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1.
Am J Transplant ; 9(5): 1037-47, 2009 May.
Article in English | MEDLINE | ID: mdl-19422333

ABSTRACT

Long-term survival after lung transplantation is limited by acute and chronic graft rejection. Induction of immune tolerance by first establishing mixed hematopoietic chimerism (MC) is a promising strategy to improve outcomes. In a preclinical canine model, stable MC was established in recipients after reduced-intensity conditioning and hematopoietic cell transplantation from a DLA-identical donor. Delayed lung transplantation was performed from the stem cell donor without pharmacological immunosuppression. Lung graft survival without loss of function was prolonged in chimeric (n = 5) vs. nonchimeric (n = 7) recipients (p < or = 0.05, Fisher's test). There were histological changes consistent with low-grade rejection in 3/5 of the lung grafts in chimeric recipients at > or =1 year. Chimeric recipients after lung transplantation had a normal immune response to a T-dependent antigen. Compared to normal dogs, there were significant increases of CD4+INFgamma+, CD4+IL-4+ and CD8+ INFgamma+ T-cell subsets in the blood (p < 0.0001 for each of the three T-cell subsets). Markers for regulatory T-cell subsets including foxP3, IL10 and TGFbeta were also increased in CD3+ T cells from the blood and peripheral tissues of chimeric recipients after lung transplantation. Establishing MC is immunomodulatory and observed changes were consistent with activation of both the effector and regulatory immune response.


Subject(s)
Lung Transplantation/immunology , Animals , Dogs , Flow Cytometry , Graft Rejection/immunology , Graft Rejection/pathology , Graft Survival/immunology , Graft Survival/physiology , Hematopoiesis , Hematopoietic Stem Cell Transplantation , Immunosuppressive Agents/therapeutic use , Lung Transplantation/physiology , Models, Animal , Respiratory Function Tests , T-Lymphocyte Subsets/immunology , Transplantation Chimera , Transplantation, Homologous
3.
Am J Physiol Lung Cell Mol Physiol ; 279(3): L583-91, 2000 Sep.
Article in English | MEDLINE | ID: mdl-10956634

ABSTRACT

T helper type 1 (Th1) cells are important effectors in a number of immune-mediated lung diseases. We recently described a murine model of lung injury induced by adoptive transfer of cloned alloreactive Th1 cells. To investigate mechanisms that result in injury to the lung, we studied the in vivo distribution of (51)Cr-labeled Th1 cells. One hour after intravenous administration, >85% of injected radioactivity was left in the lung, and at 24 h, 40% of radioactivity was left in the lung. Adherence of Th1 cells in the lung was significantly inhibited by neutralizing antibody to lymphocyte function-associated antigen-1. Th1 cell adherence also was decreased in lungs of mice deficient in intercellular adhesion molecule-1 (ICAM-1). Th1 cell transfer further induced expression of ICAM-1 and vascular cell adhesion molecule-1 in the lung. Vascular cell adhesion molecule-1-immunoreactive protein was markedly induced in lung endothelium by alloreactive Th1 cells. These findings indicate that Th1 cells localize in normal lung by a mechanism involving lymphocyte function-associated antigen-1 and ICAM-1. Alloreactive cells further induce endothelial adhesion molecules that may facilitate recruitment of inflammatory cells to the lung and amplify Th1 cell-induced lung injury.


Subject(s)
Adoptive Transfer , Isoantigens/immunology , Lung/physiology , Th1 Cells/physiology , Animals , Antibodies/pharmacology , Cell Adhesion/physiology , Clone Cells , Integrin alpha4beta1 , Integrins/metabolism , Intercellular Adhesion Molecule-1/metabolism , Intercellular Adhesion Molecule-1/physiology , Lung/cytology , Lymphocyte Function-Associated Antigen-1/immunology , Lymphocyte Function-Associated Antigen-1/metabolism , Lymphocyte Function-Associated Antigen-1/physiology , Mice , Mice, Inbred C57BL , Receptors, Lymphocyte Homing/metabolism , Th1 Cells/immunology , Th1 Cells/metabolism , Vascular Cell Adhesion Molecule-1/metabolism
4.
Transplantation ; 70(1): 39-43, 2000 Jul 15.
Article in English | MEDLINE | ID: mdl-10919572

