Acute renal failure following bone marrow transplantation

The medial preoptic nucleus (MPN) is an essential site for the regulation of male sexual behavior. Previous studies using c-fos as a marker for neural activation have shown that copulation increased c-fos expression in the MPN. Neural activation was also present in brain regions that are connected with the MPN and are involved in male sexual behavior, including the posteromedial bed nucleus of the stria terminalis (BNSTpm), posterodorsal preoptic nucleus (PD), posterodorsal medial amygdala (MEApd), and parvocellular subparafascicular thalamic nucleus (SPFp). The present study investigated whether the copulation-induced, activated neurons in these brain regions are involved in the bidirectional connections with the MPN. Therefore, mating-induced Fos expression was combined with application of anterograde (biotinylated dextran amine) or retrograde (cholera toxin B subunit) tracers in the MPN. The results demonstrated that neurons in the BNSTpm, PD, MEApd, and SPFp that project to the MPN were activated following copulation. However, in males that displayed sexual behavior but did not achieve ejaculation, few double-labeled neurons were evident, although both retrogradely labeled neurons and Fos-immunoreactive cells were present. In addition, retrograde neurons that expressed Fos were located in discrete subdivisions within the brain regions studied, where Fos is induced after ejaculation. Likewise, anterogradely labeled fibers originating from the MPN were not distributed homogeneously but were particularly dense in these discrete subdivisions. These results demonstrate that copulation-induced Fos-positive neurons in specific subdivisions of the BNSTpm, PD, MEApd, and SPFp have bidirectional connections with the MPN. Taken together with previous findings, this supports the existence of a discrete subcircuit within a larger neural network underlying male sexual behavior.     

Cyclosporine-related encephalopathy following allogeneic bone marrow transplantation

Idiopathic granulomatous hepatitis is a rare disease of unknown cause that is characterized by recurrent fevers and granuloma in the liver. Attempts to define an exact etiology of the fever of granulomatous hepatitis frequently do not yield a precise diagnosis. Idiopathic granulomatous hepatitis was confirmed after a thorough work up and negative cultures and serologies were obtained, and in the absence of another condition that could lead to granulomas in the liver. We have experienced a 67-year-old female patient who presented with prolonged fever for 2 months and revealed granuloma in liver biopsy. She was treated with glucocorticosteroid and defervescence resulted.     

Late pulmonary impairment following allogeneic bone marrow transplantation

The pulmonary function of 88 consecutive leukemic patients who had undergone allogeneic bone marrow transplantation (BMT) was studied beforehand, at 3 months, at 6 months, and annually thereafter until 5 years after grafting. The parameters for function which are indicative for obstructive and restrictive lung disease deteriorated in all patient groups during the first 3 to 6 months after BMT but partially recovered within one year. Long-term decline in lung function was similar in all patient groups, and neither the onset nor the magnitude of pulmonary dysfunction was related to the occurrence of pulmonary impairment within 6 months after grafting. Multivariate analysis was then employed to assess predictors for long-term pulmonary disease. Despite the obvious effect of chronic graft versus host disease on the course of lung function, it was in itself not a significant predictor of long-term pulmonary outcome. Rather, the conditioning regimen turned out to be indicative; compared with busulfan, fractionated total body irradiation was demonstrated to be clearly superior with a lower incidence of both restrictive and obstructive long-term lung impairment. Our data indicate a previously unknown long-term side effect of busulfan conditioning.     

