Prevention and treatment of CMV infection after allogeneic bone marrow transplant

CMV infection is the major infectious complication following bone marrow transplantation. It is most often related to reactivation of latent infection in patients who were CMV seropositive before BMT. The incidence and severity have recently been modified by the use of preventive and curative treatments. Prevention of CMV infection with the transfusion of seronegative blood products is useful only when donor and recipient are seronegative. High-dose acyclovir has been shown effective in one randomized study. A multicenter study is currently being performed in Europe to confirm this result. Intravenous gammaglobulins seemed to lower the number of patients who incur interstitial pneumonitis but not the incidence of viremia. They also decreased the incidence of gram-negative sepsis and severe GVH and improved survival. The treatment is based on the use of gancyclovir. Several studies show that gancyclovir is more effective in asymptomatic patients with viral isolation from blood or bronchoalveolar lavage. The addition to gancyclovir of high-dose gammaglobulin improves survival in symptomatic patients with interstitial pneumonitis. This progress in the prevention and treatment of CMV infection has improved the overall results of allogeneic bone marrow transplantation.     

Study of Langerhans cells after allogeneic bone marrow transplantation

We assessed the number of Langerhans cells (LC) before and after bone marrow transplantation (BMT) in 27 patients in order to study the fate and behavior of these dendritic antigen-presenting cells following allogeneic BMT. LC were identified using monoclonal antibody OKT6 on skin biopsies performed on days - 10, 0, 11, 25, 39, 120, and 365. In a control group composed of 15 healthy adults aged 20-37 yr, the mean number of LC (+/- SEM) was 25.6 +/- 1.17/0.1 sq mm of epidermal surface. Our study shows that pretransplant, the number of LC in patients with aplastic anemia or leukemia was lower than that of controls. The finding of low numbers of LC in patients with untreated aplastic anemia is suggestive of a medullary origin of LC in man. Moreover, during the early posttransplant period, nearly all patients present a severe deficit in LC. This deficit may delay the maturation of their immune system. The number of LC reaches nearly normal levels 4- 12 mo after BMT. Finally, we have noted a significant impairment of LC reconstitution in patients with acute graft-versus-host disease (GVHD), providing evidence that this defect may be an important mechanism involved in acute GVHD-related immunodeficiency.     

Tuberculosis among allogeneic bone marrow transplant recipients in India.

Allogeneic bone marrow transplant recipients have severe impairment of cell-mediated immunity and hence a higher incidence of mycobacterial infections might be expected in regions where tuberculosis is common. We reviewed the case records of 217 patients who underwent allogeneic bone marrow transplantation during the period 1986-1999 at our center in India. Mycobacterial infections were diagnosed in three patients (1.38%). All patients presented with extrapulmonary disease. Two patients had disseminated tuberculosis with one of these being diagnosed on autopsy studies. The third patient had tuberculosis involving the cervical lymph node and dorsal spine. Two patients treated with antituberculous therapy are well. Infection with Mycobacterium tuberculosis is not a common problem in allogeneic bone marrow recipients even in an endemic area, but when it occurs, it is usually disseminated with predominantly extrapulmonary involvement.     

Inadequate erythropoietin production in allogeneic bone marrow transplant patients.

BACKGROUND. There is some evidence that the erythropoietin (Epo) feedback mechanism in response to anemia can be altered in the period immediately following allogeneic bone marrow transplantation (BMT). METHODS. By using a RIA, serum erythropoietin (sEpo) levels were serially measured in 10 BMT patients, from day -10 up to day +30, and the results correlated with the concurrent hemoglobin (Hb) value. Thirty healthy subjects and 15 iron-deficiency anemic patients were used in order to construct our own reference sEpo vs Hb curve. A sEpo value recorded in BMT patients was considered to be inappropriate for any given Hb value when falling below the lower 95% confidence limit of the control curve. RESULTS. Basal sEpo levels were significantly higher than in healthy subjects, and increased further during the BMT procedure, being still higher than controls on day +30. However, Epo production resulted inappropriate for each given Hb value, when compared with the control curve, in 60 out of 67 sEpo determinations performed following graft infusion. The inadequate Epo production was not associated with the development of clinically manifest signs of kidney toxicity. CONCLUSION. These data indicate that Epo production is impaired in the period immediately following BMT and suggest a role for the administration of recombinant human Epo in the short-term management of the anemia associated with BMT.     