ABSTRACT

BACKGROUND: Lung injury occurs frequently after allogeneic bone marrow transplantation in association with graft-versus-host disease, an immune response that involves both cellular and cytokine components. In a murine model, we recently showed that cloned alloreactive T helper (Th)1 cells can cause lung injury associated with increased production of tumor necrosis factor (TNF)-alpha by alveolar macrophages (J Immunol 1998; 161: 1913). METHODS: To evaluate the role of TNF-alpha in this model, we injected in vitro-activated Th1 cells into the following: (1) recipients deficient in receptors for TNF; (2) C57BL/6 control mice; (3) C57BL/6 mice, pretreated with soluble TNFRIIFc (a dimorphic high-affinity TNF antagonist); (4) mice expressing TNFRIIFc transgene under control of the surfactant apoprotein C promoter (SPCTNFRIIFc); and (5) wild-type littermate controls (C57BL/6) (n=3-6 mice/group). RESULTS: At 1 and 3 days after i.v. Th1 cell transfer, recipients were killed for analysis of lung histology, bronchoalveolar lavage (BAL) protein, and BAL cell counts. Control mice (wild type) at day 1 after injection had a mild to moderate mononuclear perivasculitis and increased interstitial cellularity. At day 3, lesions were more severe and perivasculitis also involved larger veins. TNFR-deficient mice had normal lung or minimal lung inflammation at day 1. At day 3, perivasculitis of medium-sized vessels was present, but there was no apparent involvement of larger veins. Results in mice treated with soluble TNFRIIFc and transgenic mice (SPCsTNFRIIFc) were similar to controls. BAL protein and BAL cell counts did not differ between any of the experimental groups. CONCLUSIONS: We conclude that lung inflammation induced by Th1 cells may be only delayed when TNF-alpha action is blocked. The persistence of abnormalities indicates that other proinflammatory pathways are involved in injury caused by these cells.


Subject(s)
Lung/pathology , Th1 Cells/immunology , Tumor Necrosis Factor-alpha/physiology , Animals , Antigens, CD/genetics , Antigens, CD/physiology , Bronchoalveolar Lavage Fluid/chemistry , Bronchoalveolar Lavage Fluid/cytology , Graft vs Host Disease/etiology , Mice , Mice, Inbred C57BL , Mice, Transgenic , Proteins/analysis , Receptors, Tumor Necrosis Factor/genetics , Receptors, Tumor Necrosis Factor/physiology , Receptors, Tumor Necrosis Factor, Type II
5.
Crit Care Med ; 27(9): 1800-6, 1999 Sep.
Article in English | MEDLINE | ID: mdl-10507601

ABSTRACT

OBJECTIVE: To determine whether idiopathic pneumonia syndrome (IPS), a form of noninfectious lung injury that follows bone marrow transplantation, is associated with cytokine activation and increased susceptibility to lipopolysaccharide (LPS). DESIGN: Case series. SETTING: Tertiary referral center for marrow transplantation. PATIENTS: Recipients with biopsy-confirmed IPS; normal volunteers and marrow transplant recipients without IPS were analyzed as controls. MEASUREMENTS AND MAIN RESULTS: Levels of lymphocyte and macrophage-derived cytokines as well as components of the LPS, LPS-binding protein (LBP), and CD14 system in bronchoalveolar lavage (BAL) fluid were determined. We found evidence of increased vascular permeability (BAL protein) and inflammatory cytokine activation (interleukin-1, interleukin-2, interleukin-6, and tumor necrosis factor-alpha) in patients with IPS. Patients without IPS had BAL fluid cytokine and protein levels that were similar to levels in BAL fluid from normal volunteers. Moreover, components of the LPS amplification system (LBP and soluble CD14) were increased in patients with IPS but not in patients without IPS. CONCLUSIONS: These results provide direct evidence for proinflammatory cytokine activation in IPS and suggest that these patients might be at increased risk for LPS-mediated injury through the LBP amplification pathway.


Subject(s)
Bone Marrow Transplantation/adverse effects , Bronchi/metabolism , Cytokines/metabolism , Lipopolysaccharides/metabolism , Membrane Glycoproteins , Pneumonia/etiology , Pulmonary Alveoli/metabolism , Acute-Phase Proteins/metabolism , Adolescent , Adult , Bone Marrow Transplantation/immunology , Bronchoalveolar Lavage Fluid/chemistry , Carrier Proteins/metabolism , Case-Control Studies , Humans , Interleukin-1/metabolism , Interleukin-2/metabolism , Interleukin-6/metabolism , Lipopolysaccharide Receptors/metabolism , Middle Aged , Pneumonia/immunology , Transforming Growth Factor alpha/metabolism , Tumor Necrosis Factor-alpha/metabolism
7.
Gastrointest Endosc ; 49(5): 612-21, 1999 May.
Article in English | MEDLINE | ID: mdl-10228260

