Pulmonary dysfunction in pediatric hematopoietic stem cell transplant patients: non-infectious and long-term complications

Pulmonary complications are among the most frequently encountered sequelae of pediatric hematopoietic stem cell transplantation (HSCT). Non-infectious complications are becoming increasingly more common in this unique population. This review addresses the diagnosis and management of non-infectious manifestations of lung disease in pediatric HSCT patients and briefly discusses the long-term pulmonary function of childhood HSCT survivors.     

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??Abstract??Allogeneic hematopoietic stem cell transplantation ??HSCT?? is the only curative therapy for severe beta-thalassemia major. Patients with an available human leukocyte antigen ??HLA?? identical sibling donor should be offered HSCT as soon as possible before development of iron overload and transfusion associated complications?? and the cure rate was up to 80%??90%. High-resolution HLA typing matched unrelated donor transplants also achieved good results. HSCT from HLA-mismatched relatives or HLA-phenotypically-identical donor is an option to be performed in expert centers. Optimization of conditioning regimen and techniques to control transplant-related complications will further improve outcomes.     

Pulmonary dysfunction in pediatric hematopoietic stem cell transplant patients: overview, diagnostic considerations, and infectious complications

Pulmonary complications are among the most common and serious sequelae seen in hematopoietic stem cell transplantation (HSCT) recipients. This two-part review addresses the incidence and impact of pulmonary complications in pediatric HSCT patients. In this first part we review the available data for the use of diagnostic modalities in this population, including flexible bronchoscopy with bronchoalveolar lavage (BAL) and open lung biopsy (OLB). We also review the many infectious pulmonary complications that may occur in pediatric HSCT recipients, utilizing the traditional chronologic divisions of neutropenic phase (0-30 days following HSCT), early phase (30-100 days), and late phase (>100 days).     

Successful outcome of allogeneic stem cell transplantation in Seckel syndrome

Seckel syndrome is a rare autosomal recessive disease, genetically heterogeneous, characterized by short stature, prenatal microcephaly, intellectual disability, dysmorphic features, chromosomal instability, and hematological disorders. We report the case of a six‐yr‐old boy with Seckel syndrome and aplastic anemia who underwent successful allogeneic bone marrow transplantation from ten of ten HLA matched unrelated donor. Currently the patient is on D+771, in good health conditions and with no further complications. In conclusion, this case indicates that bone marrow transplantation is an acceptable therapeutic option for Seckel syndrome complicated by hematological alterations.     

Pulmonary function in patients undergoing bone marrow transplantation

Pulmonary function was studied prospectively in 25 children with leukemia and aplastic anemia undergoing bone marrow transplantation (BMT). Whereas 11 patients have died, only one did so primarily due to interstitial pneumonia. Fourteen patients (56%) survived a median of at least 36 months. Seventeen patients received pulmonary function tests (PFTs). Four patients transplanted for leukemia in relapse following preparation with a very intensive regimen (cyclophosphamide, 200 mg/kg, total body irradiation, 1,000 rad, BCNU, cytosine arabinoside) developed restrictive lung changes. Patients undergoing BMT for aplastic anemia and leukemia in remission prepared with more commonly used and less intensive regimens maintained normal pulmonary function. As new regimens are devised, PFTs should be utilized to characterize the pulmonary toxicity of these regimens as well.     

Engraftment syndrome following allogeneic hematopoietic stem cell transplantation in children

Abstract:  ES is a complication that occurs immediately before or at the timing of neutrophil engraftment following autologous or allogeneic SCT. It is characterized by fever, skin rash, and non-cardiac pulmonary infiltrates. We evaluated the incidence, risk factors, and outcomes of ES following allogeneic SCT in children. Of 100 pediatric patients, 20 (20%) developed ES occurring at a median of 14 days (range 8–27 days) post-transplant. Patients presented with fever (100%), skin rash (100%), diffuse pulmonary infiltration (25%), and body weight gain (85%). On multivariate analysis, significant risk factors for ES included younger age (<8 yr old) and human leukocyte antigen disparity between donors and recipients. Univariate analysis showed that patients with ES had a higher incidence of developing chronic graft-versus-host disease and ES was not associated with other complications. Event-free survival did not significantly differ between patients with and without ES regardless of the presence of malignant or non-malignant diseases.     