Cytomegalovirus prophylaxis and treatment following bone marrow transplantation

OBJECTIVE: To provide an overview of the role of cytomegalovirus (CMV) in the bone marrow transplant (BMT) population and update the current methods of prevention and treatment of CMV infection and disease, with emphasis on CMV interstitial pneumonia (CMV-IP). DATA SOURCES: The current medical literature, including abstracts presented at recent national and international meetings, is reviewed. References were identified by searching the MEDLINE database from January 1988 through June 1994. The reference lists of the published studies and reviews obtained from the initial literature search were reviewed as well. STUDY SELECTION: Data regarding the epidemiology of CMV, the risk factor associated with CMV infection and disease, as well as data on the prevention and the treatment of CMV infection and disease in the BMT population are cited. Specific attention was focused on randomized, placebo-controlled studies pertaining to the prevention of CMV infection and disease in CMV-immunoglobulin G positive recipients undergoing allogeneic BMT. Information from nonrandomized, placebo-controlled studies was included in the absence of stronger data. DATA EXTRACTION: Information contributing to CMV in the BMT population was reviewed. Data supporting and disputing specific preventive and treatment modalities are presented. DATA SYNTHESIS: The incidence of CMV seropositivity in the general population is high and while BMT becomes a widely accepted treatment modality, CMV reactivation and subsequent disease, especially CMV-IP, becomes a significant prognostic factor of morbidity and mortality. Even though antiviral agents such as ganciclovir and foscarnet can inhibit the viral replication in vivo, they have not been able to treat CMV-IP effectively. It has been suggested that CMV-IP is an immunopathologic process that can cause irreversible damage, hence, the low efficacy of antiviral therapy and the associated high mortality. Immunomodulating agents such as intravenous immune globulin and cytomegalovirus hyperimmune globulin can increase the efficacy of antivirals in the treatment of CMV-IP. This further supports the postulated immunopathologic process of this disease. The lack of understanding of the pathophysiology of the disease compromised the efforts of treatment and led to the development of preventive interventions with antiviral and immunomodulatory regimens that resulted in a significantly lower incidence of infection and disease. As a result of current data, the Eastern Cooperative Oncology Group has published guidelines for the prevention and treatment of CMV infection and disease. CONCLUSIONS: The prognosis of CMV disease in the BMT recipients has improved as a result of a wide variety of modifications in the management of BMT recipients. These include an increased understanding of the risk factors associated with CMV infection, routine screening for CMV replication and excretion, and more effective prophylactic regimens. Still, more than half of the patients who develop pneumonia will die, indicating that more studies are needed to increase the understanding of the pathophysiology and refine the preventive and therapeutic regimens against CMV.     

Fatal eosinophilic disease following autologous bone marrow transplantation

A 15-year-old girl developed massive, fatal eosinophilic disease following autologous bone marrow transplantation (BMT) for Hodgkin's disease (HD). Prior to autologous BMT, the erythrocyte sedimentation rate (ESR) was elevated, with active HD, but eosinophilia was absent. Post-autologous BMT, ESR and peripheral eosinophilia were observed to correlate with respiratory symptoms. Initial evaluation revealed no recurrent tumor, infection or other identifiable etiology. A diagnosis of chronic eosinophilic pneumonia was made following lung biopsy. A complete response was initially achieved with steroid therapy; however, when steroid therapy was tapered, the eosinophilia and elevated ESR recurred with worsening respiratory symptoms. Terminally, severe pulmonary disease developed and recurrent HD was found in lung, lymph nodes and bone marrow. During episodes of eosinophilia, the patient's serum stimulated her bone marrow as well as control marrow to produce predominantly eosinophilic colonies. Eosinophilic colony production was not observed with patient's sera obtained prior to or during autologous BMT or with control sera. This patient died of eosinophilic inflammatory disease following autologous BMT. The etiology of this disease was not definitely identified but appeared to be due to an eosinophilic-stimulating factor which developed after autologous BMT.     

Bronchoscopic evaluation of pulmonary infiltrates following bone marrow transplantation

Mutants of human prothymosin alpha with impaired ability to inhibit yeast Saccharomyces cerevisiae. cerevisiae cell growth were characterized. Two types of prothymosin alpha-inactivating mutations were observed. Mutations that belong to the first type compromised the nuclear entry of prothymosin alpha by affecting its nuclear localization signal. Analysis of subcellular distribution of GFP-prothymosin alpha fusions revealed a bipartite nuclear localization signal that is both necessary and sufficient for nuclear import of the protein in human cells. Mutations of the second type abrogated the inhibitory action of prothymosin alpha through an unknown mechanism, without influencing the nuclear import of the protein.     