Long-term sequelae after recovery from cytomegalovirus pneumonia in allogeneic bone marrow transplant recipients.

The clinical course of cytomegalovirus (CMV) pneumonia in seven consecutive bone marrow transplant (BMT) recipients during a 24-month period was studied. Retrospective analysis of clinical data on the recipients with CMV pneumonia during the illness and prospective follow-up of those who recovered from the pneumonia was performed. Those who had CMV as the sole pathogen and with lymphocytosis in the BAL or the peripheral blood during the illness recovered from the pneumonia. On the contrary, those who had mixed bacterial or fungal infection with peripheral lymphopenia died. Persistent lymphocytosis in the BAL and the peripheral blood, in the absence of CMV infection, was observed in the survivors. Two subsequently developed restrictive lung disease and two had relapse of their primary malignancy. These data suggest that CMV pneumonia in BMT patients is associated with significant long-term sequelae. The phenomenon of persistent lymphocytosis in the BAL and the peripheral blood, in the absence of CMV infection, supports Grundy's hypothesis that CMV pneumonia in BMT recipients is an immunopathologic condition.     

Invasive mold infections in allogeneic bone marrow transplant recipients.

Invasive mold infections (IMIs) are an important cause of morbidity and mortality in patients who are undergoing bone marrow transplantation (BMT). To examine the epidemiology, risk factors, and outcome of IMIs in allogeneic BMT recipients, all cases of mold infection among 94 adult patients who underwent allogeneic BMT at this institution from 1 January 1997 through 31 December 1998 were reviewed retrospectively. Fifteen cases of IMI were identified; infection occurred a median of 102 days after BMT. Aspergillus species was the most common cause of disease, and species other than Aspergillus fumigatus were present in 53% of patients. By multivariate analysis, the variable associated with infection risk was systemic glucocorticosteroid use. Prophylactic antifungal therapy that was targeted to high-risk patients had little effect on disease incidence. These observations suggest that early identification of high-risk patients and better approaches to prevention should be explored, to reduce incidence and severity of disease in this population.     

Pulmonary infections after bone marrow transplant.

Pneumonia occurs in up to 50% of patients after bone marrow transplant and is the main cause of mortality. The patient may be predisposed to pulmonary complications by previous treatment and infections, by transplant conditioning and graft-versus-host disease prophylaxis regimens, and by prolonged severe immune-suppression. The period of greatest risk is within 3 months of transplant when focal or diffuse interstitial pneumonias may occur. The most common infectious etiologies are Aspergillus or other fungi and cytomegalovirus. Idiopathic, noninfectious, interstitial pneumonia occurring in this same period may represent treatment toxicity. Both fungal and cytomegalovirus infections have been associated with high mortality, but there has been significant success in treating cytomegalovirus with the combination of ganciclovir and immunoglobulin in recent years. Late bacterial pneumonia may occur more than 6 months after transplant because of prolonged immunedeficiency and functional asplenia. Prophylactic therapy to prevent the pneumonias anticipated after transplant should be an essential part of the care of the bone marrow transplant patient.     

Twenty-year remission of rheumatoid arthritis in 2 patients after allogeneic bone marrow transplant

We describe 21 and 19 year followup of 2 patients with severe rheumatoid arthritis (RA) who in 1984 and 1986 underwent allogeneic bone marrow transplantation (BMT) after full myeloablative conditioning, for therapy-induced aplastic anemia. Regarding the arthritis, both patients are well, taking no medications, and free of signs or symptoms of active RA. One patient is in excellent health overall, while the other has coronary artery disease and chronic obstructive pulmonary disease attributable to smoking. We suggest that allogeneic BMT may be a curative treatment for severe RA.     