Neurological complications after allogeneic hematopoietic stem cell transplantation in children,a single center experience

In this study, we retrospectively examined the data of children who underwent allo‐HSCT from HLA‐matched family donors. We analyzed the incidence, etiological factors, clinical characteristics, possible reasons, risk factors, and follow‐up of neurologic complications. BU‐based conditioning regimens were used in most of the cases (n = 62). The median duration of follow‐up for the 89 patients was 20 months (range 1–41 months). Eleven percent of transplanted children developed one or more neurological symptoms after HSCT with a median observation time of two months (range ?6 days to 18 months). The median age of the four girls and six boys with neurological complication was 13 yr (range 5.3–17.6 yr). Cylosporine A neurotoxicity was diagnosed in five children, four of them were PRES. The rest of complications were BU and lorazepam toxicity, an intracranial hemorrhage, a sinovenous thrombosis, and a transient ischemic attack during extracorpereal photopheresis. No difference was found between groups of neurological complication according to age, gender, diagnosis, hospitalization time, neutrophil and platelet engraftment time, stem cell source, and conditioning regimen, acute and chronic GVHD or VOD. Neurological complication was the cause of death in one patient (1.1%).     

Sirolimus‐induced interstitial lung disease following pediatric stem cell transplantation

Sirolimus‐induced ILD is a known but rare complication in adults who have undergone SOT. However, little is known about this adverse effect in children. Diagnosis of sirolimus‐induced ILD can be challenging, especially in patients who have difficulty participating in lung function testing. We present a case of presumed sirolimus‐induced ILD in a pediatric stem cell transplant patient who developed polycythemia and hypoxemia. To our knowledge, no other cases of sirolimus‐induced pulmonary toxicity in children after HCT have been reported.     

Insulin-related metabolism following hematopoietic stem cell transplantation in childhood

Objectives:  To assess insulin-related metabolism following hematopoietic stem cell transplantation (HSCT) in childhood.
Study design:  Thirty-four patients who underwent HSCT were compared with 21 patients with similar diseases who were not transplanted. Median follow-up was 3.6 yr after HSCT. Anthropometric parameters, fasting plasma glucose and insulin levels, hemoglobin A_1c (HbA_1c) and lipid profile were measured and compared.
Results:  HbA_1c was significantly higher (p = 0.001) in the study group. Two (5.8%) patients in the study group developed type 2 diabetes mellitus. Among thalassemic patients, significantly lower insulin resistance indices (p = 0.05) and fasting plasma insulin levels (p = 0.033) were found in the study group compared with the control group.
Conclusions:  Attentive follow-up of insulin-related metabolism following HSCT in children is needed. The significance of the higher HbA1c values in the study group remains to be evaluated in a larger cohort of patients.     

Neutrophil function in children following allogeneic hematopoietic stem cell transplant

HSCT is a lifesaving procedure for children with malignant and non‐malignant conditions. The conditioning regimen renders the patient severely immunocompromised and recovery starts with neutrophil (PMN) engraftment. We hypothesize that children demonstrate minimal PMN dysfunction at engraftment and beyond, which is influenced by the stem cell source and the conditioning regimen. Peripheral blood was serially collected from children at 1 to 12 months following allogeneic HSCT. PMN superoxide () production, degranulation (elastase), CD11b surface expression, and phagocytosis were assessed. Twenty‐five patients, mean age of 10.5 yr with 65% males, comprised the study and transplant types included: 14 unrelated cord blood stem cells (cords), seven matched related bone marrow donors, three matched unrelated bone marrow donors, and one peripheral blood progenitor cells. Engraftment occurred at 24 days. There were no significant differences between controls and patients in PMN production, phagocytosis, CD11b surface expression, and total PMN elastase. Elastase release was significantly decreased <6 months vs. controls (p < 0.05) and showed normalization by six months for cords only. The conditioning regimen did not affect PMN function. PMN function returns with engraftment, save elastase release, which occurs later related to the graft source utilized, and its clinical significance is unknown.     

The incidence of autoimmune hemolytic anemia in pediatric hematopoietic stem cell recipients post‐first and post‐second hematopoietic stem cell transplant

The reported incidence of post‐allogeneic HSCT AIHA was between 4.4% and 6% following a single transplant. Cord blood transplantation, T‐cell depletion, and chronic GvHD are significantly associated with post‐transplant AIHA. During an 11‐yr period, data for 500 pediatric HSCT recipients were eligible for evaluation of the incidence of AIHA post‐first and post‐second transplants. Demographic, transplant, and post‐transplant‐related variables were analyzed. Twelve of 500 (2.4%) recipients at a median of 273 days and seven of 72 (9.7%) recipients at a median of 157 days developed AIHA post‐first and post‐second HSCT, respectively. Post‐first HSCT, none of the MRD recipients developed AIHA (0/175 MRD vs. 12/325 other donors, p = 0.04). Four of 12 required a second HSCT to control the AIHA. After the second HSCT, MUD was significantly associated with the development of AIHA. No other variables were associated with the post‐second transplant AIHA. The incidence of AIHA post‐first and post‐second HSCT was less than the reported. The increased incidence of AIHA among recipients of second HSCT is most likely due to the profound immune dysregulation. A much larger, prospective study would be needed to evaluate the incidence, complications, and management of post‐transplant AIHA.     