Skin manifestations of graft-versus-host reaction following bone marrow transplantation

We review the cutaneous manifestations of acute and chronic graft versus host disease (GvHD). Acute GvHD is characterized by initial itching, pain on pressure and erythema which begins on posterior auricular skin, palms and soles. The disease evolves into a typical but nonspecific maculopapular rash. Confluent rashes and follicular erythema may occur. Erosive oral lesions usually develop. The most severe variant of GvHD is toxic epidermal necrolysis, which often has a fatal outcome. The onset of chronic GvHD usually occurs more than 100 days after bone marrow transplantation and may be preceded by the acute form. The spectrum of skin changes includes lichenoid pruritic lesions with violaceous color and scleroderma-like skin involvement. Investigation of unknown rashes in these patients includes skin biopsy, which clearly differentiates leukocytoclastic vasculitis and erythema exsudativum multiforme with lymphocytic vasculitis from cutaneous manifestations of GvHD. Special stains may reveal bacteria and fungus in septicemic patients. The therapeutic options are discussed.     

Energy level and sleep quality following bone marrow transplantation

Hypothalamic-pituitary-adrenal (HPA) axis disturbances in depressed children with a history of abuse were examined. Thirteen depressed abused, 13 depressed nonabused, and 13 normal control children were given 1.0 microgram/kg of human corticotropin-releasing hormone (CRH) intravenously. Blood samples for corticotropin (ACTH) and cortisol were obtained at nine intervals. When compared to depressed nonabused and normal control children, depressed abused children had significantly greater peak, total, and net ACTH secretion post-CRH. Increased ACTH secretion was only observed in depressed abused children experiencing ongoing chronic adversity (marital violence, emotional abuse, poverty, lack of supports). The pattern of findings of the depressed abused children experiencing ongoing adversity parallels the pattern of HPA axis dysregulation reported in animal studies of chronic stress. They add to a growing body of literature suggesting measures of past trauma and current adversity are important sources of variability in psychobiological correlates of major depression.     

Long-term persistence of hemopoietic chimerism following sex-mismatched bone marrow transplantation

Wegener's granulomatosis is a distinct clinicopathologic entity characterized by granulomatous vasculitis of the upper and lower respiratory tract and glomerulonephritis. This disease can present as a clinical picture which resembles sepsis and adult respiratory distress syndrome (ARDS). Wegener's disease requires immunosuppression which can have detrimental consequences when used in sepsis. The following case report illustrates the diagnostic difficulties encountered by intensive care physicians treating severe pulmonary failure and multiple organ dysfunction in Wegener's granulomatosis appearing as ARDS with sepsis. CASE REPORT: A 19-year-old female patient had developed acute respiratory and renal failure after a prolonged period (many months) of antibiotic resistant otitis, sinusitis and mastoiditis. The patient had required intubation at another hospital and there was a history of tension pneumothorax and cardiopulmonary resuscitation during mechanical ventilation. Emergency extracorporeal membrane oxygenation (ECMO) for acute hypercapnic and hypoxic respiratory failure was instituted and the patient was transported to our institution while on ECMO. The patient was treated empirically for suspected pulmonary and systemic infection and received hydrocortisone (0.18 mg/kg/h) as part of a protocol-driven treatment of septic shock in addition to antibiotic and antimycotic regime. The use of ECMO was required for 10 and mechanical ventilation for another 50 days after admission. After successful extubation, central nervous system dysfunction became evident with a somnolent and generally unresponsive patient. When the hydrocortisone dose was gradually tapered, the clinical status of the patient further deteriorated, pulmonary gas exchange worsened and she developed renal failure with proteinura and hematuria. A renal biopsy was performed demonstrating vasculitis and focal segmental glomerulonephritis, a systemic granulomatous vasculitis was suspected; the serum was tested for anti-proteinase 3 antibodies (PR3-ANCA) and turned out to be positive (17.5 U/ml; normal range < 7 U/ml). The morphologic findings from renal biopsy, the positive test for antiproteinase 3 antibodies and the pulmonary-renal involvement with evidence of multisystem disease established the diagnosis of Wegener's granulomatosis. Immunosuppressive therapy with cyclophosphamide and prednisolone was instituted resulting in rapid improvement with recovery of pulmonary, renal and central nervous system function within two weeks. The use of ECMO in this patient served as a life-saving immediate measure usefull to "buy time" until a definite diagnosis could be established. ARDS represents an uniform pulmonary reaction to a large number of different noxious stimuli and disease entities. This case demonstrates that intensive care physicians caring for critically ill patients with ARDS should include even rare causes of pulmonary injury into their differential diagnosis.     