ABSTRACT

BACKGROUND: Gastrointestinal graft-versus-host disease after allogeneic hematopoietic cell transplantation presents a range of upper gastrointestinal endoscopic and histologic abnormalities. Recognition of these sometimes subtle abnormalities is critical for directing specific therapy. METHODS: Endoscopic and histologic abnormalities in 10 patients with gastrointestinal graft-versus-host disease are reviewed to detail the spectrum of findings. RESULTS: The endoscopic appearance of the stomach and duodenum varies from subtle mucosal erythema and edema to frank ulceration and mucosal slough. Histologic findings include crypt epithelial cell apoptosis and dropout, crypt destruction, and variable lymphocytic infiltration of the epithelium and lamina propria. The involvement may vary from diffuse and uniform to focal, with either the stomach or the duodenum appearing much more involved. CONCLUSIONS: Endoscopic evaluation of the stomach and duodenum and histologic evaluation of biopsies of the gastric antrum can be used to diagnose gastrointestinal graft-versus-host disease. The gross appearance of the mucosa and the histology of gastric biopsies are mutually complementary. However, both the endoscopic evaluation and the histology of the upper gut can underestimate the severity of acute graft-versus-host disease elsewhere in the intestine unless extensive mucosal sloughing is seen.


Subject(s)
Endoscopy, Gastrointestinal , Graft vs Host Disease/diagnosis , Hematopoietic Stem Cell Transplantation/adverse effects , Intestinal Diseases/diagnosis , Acute Disease , Adolescent , Adult , Biopsy , Duodenum/pathology , Gastric Mucosa/pathology , Graft vs Host Disease/pathology , Hematopoietic Stem Cell Transplantation/methods , Humans , Intestinal Diseases/pathology , Intestinal Mucosa/pathology , Middle Aged
8.
Am J Respir Cell Mol Biol ; 20(5): 924-34, 1999 May.
Article in English | MEDLINE | ID: mdl-10226062

ABSTRACT

Despite evidence that implicates transforming growth factor-alpha (TGF-alpha) in the pathogenesis of acute lung injury, the contribution of TGF-alpha to the fibroproliferative response is unknown. To determine whether the development of pulmonary fibrosis depends on TGF-alpha, we induced lung injury with bleomycin in TGF-alpha null-mutation transgenic mice and wild-type mice. Lung hydroxyproline content was 1.3, 1.2, and 1.6 times greater in wild-genotype mice than in TGF-alpha-deficient animals at Days 10, 21, and 28, respectively, after a single intratracheal injection of bleomycin. At Days 7 and 10 after bleomycin treatment, lung total RNA content was 1.5 times greater in wild-genotype mice than in TGF-alpha-deficient animals. There was no significant difference between mice of the two genotypes in lung total DNA content or nuclear labeling indices after bleomycin administration. Wild-genotype mice had significantly higher lung fibrosis scores at Days 7 and 14 after bleomycin treatment than did TGF-alpha-deficient animals. There was no significant difference between TGF-alpha-deficient mice and wild-genotype mice in lung inflammation scores after bleomycin administration. To determine whether expression of other members of the epidermal growth factor (EGF) family is increased after bleomycin-induced injury, we measured lung EGF and heparin-binding- epidermal growth factor (HB-EGF) mRNA levels. Steady-state HB-EGF mRNA levels were 321% and 478% of control values in bleomycin-treated lungs at Days 7 and 10, respectively, but were not significantly different in TGF-alpha-deficient and in wild-genotype mice. EGF mRNA was not detected in normal or bleomycin-treated lungs of mice of either genotype. These results show that TGF-alpha contributes significantly to the pathogenesis of pulmonary fibrosis after bleomycin-induced injury, and that compensatory increases in other EGF family members do not occur in TGF-alpha-deficient mice.


Subject(s)
Pulmonary Fibrosis/genetics , Transforming Growth Factor alpha/deficiency , Animals , Base Sequence , Bleomycin/toxicity , Cell Division , Collagen/metabolism , DNA/metabolism , DNA Primers , Epidermal Growth Factor/genetics , Genotype , Heparin-binding EGF-like Growth Factor , Intercellular Signaling Peptides and Proteins , Lung/cytology , Lung/drug effects , Lung/metabolism , Mice , Mice, Knockout , Mice, Transgenic , Pulmonary Fibrosis/chemically induced , Pulmonary Fibrosis/pathology , RNA/metabolism , Transforming Growth Factor alpha/genetics
9.
Biol Blood Marrow Transplant ; 4(1): 43-8, 1998.
Article in English | MEDLINE | ID: mdl-9701391

