Oral Candida albicans in bone marrow transplant patients given chlorhexidine rinses: occurrence and susceptibilities to the agent.

The tongue and buccal mucosa of 26 bone marrow transplant recipients given three 0.12% chlorhexidine digluconate (CHX) oral rinses daily for 8 weeks were sampled weekly for oral Candida albicans. Putative C. albicans colony-forming units on selective bismuth sulfite glucose glycine yeast agar plates were identified with the API 20C system. The CHX minimum inhibitory concentrations (MICs) of oral C. albicans isolates obtained at all 8 sample weeks was determined with a microbroth dilution sensitivity assay. The CHX MIC range for yeast isolates selected randomly at all sample weeks was up to 2.5 to up to 20 micrograms/ml (mean MIC less than or equal to 8.5 micrograms/ml). The CHX MIC range for isolates at week 1 was less than or equal to 5 to less than or equal to 10 micrograms/ml (mean MIC less than or equal to 7.9 micrograms/ml) compared with less than or equal to 2.5 to less than or equal to 20 micrograms/ml at week 8 (mean MIC less than or equal to 8.8 micrograms/ml). Therefore the persistence of oral C. albicans in bone marrow transplant recipients using CHX rinses was due neither to low CHX susceptibilities nor to the development of resistance to the agent.

Bone marrow transplantation from related donors other than HLA-identical siblings: effect of T cell depletion.

Results of 470 bone marrow transplants from related donors other than genotypically HLA-identical siblings (alternative related donors) were analysed to identify factors associated with transplant outcome and to determine whether T cell depletion improved results. As compared to 3648 transplant from HLA-identical siblings, alternative related donor transplants were associated with increased graft failure, increased acute graft-versus-host disease (GVHD), and lower disease-free survival. The likelihood of adverse outcome correlated with increasing donor-recipient HLA-disparity. In multivariate analysis of alternative related donor transplants, donor age greater than or equal to 30 years, (relative risk [RR] 1.7, p less than 0.006), intermediate and advanced leukemia (RR 1.5 and 1.6, p less than 0.01 and p less than 0.003), infection pretransplant (RR 1.7, p less than 0.005) and 2- and 3-locus donor-recipient HLA-disparity (RR 1.3, p less than 0.04) were associated with increased risks of treatment failure. The 2-year probability of leukemia-free survival after alternative related donor transplants (n = 43) with none of these adverse prognostic features was 44% (95% confidence interval 28-59%) compared to 56% (95% confidence interval 52-59%) for similar patients receiving HLA-identical sibling transplants (n = 868, univariate p less than 0.03). T cell depletion increased graft failure and decreased acute GVHD after alternative related donor transplants but did not improve leukemia-free survival.

In vitro effect of chlorhexidine and amikacin on oral gram-negative bacilli from bone marrow transplant recipients.

Prophylactic use of chlorhexidine (CHX) mouthrinses has been shown to benefit the oral health status of bone marrow transplant recipients and other immunosuppressed persons and to reduce systemic complications of oral origin. However, a problem that often emerges with these patients is oropharyngeal and lower respiratory tract colonization by opportunistic aerobic or facultative gram-negative bacilli (GNB). Trends in four studies indicated that CHX rinses may predispose these persons to oral colonization by GNB such as the enterobacteria, Klebsiella pneumoniae and Enterobacter cloacae. Since GNB are generally susceptible to broad-spectrum aminoglycoside antibiotics such as amikacin, the in vitro sensitivities of K. pneumoniae, E. cloacae, Pseudomonas aeruginosa, and Escherichia coli ATCC reference strains and K. pneumoniae and E. cloacae oral clinical isolates to combinations of CHX and amikacin were determined by means of a disk diffusion sensitivity assay on Mueller-Hinton agar. The amikacin minimum inhibitory concentrations for all GNB tested were much lower (less than or equal to 4.69 to less than or equal to 9.37 micrograms/ml) than those for CHX (less than or equal to 18.75 to less than or equal to 300 micrograms/ml), and combinations of CHX and amikacin gave larger growth inhibition zones than CHX alone. No antibacterial antagonism between CHX and amikacin was found, and their solubilities were compatible. Therefore use of topical amikacin in conjunction with CHX rinses may reduce oral colonization by GNB in severely immunocompromised patient populations.