Outcomes following mechanical ventilation in children undergoing bone marrow transplantation

Between 1976 and 1992, 869 patients <19 years of age underwent BMT at the University of Minnesota for a variety of malignant and non-malignant disorders. One hundred and ninety-six required mechanical ventilation (MV) at some time from the start of pre-BMT cyto reduction through the first year following BMT. Reasons for MV included respiratory compromise, upper airway management and non-pulmonary indications for respiratory support. In multivariate models, underlying diagnosis, receipt of HLA-mismatched marrow and the presence of acute graft-versus-host disease (aGVHD) were independent predictors of the need for MV. Indication for MV, underlying diagnosis, and presence of aGVHD were independent predictors of successful extubation. Overall survival at 2 years was 14% among MV patients and 52% among non-MV patients. While the need for MV during BMT reduces the overall likelihood of survival, 40% of children who required MV were successfully extubated; 35% of these extubated patients were long-term survivors. This outcome is better than that reported for adult BMT patients requiring respiratory support, who show survival of <5% at 6 months following BMT. Our data suggest extrapolation of outcome data from adult to pediatric patients is not appropriate and aggressive care of pediatric patients requiring respiratory support is not futile.     

Allogeneic bone marrow transplantation

Allogeneic bone marrow transplantation (BMT) after high-dose, marrow-ablative chemoradiotherapy has been established as the treatment of choice for various hematologic, neoplastic, and congenital disorders. The most common type of marrow graft is an allogeneic one from a sibling donor who has compatible human leukocyte antigen (HLA). Only 30% of patients requiring allogeneic BMT have an HLA-compatible sibling donor. Over the past few years, marrows from unrelated HLA-compatible donors have been used with increasing frequency and promising outcome in certain hematologic malignancies. Despite the morbidity and mortality associated with this treatment modality, allogeneic BMT may provide a 20% to 90% chance of long-term, disease-free survival to patients with a wide variety of neoplastic and abnormal marrow disorders.     

Sequential respiratory syncytial virus and cytomegalovirus pneumonia following bone marrow transplantation

A 6-month-old child with familial hemophagocytic lymphohistiocytosis (FHL) experienced early sequential pneumonia due to respiratory syncytial virus (RSV) and cytomegalovirus (CMV) following bone marrow transplantation (BMT). The patient was deficient in natural killer (NK) cell activity (as found frequently in patients with FHL), and this risk factor may have played a major role in the concomitant infection by the two viral pathogens. Rapid diagnostic methods for both viruses are essential and early specific treatment may serve to ameliorate RSV- and CMV-induced lung injury in these life-threatening infections.     

Human herpesvirus 6 infection and associated pathogenesis following bone marrow transplantation

Human herpesvirus 6 (HHV-6) infections following bone marrow transplantation (BMT) have been shown to be associated with fever, skin rash, graft versus host disease, encephalitis, delay in engraftment, marrow suppression, and pneumonia. Unfortunately several of these studies were case reports and although the results were suggestive they prompted us to study these pathological events systematically. These associations were primarily based on either HHV-6 isolation, HHV-6 DNA detection, antigen detection or increases in HHV-6 specific antibodies. HHV-6 activity was more frequent during the post- rather than the pre-transplantation period. All HHV-6 isolates from BMT patients have been shown to be variant B. A better understanding of HHV-6 associated pathogenesis gained by larger prospective trials is needed to facilitate proper treatment of cases of idiopathic illnesses or those associated with symptoms (fever, skin rash) similar to those caused by HHV-6.     