Options and limitations of long-term oral ciprofloxacin as antibacterial prophylaxis in allogeneic bone marrow transplant recipients

The efficacy and safety of ciprofloxacin as long-term antibacterial prophylaxis after allogeneic bone marrow transplantation were assessed prospectively. Eighty-nine recipients of lymphocyte-depleted marrow grafts were each given ciprofloxacin orally, 500 mg twice daily. Fever developed in 71 out of 78 evaluable patients (91%) and was accompanied by positive blood cultures in 42 cases (59%). 'Viridans' streptococci, all but one with reduced in vitro susceptibility to ciprofloxacin, accounted for 35 episodes of bacteraemia. Thirty-three episodes occurred in patients given anthracyclines compared with only two episodes in other patients (chi 2 = 5.58: p less than 0.05). All bacteraemic fevers occurred within 11 days post-transplant. Gram-negative sepsis did not occur in any patient. Sixteen patients died but none due to a bacterial cause. Allergy to ciprofloxacin was registered in three out of 76 assessable cases (4%).     

Neurologic complications in allogeneic bone marrow transplant patients receiving cyclosporin.

Regimens using cyclosporin (CSP) and either methylprednisolone (MP) or methotrexate (MTX) have been useful in the prophylaxis of acute graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation (BMT). However, CSP produces a number of side effects, including neurologic toxicity. A retrospective review of recipients of 239 BMTs given CSP-based prophylactic regimens revealed that 10 patients (4.2%, 95% confidence interval 0% to 10.4%) experienced a syndrome characterized by hypertension, severe visual disturbances, seizures and occipital lobe density changes on brain computed tomography (nine patients) or nuclear magnetic resonance imaging (one patient). Neurologic findings were reversible in all cases, usually after temporary discontinuation of CSP. Univariate analysis identified the following risk factors for neurotoxicity: use of unrelated or HLA-mismatched related donors, administration of etoposide (VP-16) or total body irradiation as part of conditioning, use of corticosteroids for prophylaxis or treatment of acute GVHD, or development of either acute GVHD or clinically significant microangiopathic hemolytic anemia (MAHA) post-BMT. In multivariate analysis, the most important predictors were the use of VP-16 (p = 0.008), the use of a continuous infusion CSP plus MP prophylactic regimen for GVHD (p = 0.003) and the development of MAHA after BMT (p less than 0.001). The strong association with MAHA suggests that endothelial damage is related to the development of this complication.     

Antibody-mediated marrow failure after allogeneic bone marrow transplantation

Marrow graft failure observed in association with histocompatibility differences between donor and recipient is often attributed to rejection mediated by host-derived cytolytic T lymphocytes. The data presented in this report indicate that persistent host antibodies specific for donor antigen may also mediate graft failure, either by antibody-dependent cell-mediated cytotoxicity (ADCC), or complement- mediated cytotoxicity. In the case of HLA Class I disparity, where all donor cells express the target antigen, the presence of alpha-donor antibody was associated with complete graft failure and death. In the case of ABO blood group antigen disparity, the presence of alpha-donor antibody resulted in erythroid hypoplasia. The latter cases proved informative insofar as they established that host antibodies could persist for more than 18 months after chemoradiotherapy and impair marrow function.     

Orthotopic liver transplantation for life-threatening veno-occlusive disease of the liver after allogeneic bone marrow transplant.