Use of an anti-pan T-lymphocyte ricin a chain immunotoxin in steroid-resistant acute graft-versus-host disease.

Acute steroid-resistant graft-versus-host disease (AGVHD) after allogeneic bone marrow transplantation is frequently fatal. A new treatment for this T-lymphocyte-mediated condition uses an immunotoxin, H65-RTA, comprised of a monoclonal antibody that recognizes the CD5 lymphocyte differentiation antigen coupled to ricin A chain, a cytotoxic enzyme that inhibits protein synthesis. The safety and efficacy of this lymphocyte-targeted immunotoxin was evaluated in patients with severe AGVHD in a phase I-II dose escalation study with group expansion at the two middle doses. Thirty-four patients received up to 14 daily intravenous infusions of the immunotoxin. The principal side effects were constitutional symptoms such as fatigue and myalgias, and hypoalbuminemia with weight gain was seen at all doses. Thirty-two patients were evaluated for improvement or resolution of disease. Durable complete or partial responses were not dose-related and were seen in 16 patients. Skin GVHD had the highest incidence of response (73%), although improvement or resolution in gastrointestinal tract (45%) and liver (28%) GVHD was also noted. Survival in responding patients was significantly prolonged at all times as compared with those with no response (P = .03). Treatment was associated with a rapid decrease in peripheral blood T lymphocytes, which persisted for greater than 1 month after therapy. Anti-immunotoxin antibodies were seen in 6 of the 23 patients tested; these were of low titer and did not block immunotoxin binding to T cells. Results of this study indicate that anti-T-lymphocyte immunotoxins may form a new class of immunosuppressive agents useful in T-lymphocyte-mediated diseases.

Longitudinal assessment of psychosocial functioning of adult survivors of allogeneic bone marrow transplantation.

Existing research regarding the psychosocial functioning of adult survivors of allogeneic bone marrow transplantation (BMT) indicates that many patients experience difficulties in a variety of functional domains. A critical issue which has remained unexamined concerns the extent to which functioning improves, remains static, or perhaps even deteriorates with the passage of time post-BMT. To address this issue, the psychosocial functioning of 16 adult allogeneic BMT patients was assessed via a set of questionnaires on three occasions following their transplant. The initial assessment occurred a mean of 28 months post-BMT while the third assessment was a mean of 52 months post-BMT. Consistent with previous cross-sectional research, results indicated that many BMT survivors experience some long-term difficulties in physical, occupational, emotional, and cognitive functioning. Results indicated little change in functioning with the passage of time, suggesting that most patients might achieve a ceiling level of functioning within a couple of years post-BMT. At that time, further recovery of psychosocial functioning is likely to be minimal. Results are discussed with respect to their implications for both the encouragement of realistic expectations for post-BMT functioning as well as the development of post-BMT rehabilitation programs.

Oral gram-negative bacilli in bone marrow transplant patients given chlorhexidine rinses.

Fifteen bone marrow transplant (BMT) patients who received three 0.12% chlorhexidine digluconate (CHX) mouthrinses daily for eight weeks were monitored weekly for the occurrence of oral opportunistic Gram-negative bacilli (GNB). Tongue and buccal mucosa were sampled with use of Culturette swabs that were streaked on plates containing selective MacConkey agar. After incubation, colony-forming units were scored and putative GNB classified with use of the API 20E rapid identification system and supplemental biochemical tests. After identification, the susceptibilities of all GNB to CHX were determined by means of a disk diffusion sensitivity assay. Sixty-seven percent (10) of the BMT subjects had at least one GNB-positive tongue culture, and 53% (8) had GNB in samples taken from the buccal mucosa. Of 218 samples taken, 26% and 24% from the tongue and buccal mucosa, respectively, were GNB-positive. The predominant clinical GNB isolates were Enterobacter cloacae (46%) and Klebsiella pneumoniac (30%). Their respective CHX minimum inhibitory concentrations (MICs) were similar to those of ATCC reference strains. Although the CHX MIC values of the clinical GNB isolates were high (less than or equal to 37.5 to less than or equal to 300 micrograms/mL), they were not dependent upon length of exposure to the agent. Therefore, changes in sensitivity or resistance to CHX did not appear to occur. The results suggest that the mouths of BMT patients--and perhaps of other immunosuppressed individuals--should be routinely monitored for GNB, as are other clinically important sites, such as the throat and the urinary and gastro-intestinal tracts.