Reconstitution of the T-cell compartment after bone marrow transplantation: restoration of the repertoire by thymic emigrants

We have studied the reconstitution of the T-cell compartment after bone marrow transplantation (BMT) in five patients who received a graft-versus-host disease (GVHD) prophylaxis consisting of methotrexate, cyclosporin, and 10 daily injections (day -4 to day +5) of Campath-1G. This treatment eliminated virtually all T cells (7 +/- 8 T cells/microL at day 14) which facilitated the analysis of the thymus-dependent and independent pathways of T-cell regeneration. During the first 6 months, the peripheral T-cell pool was repopulated exclusively through expansion of residual T cells with all CD4(+) T cells expressing the CD45RO-memory marker. In two patients, the expansion was extensive and within 2 months, the total number of T cells (CD8>CD4) exceeded 1,000/microL. In the other three patients, T cells remained low (87 +/- 64 T cells/microL at 6 months) and remained below normal values during the 2 years of the study. In all patients, the first CD4(+)CD45RA+RO- T cells appeared after 6 months and accumulated thereafter. In the youngest patient (age 13), the increase was relatively fast and naive CD4(+) T cells reached normal levels (600 T cells/microL) 1 year later. In the four adult patients (age 25 +/- 5), the levels reached at that time-point were significantly lower (71 +/- 50 T cells/microL). In all patients, the T-cell repertoire that had been very limited, diversified with the advent of the CD4(+)CD45RA+RO- T cells. Cell sorting experiments showed that this could be attributed to the complexity of the T-cell repertoire of the CD4(+)CD45RA+RO- T cells that was comparable to that of a normal individual and that, therefore, it is likely that these cells are thymic emigrants. We conclude that after BMT, the thymus is essential for the restoration of the T-cell repertoire. Because the thymic activity is restored with a lag time of approximately 6 months, this might explain why, in particular in recipients of a T-cell-depleted graft, immune recovery is delayed.     

Fulminant, CMV-associated, haemophagocytic syndrome following unrelated bone marrow transplantation

We report a case of haemophagocytic syndrome (HPS) occurring after allogeneic bone marrow transplantation (BMT) for acute promyelocytic leukaemia (APL) in a patient in fourth complete remission (CR). Anti-cytomegalovirus (CMV) antibody (Ab) was negative in this patient before BMT. BMT was performed from an HLA-identical unrelated donor who was positive for CMV Ab. After bone marrow engraftment and haematological recovery, severe acute graft-versus-host disease (GVHD) developed. This patient was treated with methylprednisolone in addition to cyclosporin A (CsA). Acute GVHD showed partial improvement, but CMV antigenaemia was observed. Despite administration of gancyclovir and immunoglobulin, CMV antigenaemia showed no improvement and HPS developed. As no other infections or malignancies were observed, we suspect that CMV infection was the trigger for development of HPS.     

Low incidence of myelodysplastic syndrome following transplantation using autologous non-cryopreserved bone marrow

Between May 1984 and October 1995 we performed 114 autologous stem cell transplants for lymphoma in our centre; 77/114 (68%) were transplanted after primary therapy. The conditioning regimen varied according to diagnosis; 26 patients were conditioned with melphalan and total body irradiation, 66 received melphalan and etoposide and the remainder (50) were conditioned with melphalan alone. The median follow-up is 62 months. Only two new haematological malignancies have occurred, both in patients with Hodgkin's disease. One patient developed Ph+ chronic myeloid leukaemia 18 months post-transplant. In this case, because of the timing of the haematological disorder, we considered the malignancy to be concurrent with or to have preceded the transplant. A second patient developed acute myeloid leukaemia 20 months post-transplant. She had been treated for Hodgkin's disease for 10 years and was transplanted in third complete remission. Cytogenetic analysis in this case showed trisomy 11. We believe this to have been an unequivocal second malignancy. Our finding of a 1.1% incidence of secondary haematological malignancy (95% CI 0.02-4.96) from a census population adds weight to the hypothesis that haematological problems post-transplant reflects prior chemotherapy rather than toxicity from the transplant procedure itself.     