Veno-occlusive disease (VOD) of the liver is a serious and often lethal sequela to bone marrow transplantation. Although a history of prior hepatitis moderately increases the risk of VOD, reliable screening methods for identifying high risk patients are not available. New approaches to managing patients who develop serious VOD are needed. One approach may be the use of orthotopic liver transplantation in selected patients who are likely to die of the disease. In this report we describe a patient who underwent liver transplantation for life-threatening VOD following allogeneic transplantation for CML. Although this patient died early from interstitial pneumonitis, the orthotopic liver functioned well up to her death. Other reports describing successful liver transplants in patients with advanced VOD or graft-versus-host disease of the liver are discussed and the possible indications for liver transplantation for VOD after marrow transplantation are considered. Taken together, these reports suggest that orthotopic liver transplantation may be a feasible and potentially effective approach to managing select patients with life-threatening liver dysfunction after marrow transplantation.     

Cytokine activity after allogeneic bone marrow transplantation. IV. Production of mRNA for IL-3 and GM-CSF by mitogen-stimulated circulating mononuclear cells.

The ability of circulating mononuclear cells from recipients of HLA identical sibling marrow transplants to generate messenger (m) RNA for the haemopoietic growth factors interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF) upon mitogen stimulation was investigated. The amount of IL-3 mRNA per ml of blood and IL-3 mRNA per 10(7) mononuclear cells as well as the amount of GM-CSF mRNA per ml of blood was significantly lower in transplant recipients than in normal volunteers. Lower values for mRNA expression for both IL-3 and GM-CSF were associated with the use of immunosuppressive therapy post transplant. No correlation was found between the expression of message for either cytokine, or the presence or absence of acute graft-versus-host disease at the time of testing. While there was no correlation between the quantity of GM-CSF message produced and time elapsed post transplant, IL-3 message expression increased slightly with increasing time post transplant. These defects of haemopoietic regulators constitute another parameter of impaired cellular immunity occurring after allogeneic marrow transplantation.     

Infections among allogeneic bone marrow transplant recipients in India

Summary:Infections are a major cause of morbidity and mortality in patients undergoing high-dose therapy and allogeneic bone marrow transplantation (BMT) despite prophylaxis, use of growth factors and newer antimicrobial drugs. We report the clinical profile of infections among 297 patients who underwent 304 allogeneic transplants between 1986 and December 2001. All patients developed febrile neutropenia. There were 415 documented infections among 304 transplants. This included bacterial (34.9%), viral (42.9%), fungal (15.9%) and other infections (6.3%) including tuberculosis. Bacterial pathogens were mainly Gram-negative bacteria (80%) as compared to Gram-positive (20%) bacteria. The common Gram-negative bacteria were nonfermenting Gram-negative bacteria (NFGNB) (24.9%), Pseudomonas (17.9%), Escherichia coli (17.9%) and Klebsiella (9.7%). The major source of positive cultures was blood (53.7%) followed by urine (25.5%) and sputum (8.9%). In all, 133/304 (43.7%) transplants had 178 documented viral infections. The common viral infections were due to cytomegalovirus, herpes group of viruses and transfusion-related hepatitis; and 60/304 (19.7%) transplants had 66 documented fungal infections. Common fungi included Aspergillus species (69.7%), Candida (22.2%) and Zygomycetes (8.1%). Tuberculosis was documented in 2.3% of the transplants. Catheter infections were suspected or documented in 7.8% of the transplants (24/304). The incidence of infections in this series from developing countries is not significantly different from reports from the West.Bone Marrow Transplantation (2004) 33, 311-315. doi:10.1038/sj.bmt.1704347 Published online 1 December 2003     

Evaluation of mixed chimaerism and origin of bone marrow derived fibroblastoid cells after allogeneic bone marrow transplantation

Summary We assessed the origin of bone marrow derived fibroblastoid cells (BMF) in long-term cultures of 13 samples obtained from nine patients after allo-BMT by polymerase chain reaction (PCR) amplification of MCT118, one of the variable number of tandem repeats regions (VNTR). BMF showed a complete recipient pattern in nine samples obtained from seven patients; however, a recipient-predominant mixed chimaeric pattern was detected in BMF from four patients. Also, two of the four patients died with bone marrow hypoplasia. These data suggest that mixed chimaeric pattern of BMF may be correlated with bone marrow hypoplasia.