ABSTRACT

Although cutaneous graft-vs.-host disease (GVHD) has been noted after autologous hematopoietic cell transplantation, intestinal involvement has not been well documented. We evaluated 197 patients undergoing autologous transplantation for intestinal symptoms; the source for hematopoietic cells was marrow (n=32), peripheral blood stem cells (n=146), or both (n=19). Patients with persistent nausea, vomiting, and anorexia after day 20 underwent upper intestinal endoscopy and mucosal biopsy. Eight patients (4.1%) had diffuse edema, erythema of gastric mucosa, and histological evidence of lymphocytic gastritis with focal apoptosis of crypt epithelial cells-typical of the findings in acute GVHD. All studies for viral, fungal, or bacterial causes were negative. Two patients showed evidence of GVHD in skin and liver, respectively. All patients received 1 mg/kg/day of oral prednisone for 10 days; symptomatic improvement often occurred within days of therapy onset. At the end of corticosteroid treatment, complete resolution of symptoms was seen in all eight patients. In one patient, elevated serum alkaline phosphatase levels gradually normalized over the ensuing 3-4 weeks. When followed up 3 months after treatment, all patients remained symptom-free without evidence of recurrent intestinal symptoms. We concluded that recipients of autologous hematopoietic cells may develop intestinal symptoms caused by a lymphocytic gastritis that is typical of acute GVHD. Patients with this syndrome promptly responded to treatment of a short course of prednisone. The pathogenesis of gastric epithelial damage after autologous transplant is unknown.


Subject(s)
Gastritis/etiology , Gastritis/immunology , Hematopoietic Stem Cell Transplantation/adverse effects , Immunity, Mucosal , Lymphocytes/immunology , Adult , Aged , Diagnosis, Differential , Female , Gastritis/diagnosis , Gastritis/drug therapy , Gastritis/physiopathology , Graft vs Host Disease/diagnosis , Graft vs Host Disease/immunology , Humans , Intestinal Mucosa/immunology , Intestinal Mucosa/physiopathology , Male , Middle Aged , Prednisone/therapeutic use , Transplantation, Autologous
10.
Medicine (Baltimore) ; 77(4): 246-54, 1998 Jul.
Article in English | MEDLINE | ID: mdl-9715729

ABSTRACT

We reviewed 355 autopsies performed between 1990 and 1994 at a major marrow transplant center to determine whether fluconazole prophylaxis prevented visceral fungal infection. Fluconazole prophylaxis was defined by a minimum of 5 prophylactic doses. Fungal infection (any site) was found in 40% of patients transplanted and autopsied at the center. Overall, the proportion of autopsies with any fungal infection was not different for those patients receiving no fluconazole prophylaxis versus those with prophylactic fluconazole. With fluconazole prophylaxis, candidal infections were less frequent, decreasing from 27% to 8%, while Aspergillus infections were more frequent, increasing from 18% to 29%. No increase in deaths related to non-albicans Candida infections was seen. Of the 329 patients with livers examined, hepatic infection caused by Candida species was significantly less common in patients who had received fluconazole. Fungal liver infection was found in 31 patients (9%), 16% of those who were not treated with fluconazole and 3% of those who were treated with fluconazole. Since patients with candidal infections died earlier after marrow transplant than patients with mold infections, we speculate that a longer length of survival may dispose toward acquisition of mold infections. Fluconazole prophylaxis in this cohort of marrow transplant patients undergoing autopsy resulted in a significant reduction in infection caused by Candida species and an increase in mold infections.


Subject(s)
Antifungal Agents/therapeutic use , Bone Marrow Transplantation , Candidiasis/prevention & control , Fluconazole/therapeutic use , Liver/microbiology , Adolescent , Adult , Autopsy , Cohort Studies , Female , Graft vs Host Disease/prevention & control , Humans , Male , Premedication , Retrospective Studies
11.
J Immunol ; 161(4): 1913-20, 1998 Aug 15.
Article in English | MEDLINE | ID: mdl-9712061

ABSTRACT

We have investigated a murine model of acute lung injury caused by i.v. administration of a T cell clone (CD4+, Th1 phenotype) that recognizes Ly5, a polymorphic cell surface glycoprotein expressed on hemopoietic cells. Alloreactive cloned T cells, specific for host Ly5 Ag, cause a mononuclear cell pulmonary vasculitis and interstitial pneumonitis. In further studies of the cellular mechanisms involved in this model, we found that mature host T cells or B cells are not required, since lung injury was comparable in transgenic host mice that lack these cells (RAG-1 knockout). Cloned T cells labeled in vitro with bromodeoxyuridine were localized in inflammation foci in lung, but the majority of cells in the foci were not labeled. Using transgenic mice that constitutively express lacZ, we determined that the mononuclear cell vasculitis is of host cell origin. Alveolar macrophages (AM) from T cell-treated mice spontaneously secreted TNF-alpha in culture, whereas TNF-alpha was not detected in AM cultures from control mice. TNF-alpha production in response to LPS stimulation was significantly higher in AM cultures derived from T cell-treated mice than in those from control mice. Challenge with sublethal doses of LPS resulted in 50% mortality in T cell-treated mice and was associated with augmented AM TNF-alpha production and protein in bronchoalveolar lavage fluid. We conclude that immune activation of T cells of the Th1 phenotype can initiate lung injury characterized by a host-derived mononuclear cell inflammation and activation of AM.