Antithrombin-III for the treatment of chemotherapy-induced organ dysfunction following bone marrow transplantation

A hypercoaguable state has been shown to follow high-dose chemotherapy for bone marrow transplantation (BMT). Deficiency of the natural anticoagulants, antithrombin III (AT-III), protein C and protein S correlate with organ dysfunction following BMT. We treated 10 patients with severe post-BMT organ dysfunction with AT-III concentrate. Indications for treatment included AT-III anticoagulant level less than 88% and life-threatening single or multiorgan dysfunction. All patients were loaded with 50 units/kg AT-III every 8 h for three doses followed by 50 units/kg/day each day for 3-12 days. Clinical improvement was seen within 1-5 days of start of therapy in all patients. Patients with veno-occlusive disease (VOD) showed a decrease in platelet consumption in nine of nine patients, resolution of hepatic tenderness in six of eight patients, and reduction of severe ascites and weight gain in four of five patients. The probability of death due to VOD and life-threatening organ dysfunction was significantly less in the AT-III-treated group when compared to a historical control group receiving the same preparative regimen (P = 0.047 and P = 0.034, respectively). Significant improvements in organ dysfunction following AT-III treatment in this small study supports a causal relationship between AT-III deficiency and post-BMT chemotherapy-induced organ dysfunction.     

Oligoclonal dominance of immunoglobulin VH3 rearrangements following allogeneic bone marrow transplantation

Normal numbers of circulating B lymphocytes are reached during the first 6 months following allogeneic BMT, but humoral immunity remains poor. The molecular basis for this lack of function in the first appearing B lymphocytes has not been clarified. Accordingly, we have studied the reconstitution of the VH3 containing Ig repertoire in two CML patients transplanted with allogeneic BM and one healthy control. PBMCs were isolated at several time-points after BMT and mRNA was prepared. VH3 containing Ig rearrangements were amplified with RT-PCR and then cloned and analyzed with colony hybridization using complementary determining region 3 (CDR3)-specific oligonucleotide probes. Four weeks after BMT, two individual clones together represented 52% of the analyzed CDR3 regions. At 6, 8 and 12 weeks after BMT the corresponding probes hybridized with 2-6% of the colonies. A similar pattern was obtained for the other patient. In samples from the healthy control no clones were detected using CDR3-specific oligonucleotide probes from the control. We conclude that the VH3 containing Ig repertoire after BMT is oligoclonal and that specific rearrangements dominate at different time-points. This restriction of the B cell repertoire may contribute to the impaired humoral immunity observed in BMT recipients.     

Endothelium and bone marrow transplantation

Thrombotic complications may occur early after marrow transplantation and many data suggest that endothelial injury plays a pivotal role in their pathogenesis. Since plasma thrombomodulin and P-selectin are thought to be of value as markers of vascular endothelial cell membrane injury, we investigated their plasma concentration in bone marrow transplant patients aiming better to clarify the degree of endothelial involvement. Plasma thrombomodulin and P-selectin were monitored in 25 patients without thrombotic complications before transplant, on day 0 and weekly for 1 month thereafter, while in three patients who developed VOD monitoring continued until day +52. These proteins were in the normal range in all the uncomplicated patients and in two with reversible VOD, while they were always very high in the only patient who developed very severe and lethal VOD. In conclusion, we suggest that endothelial activation/damage occurs rarely in the course of BMT for hematological malignancies; we were able to document endothelial injury in only one patient with very severe thrombotic complication.