle of cytokine production and inflammation. , GVHD was historically categorized by the time of occurrence following transplant, with acute GVHD diagnosed if symptoms developed before day 100 or chronic if the presentation was after day 100. The traditional definitions of acute and chronic GVHD do not fully address the pathophysiology of the diseases and have evolved. Consensus recommendations from the 2014 National Institutes of Health Consensus Development Project on criteria for clinical trials in chronic GVHD advise classification based on the clinical features rather than the posttransplant day and provide revisions to 2005 recommendations. This classification recognizes two main categories of GVHD (acute and chronic), each with subcategories. Acute GVHD includes classic acute GVHD that develops within 100 days after transplant and persistent, recurrent, or late-onset acute GVHD that clinically resembles acute GVHD but occurs greater than 100 days after transplantation. Chronic GVHD includes classic chronic GVHD occurring more than 100 days after HCT with manifestations specific to chronic GVHD and an overlap syndrome, which has features of chronic GVHD and features typical of acute GVHD.


The skin, gastrointestinal tract, and liver are the most common involved systems in acute GVHD. The cutaneous presentation is typically an erythematous maculopapular rash, although there are a wide variety of possible skin findings. Diffuse bullous lesions with skin sloughing are the most severe manifestation of cutaneous GVHD. Acute gastrointestinal GVHD is characterized by diarrhea that is often bloody, may contain tissue, and is accompanied by severe abdominal pain and cramping. Hepatic acute GVHD typically presents with a cholestatic pattern of elevated bilirubin and alkaline phosphatase. Isolated transaminase elevation is uncommon. Less common presentations of acute GVHD are oral inflammation with possible ulceration and ocular inflammation. Acute GVHD is graded according to severity of the systems involved ( eTable 93.2 ).


Jun 26, 2021 | Posted by in CRITICAL CARE | Comments Off on Critical illness in children undergoing hematopoietic progenitor cell transplantation
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