Subject(s)
Leukocytes, Mononuclear/pathology , Lung/immunology , Lung/pathology , Lymphocyte Activation/immunology , Macrophage Activation/immunology , Macrophages, Alveolar/immunology , Th1 Cells/immunology , Adoptive Transfer , Animals , B-Lymphocytes/pathology , Bromodeoxyuridine/metabolism , Bronchoalveolar Lavage Fluid/chemistry , Bronchoalveolar Lavage Fluid/immunology , Clone Cells , Immunity, Innate , Immunohistochemistry , Inflammation/immunology , Inflammation/pathology , Interferon-gamma/metabolism , Isoantigens/immunology , Leukocyte Common Antigens/genetics , Leukocytes, Mononuclear/immunology , Lipopolysaccharides/toxicity , Lung/chemistry , Lymphopenia/genetics , Lymphopenia/immunology , Lymphopenia/therapy , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Proteins/metabolism , T-Lymphocytes/pathology , T-Lymphocytes/transplantation , Th1 Cells/chemistry , Th1 Cells/transplantation , Tumor Necrosis Factor-alpha/metabolism
12.
J Immunol ; 161(2): 909-18, 1998 Jul 15.
Article in English | MEDLINE | ID: mdl-9670969

ABSTRACT

To study the character of graft-vs-host disease (GVHD) induced by T cells specific for hemopoietic cells, T cells specific for a polymorphic segment of CD45 were transferred into CD45 congenic mice. C57BL/6 mice that express the CD45b allele were immunized with a 13 mer peptide representing the polymorphic segment (p257-268) of CD45a protein. Conversely, C57BL/6 mice congenic for CD45a were immunized with the CD45b peptide. CD4+ T cells specific for allelic CD45 peptides were elicited. Importantly, T cells specific for CD45 peptides proliferated specifically and vigorously in response to spleen cells expressing the appropriate polymorphic CD45 protein. T cells specific for CD45 induced a substantial graft-vs-host response (GVHR) with predominant early pulmonary vasculitis and later more widespread interstitial mononuclear cell infiltration and alveolitis. No GVHR was induced in bone marrow chimeras expressing only donor hemopoietic cells. Thus, donor T cell recognition of host hemopoietic cells is sufficient to elicit GVHR, but the classical skin, liver, and gut manifestations of GVHD were not observed. The CD45-specific T cells used secreted Th1 cytokines, but without detectable soluble IL-2. Studies using CD45-specific T cells with different effector functions might allow further dissection of donor cell requirements for GVHD syndromes.


Subject(s)
Graft vs Host Disease/immunology , Leukocyte Common Antigens/immunology , Lung Diseases/immunology , Peptide Fragments/immunology , Polymorphism, Genetic , T-Lymphocyte Subsets/immunology , Vasculitis/immunology , Animals , Cell Communication/immunology , Cell Line , Cell Movement/immunology , Clone Cells , Epitopes, T-Lymphocyte/immunology , Female , Graft vs Host Disease/pathology , Hematopoietic Stem Cells/immunology , Injections, Intravenous , Leukocyte Common Antigens/biosynthesis , Leukocyte Common Antigens/genetics , Leukocytes, Mononuclear/immunology , Leukocytes, Mononuclear/pathology , Liver/pathology , Lung Diseases/pathology , Lymphocyte Activation/genetics , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Peptide Fragments/genetics , Pulmonary Fibrosis/immunology , Pulmonary Fibrosis/pathology , Spleen/cytology , Spleen/immunology , Spleen/metabolism , T-Lymphocyte Subsets/transplantation , Vasculitis/pathology
13.
Exp Hematol ; 25(12): 1240-5, 1997 Nov.
Article in English | MEDLINE | ID: mdl-9357967

ABSTRACT

We studied the effect of recombinant canine stem cell factor (rcSCF) on hematopoietic recovery, incidence of graft failure, graft-vs.-host disease (GVHD), and survival after marrow transplantation from dog leukocyte antigen (DLA)-identical canine littermates. Ten animals received 100 microg rcSCF/kg/day b.i.d. by subcutaneous injection on days 1 through 10 after 920 cGy total body irradiation and transplantation of a mean of 3.7x10(8) marrow cells/kg body weight. None of the dogs received GVHD prophylaxis. All animals showed hematopoietic engraftment. The median number of days to achieve 1000 neutrophils/mm3 was 9; 100 monocytes/mm3 were reached after 15 days, 500 lymphocytes/mm3 after 21 days, and 20,000 platelets/mm3 after 16 days. One animal developed GVHD involving skin, gut, and liver and died of bacterial pneumonia 21 days after transplantation. The remaining nine dogs were observed for a median of 37 days (range 29-84 days) posttransplantation until they were killed. Facial edema was seen in three dogs during the first 2-3 days of rcSCF administration. These results show that within the limits of this study it appears to be safe to administer SCF after DLA-identical littermate marrow transplants in dogs. Comparison with previously published data in the same model showed that neutrophil and monocyte recovery was significantly faster in dogs receiving SCF treatment compared with dogs without growth factor treatment (recovery to achieve 1000 neutrophils/mm3: median 9 days vs. 13 days, p = 0.002; recovery to 100 monocytes/mm3: median 15 days vs. 105 days, p = 0.0002). Otherwise, no significant differences were seen. Results obtained with SCF treatment were similar to those previously obtained in the same model with recombinant human granulocyte colony-stimulating factor (rhG-CSF) treatment except that recovery of lymphocytes to 500/mm3 appeared to be more rapid in G-CSF-treated dogs (median 15 days vs. 21 days, p = 0.03).