Physical and psychosocial functioning of adult survivors of allogeneic bone marrow transplantation.

While prospects for long-term survival following bone marrow transplantation (BMT) have increased, little is known about the quality of that survival. The present study was intended to document the physical and psychosocial functioning of survivors of allogeneic BMT as well as identify factors associated with variability in post-BMT functioning. Twenty-three patients who were living at home and were between 3 and 52 months post-BMT completed the Functional Living Index - Cancer and the Profile of Mood States. Results revealed that current functioning varied considerably across patients. The older a patient was at time of transplant, the poorer his current functioning was, particularly in the physical domain. Current functioning was not significantly associated with time since transplant, the diagnosis of acute or chronic graft-versus-host disease, or dose of total body irradiation given as part of BMT conditioning. Despite differences in functional status, however, only one patient indicated that he would not make the same choice again to undergo BMT. Information about the long-term functioning of BMT survivors is critical for the process of obtaining informed consent. Additionally, understanding of factors associated with variability in post-BMT functioning can increase the likelihood that patients will ultimately return to a normal, productive life.

Laboratory control in predicting clinical efficacy of T cell-depletion procedures used for prevention of graft-versus-host disease: importance of limiting dilution analysis.

In an attempt to assess the usefulness of partial elimination of T lymphocytes from histocompatible donor bone marrow as a sole method of graft-versus-host disease prophylaxis in patients undergoing bone marrow transplantation, we compared in vitro and clinically the efficacy of two depletion protocols, each resulting in a different degree of T cell reduction. The protocols were based on complement-dependent T cell lysis induced either by one (T10B9) or two (T10B9 and T12A10) monoclonal antibodies, contributing respectively to 95% and 99% depletion of T cells defined functionally by limiting dilution analysis. Phenotypic analysis was unsuitable for detecting differences in the efficiency of the two depletion modalities due to very low numbers of residual OKT3-positive cells generally present. Of the 34 patients with advanced leukemias transplanted with marrow from HLA-matched sibling donors, 26 (ages 15-52) received two-antibody depleted grafts (group I) with subsequent incidence of severe acute graft-versus-host disease of 8% (in two of 24 engrafted). The T cell dose for two patients of this group whose grafts were directly evaluated by limiting dilution analysis was less than 2 x 10(5)/kg and presumably did not exceed 3.2 x 10(5)/kg for others, based on the depletion efficiency of the protocol estimated in additional small marrow samples. The remaining eight patients (ages 8-55) received one-antibody depleted grafts (group II) with 5-18 x 10(5) T cells/kg defined functionally in five grafts. Severe acute graft-versus-host disease (grade 3-4) developed in all seven engrafted subjects. Although with phenotypic analysis several grafts in this group revealed no residual T lymphocytes, they apparently carried doses of donor T cells not tolerable in a HLA-identical host unprotected by additional immunosuppression. Careful evaluation by functional T cell analysis should be considered in choosing a depletion protocol as a method for reducing the risk of graft-versus-host disease in allogeneic bone marrow transplantation.

Fatal adenovirus meningoencephalitis in a bone marrow transplant patient.

We describe a bone marrow transplant patient with fatal subacute adenovirus meningoencephalitis, the first such patient reported. Neuropathological examination revealed unique, bilaterally symmetrical degeneration in the inferomedial temporal cortex, amygdaloid nuclei, hippocampi, hypothalamus, and some brainstem nuclei. Viral intranuclear inclusions were noted in these areas by light microscopy and confirmed by electron microscopy. Identification was authenticated by viral culture and the isolation of adenovirus from cerebral cortical tissues, and further confirmed by immunofluorescence and serological methods.