Human herpesvirus 7 in pediatric hematopoietic stem cell transplantation

BACKGROUND: Little is known about the significance of human herpesvirus 7 (HHV-7) in pediatric hematopoietic stem cell transplantation (HSCT). OBJECTIVE: To evaluate children post autologous and allogeneic HSCT, with a positive PCR or immunohistochemistry for HHV-7 either from blood, cerebrospinal fluid (CSF) or any other pathology specimen. Clinical data for these patients were collected examining symptoms and signs, engraftment, acute infectious complications, graft versus host disease (GVHD) where applicable, and survival. RESULTS: Between June 1999 and June 2003, 265 HSCT were performed in The Hospital for Sick Children, Toronto, allogeneic (n = 163) and autologous (n = 102). Nine children were positive for HHV-7 at a median of 21 days (range 16-27 days) post-HSCT. All had allogeneic transplantation. The most common underlying diagnosis was acute leukemia and 7 had matched unrelated donor (MUD) transplantation. Eight of the nine patients had grade II-IV acute GVHD and all of them had multiple infectious episodes with fungal, bacterial and other viral pathogens. Although not fully attributed to HHV-7, the clinical syndrome varied from fever, vomiting and diarrhea to septic shock. Four patients died due to GVHD and sepsis. CONCLUSION: HHV-7 was uncommon post-HSCT. It was associated with severe GVHD and sepsis secondary to severe immunosuppression.     

Solid organ transplants following hematopoietic stem cell transplant in children

Bunin N, Guzikowski V, Rand ER, Goldfarb S, Baluarte J, Meyers K, Olthoff KM. Solid organ transplants following hematopoietic stem cell transplant in children.
Pediatr Transplantation 2010: 14:1030–1035. © 2010 John Wiley & Sons A/S. Abstract: SOT may be indicated for a select group of pediatric patients who experience permanent organ failure following HSCT. However, there is limited information available about outcomes. We identified eight children at our center who received an SOT following an HSCT. Patients were six months to 18 yr at HSCT. Diseases for which children underwent HSCT included thalassemia, Wiskott–Aldrich syndrome, Shwachman–Diamond/bone marrow failure, sickle cell disease (SCD), erythropoietic porphyria (EP), ALL, chronic granulomatous disease, and neuroblastoma. Time from HSCT to SOT was 13 days to seven yr (median, 27 months. Lung SOT was performed for two patients with BO, kidney transplants for three patients, and liver transplants for three patients (VOD, chronic GVHD). Seven patients are alive with functioning allografts 6–180 months from SOT. Advances in organ procurement, operative technique, immunosuppressant therapy, and infection control may allow SOT for a select group of patients post‐HSCT. However, scarcity of donor organs available in a timely fashion continues to be a limiting factor. Children who have undergone HSCT and develop single organ failure should be considered for an SOT if there is a high likelihood of cure of the primary disease.     

Management of refractory hemorrhagic cystitis following hematopoietic stem cell transplantation in children

HC is a complication associated with HSCT, but occurs rarely in solid organ recipients. The reported incidence varies from <10% to more than 70%. HC is characterized by hemorrhagic inflammation in urinary tract mucosa with symptoms varying from asymptomatic microscopic hematuria to frank hematuria with clot formation and urinary tract obstruction. Early onset HC may be explained by toxicity of chemo- and/or radiotherapy, while multiple factors including viral infections and their interplay seem to be involved in late onset HC. So far, only incidence of cyclophosphamide-associated HC has been reduced with preventive treatment. Likely, once HC is established, the treatment principles are similar regardless of the etiology and depend on the intensity of HC. Prevention of urinary tract obstruction, transfusion support, analgesic, and spasmolytic therapy are generally accepted in HC management. Treatment beyond this conservative approach entails higher risk for side effects, and thus treatment escalation proportional to HC intensity is warranted. No standard and evidence-based treatment escalation algorithm has been widely adopted yet. As severe HC following HSCT is a potentially life-threatening complication, a multidisciplinary and individual approach is required in children suffering from this devastating complication.     

Eltrombopag for thrombocytopenia following allogeneic hematopoietic stem cell transplantation in children

Persistent thrombocytopenia is a common complication after allogeneic hematopoietic stem cell transplantation (HSCT). While the use of thrombopoietin receptor agonists was retrospectively investigated in adults, data in pediatric posttransplant thrombocytopenia are lacking. We evaluated the safety and efficacy of eltrombopag in nine children with platelet transfusion‐dependent persistent thrombocytopenia after HSCT. Eltrombopag was started at a median of 147 days after allo‐SCT and continued for a median period of 64 days, the starting dose being 50 mg per day. The therapy was well tolerated. After a median time of treatment of 36 days, eight patients (88%) reached sustained platelets count >50 000/μL.