Subject(s)
Bone Marrow Transplantation/veterinary , Hematopoiesis/drug effects , Stem Cell Factor/pharmacology , Animals , Bone Marrow Transplantation/immunology , Dogs , Female , Graft Survival , Graft vs Host Disease/etiology , Granulocyte Colony-Stimulating Factor/pharmacology , Histocompatibility , Male , Recombinant Proteins/pharmacology , Time Factors
14.
Blood ; 90(6): 2502-8, 1997 Sep 15.
Article in English | MEDLINE | ID: mdl-9310503

ABSTRACT

To determine risk factors, frequency, time patterns, and outcome of ganciclovir-related neutropenia in allogeneic marrow transplant recipients, 278 consecutive patients receiving ganciclovir from engraftment until day 100 were studied. In this cohort, 159 patients (57%) had absolute neutrophil counts (ANC) less than 1,500/microL, 112 (41%) had an ANC less than 1,000/microL, 87 (31%) less than 750/microL, and 56 (21%) less than 500/microL for at least 2 consecutive days. Statistically significant risk factors for neutropenia in a Cox model were low marrow cellularity between day 21 and 28 (relative risk [RR] 2.4, P = .0002), hyperbilirubinemia > or =6 mg/dL during the first 20 days (RR 2.5, P = .0001), and elevation of serum creatinine > or =2 mg/dL after day 21 after transplant (RR 2.1, P = .001). Restriction to factors present at engraftment resulted in a similar model with low marrow cellularity, hyperbilirubinemia > or =6 mg/dL, and elevated serum creatinine as significant risk factors. Patients with no risk factor had an incidence of neutropenia of 21%, an incidence of 31% for one risk factor, and of 57% for two or more risk factors (RR 3.8, P = .001). Neutropenia was a negative predictor of overall (RR 2.0, P = .0001) and event-free survival (RR 2.1, P < .0001), and a predictor of relapse (RR 1.7, P = .03) and nonrelapse mortality (RR 2.1, P = .003). Thus, early liver dysfunction, elevated serum creatinine, and low marrow cellularity are risk factors for ganciclovir-related neutropenia. Neutropenia in ganciclovir recipients after marrow transplantation is an independent risk factor for mortality.


Subject(s)
Bone Marrow Transplantation/methods , Cytomegalovirus Infections/prevention & control , Ganciclovir/adverse effects , Neutropenia/etiology , Adolescent , Adult , Aged , Bone Marrow Cells , Child , Child, Preschool , Creatinine/blood , Female , Ganciclovir/therapeutic use , Humans , Hyperbilirubinemia/complications , Infant , Male , Middle Aged , Outcome Assessment, Health Care , Risk Factors , Time Factors , Transplantation, Homologous
15.
Clin Infect Dis ; 24(6): 1154-60, 1997 Jun.
Article in English | MEDLINE | ID: mdl-9195074

ABSTRACT

To evaluate the spectrum of nocardiosis after marrow transplantation, we reviewed the medical records of 27 patients with nocardiosis who were treated at three centers, and we reviewed the findings of three cases reported in the literature. Nocardial involvement was defined as invasive nocardiosis (n = 25), colonization (n = 4), or contamination (n = 1). The median time to the diagnosis of nocardiosis after marrow transplantation was 210 days. Nocardia asteroides complex accounted for 96% of isolates. All 25 invasive infections occurred in allogeneic marrow recipients. Ten (40%) of 25 patients with invasive nocardiosis were receiving double-strength oral trimethoprimsulfamethoxazole twice weekly as prophylaxis for Pneumocystis carinii pneumonia. Treatment regimens for nocardiosis included sulfonamides; synergistic agents were also often added. The overall survival rate at 6 years was 34%; survival from the infection itself was 84%. Two of four nocardiosis-related deaths also involved other pathogens. The incidence of nocardiosis among allogeneic marrow recipients averaged 0.3% over 25 years. We conclude that nocardiosis is a rare infection that occurs later after marrow transplantation than other infections and that is marginally associated with increased mortality among long-term survivors of allogeneic marrow transplantation.


Subject(s)
Bone Marrow Transplantation/adverse effects , Nocardia Infections/etiology , Adolescent , Adult , Child , Child, Preschool , Female , Humans , Male , Middle Aged , Nocardia/isolation & purification , Nocardia Infections/pathology , Nocardia Infections/therapy , Retrospective Studies
16.
Transplantation ; 63(8): 1079-86, 1997 Apr 27.
Article in English | MEDLINE | ID: mdl-9133468

ABSTRACT

BACKGROUND: The aim of our study was to describe the incidence, clinical course, and risk factors for the idiopathic pneumonia syndrome (IPS), compared with those previously described for "idiopathic pneumonia," after bone marrow transplantation (BMT). METHODS: Our study design was a case-series review with determination of risk by comparison with unaffected controls by log-rank or Fisher's exact (two-tailed) test and logistic regression analyses. The study group comprised 1165 consecutive marrow recipients at a single center from 1988 to 1991. RESULTS: IPS was documented in 85 BMT recipients (7.3%) by bronchoalveolar lavage (n=68), open lung biopsy (n=3), or autopsy (n=14). The calculated actuarial incidence for IPS within 120 days after BMT was 7.7%. Median time to onset was 21 days (mean 34+/-30). Hospital mortality was 74%, and 53 BMT recipients (62%) died with progressive respiratory failure. IPS resolved in 22 patients (26%); 18 patients (21%) survived to discharge. Mechanical ventilation was required by 59 BMT recipients (69%), within a median of 2 days of onset of infiltrates. Two of these 59 recipients (3%) survived to discharge. Pulmonary infection (predominantly fungal) was noted in 7 of 25 (28%) BMT recipients who had an autopsy. Potential risk factors for IPS were assessed in univariate and multivariate logistic regression analyses. Although the incidence was not significantly different between autologous (5.7%) and allogeneic marrow recipients (7.6%), risks were identified only for the latter: malignancy other than leukemia (odds ratio=6.5 compared with aplastic anemia), and grade 4 graft-versus-host disease (odds ratio=5.4 compared with lower grades). No factors were associated with recovery. CONCLUSIONS: The incidence of idiopathic lung injury seems lower, the onset earlier, and the risk factors different from those previously reported. The major risks seem to be regimen-related toxicity and multi-organ dysfunction associated with alloreactive processes.


Subject(s)
Bone Marrow Transplantation/adverse effects , Pneumonia/etiology , Adult , Bilirubin/blood , Bronchoalveolar Lavage Fluid/cytology , Bronchoalveolar Lavage Fluid/microbiology , Bronchoalveolar Lavage Fluid/virology , Female , Humans , Incidence , Male , Multivariate Analysis , Pneumonia/epidemiology , Pneumonia/therapy , Regression Analysis , Respiration, Artificial , Risk Factors , Syndrome
17.
Bone Marrow Transplant ; 20(12): 1081-6, 1997 Dec.
Article in English | MEDLINE | ID: mdl-9466282

ABSTRACT

Pancreatitis has been described as an infrequent complication of marrow transplantation. This study investigated the prevalence of pancreatitis at autopsy in marrow transplant patients and determined risk factors for its development. We reviewed consecutive autopsy reports from 1991 to 1993. Medical records and laboratory reports were reviewed for analysis of clinical variables. Autopsy findings and clinical variables were correlated with the autopsy diagnosis of pancreatitis. Pancreatitis was found in 51 of 184 (28%) patients at autopsy. Of those with pancreatitis, 35% had abdominal pain, 10% had measurements of serum pancreatic enzymes, and 20% had abdominal imaging studies in the week prior to death. By univariable analysis, risk factors associated with development of pancreatitis included clinical grades 3 and 4 GVHD, GVHD at autopsy, liver GVHD at autopsy, major infection at autopsy, and increasing days of survival. By multivariable analysis, independent risk factors for its development included any GVHD at autopsy, increasing length of survival after transplantation, and major infection at autopsy. We conclude that pancreatitis is a common but often subclinical complication of marrow transplantation. Its development may be associated with a high prevalence of biliary sludge and prolonged treatment of GVHD with cyclosporine and prednisone.


Subject(s)
Bone Marrow Transplantation/adverse effects , Pancreatitis/etiology , Abdominal Pain/epidemiology , Abdominal Pain/etiology , Acute Disease , Adult , Amylases/blood , Bile/chemistry , Biomarkers , Bone Marrow Transplantation/mortality , Cause of Death , Cohort Studies , Cyclosporine/administration & dosage , Cyclosporine/adverse effects , Drug Therapy, Combination , Female , Gallbladder/pathology , Graft vs Host Disease/complications , Graft vs Host Disease/mortality , Humans , Immunosuppressive Agents/adverse effects , Male , Methotrexate/administration & dosage , Neoplasms/complications , Neoplasms/therapy , Pancreatitis/epidemiology , Prednisone/administration & dosage , Prednisone/adverse effects , Prevalence , Risk Factors , Transplantation Conditioning/adverse effects , Whole-Body Irradiation/adverse effects
18.
Gastrointest Endosc ; 44(3): 223-9, 1996 Sep.
Article in English | MEDLINE | ID: mdl-8885337

ABSTRACT

BACKGROUND: Gastric antral vascular ectasia (GAVE) leads to blood loss in the disorders of "watermelon stomach" and portal gastropathy, but is not a commonly recognized complication of marrow transplantation. METHODS: GAVE was diagnosed when capillary ectasia, focal capillary thromboses, and fibromuscular hyperplasia were identified in antral mucosal biopsy specimens. Marrow transplant patients bleeding from GAVE were reviewed to ascertain common variables in their pretransplant, posttransplant, and bleeding course. RESULTS: Six patients developed bleeding due to GAVE. The onset of bleeding was 18 to 94 days after transplant and required an average of 37 U of blood (range, 2 to 130 U). Two patients stopped bleeding after restoration of platelet counts. Two patients had surgical antral resections; both died of multiorgan failure after surgery. Two patients had successful endoscopic laser ablation of vascular lesions and survived. Factors possibly associated with GAVE included male gender, VOD of the liver, oral busulfan as part of the conditioning regimen, and growth factor use after transplant. CONCLUSIONS: GAVE was a cause of gastric bleeding in six patients with marrow transplant patients. Restoration of platelet counts and endoscopic laser photocoagulation are the therapies of choice for ongoing bleeding in these patients.


Subject(s)
Bone Marrow Transplantation , Gastrointestinal Hemorrhage/etiology , Pyloric Antrum/blood supply , Adolescent , Capillaries/pathology , Dilatation, Pathologic , Fibromuscular Dysplasia/pathology , Gastrointestinal Hemorrhage/pathology , Gastrointestinal Hemorrhage/surgery , Humans , Laser Therapy , Male , Middle Aged , Platelet Count , Pyloric Antrum/pathology
19.
Bone Marrow Transplant ; 18(2): 361-8, 1996 Aug.
Article in English | MEDLINE | ID: mdl-8864447

ABSTRACT

We reviewed 10 cases of culture proven legionellosis that occurred at a marrow transplant center (Fred Hutchinson Cancer Research Center, Seattle, WA, USA) over a 6-year period ending in 1993. Infections were caused by four species of Legionella with no apparent clustering of cases. Detection of Legionella using direct fluorescent antibody assays proved unreliable due to the high proportion of rare Legionella species isolated. The clinical presentation, course and outcome of patients varied and did not correlate with underlying disease, type of transplant, transplant day or engraftment status. However, five of the seven patients infected with non-pneumophila species recovered from their pneumonia compared to none of the three patients infected with L. pneumophila. Persistent or relapsed infection after 3 weeks of appropriate therapy was documented in one case suggesting that prolonged antibiotic treatment is indicated in these patients.


Subject(s)
Bone Marrow Transplantation/adverse effects , Legionellosis/etiology , Adolescent , Adult , Child , Female , Humans , Legionellosis/diagnosis , Legionellosis/drug therapy , Male , Middle Aged
20.
J Clin Microbiol ; 34(4): 877-81, 1996 Apr.
Article in English | MEDLINE | ID: mdl-8815100

ABSTRACT

Human herpesvirus 6 (HHV-6) variant B is frequently identified in peripheral blood, but identification of HHV-6 variant A is relatively rare. We devised a PCR-based method for sensitive, simultaneous detection of both HHV-6 variants. The method was applied to 34 lung tissue specimens that were previously shown to contain HHV-6 DNA. A total of 22 lung tissue samples showed coinfections with HHV-6 variants A and B, 2 had only HHV-6 variant A DNA, and 10 had only HHV-6 variant B DNA. The prevalences of coinfections in lung tissues from healthy controls (54% coinfected) and in those from bone marrow transplant patients with pneumonia (67% coinfected) were similar. These data indicate that coinfections of HHV-6 variants A and B commonly occur in lung tissues of healthy and diseased individuals.


Subject(s)
Genetic Variation , Herpesviridae Infections/virology , Herpesvirus 6, Human/genetics , Herpesvirus 6, Human/isolation & purification , Lung/virology , Pneumonia, Viral/virology , Base Sequence , Bone Marrow Transplantation/adverse effects , Case-Control Studies , DNA Primers/genetics , DNA Probes/genetics , DNA, Viral/genetics , Herpesvirus 6, Human/classification , Humans , Molecular Sequence Data , Polymerase Chain Reaction/methods , Polymerase Chain Reaction/statistics & numerical data , Sensitivity and Specificity
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