[EurSafety Health-Net: MRSA Eradication in Nursing Homes and Home Care - A Practice Report]. / EurSafety Health-Net: MRSA-Sanierung in der Pflege (MSP) - ein Praxisbericht.

In 2009 the project EurSafety Health-Net, funded by Interreg IVa, was initiated in order to create a cross-border quality alliance to enhance patient safety in the field of infectious diseases. Within this framework, several studies and projects addressing key topics of infection control were carried out. We describe the two-year project "MRSA decolonisation in care settings (MSP)", which aimed at evaluating a simple and economic way of decolonisation of non-hospitalised MRSA carriers in 2 districts in Lower Saxony. In the course of the project 181 decolonisations of MRSA carriers were performed by nursing homes and nursing services for outpatients in cooperation with the local public health authorities of the districts Ammerland and Grafschaft Bentheim. Of 181 cases 134 were eligible for statistical analysis. The project provided protocols for 2 different starting situations: 1) Continuing and completing a decolonisation treatment subsequent to a hospital stay by nursing services for outpatients or in a nursing home. 2) Starting a decolonisation treatment in a nursing home or by nursing services for outpatients. The carriers were provided with the required materials either by the hospitals (situation 1) or by the local public health authorities (situation 2) free of charge. The decolonisation treatment and the testing were offered only to carriers free of properties deemed as decolonisation obstacles and was applied without involvement of the general practitioner. Short- and long-term success of the 5 day decolonisation treatment was tested afterwards by two swabs (14 days and 6 months after the end of the treatment). The results of the 6-month control swabs showed that 45% of the carriers were successfully decolonised in the long term. All parties involved regarded the procedure of the MSP project as effective with respect to the target. Thus, even after the project was finished, both districts continued applying the MSP protocol.

Skin response using NIH consensus criteria vs Hopkins scale in a phase II study for steroid-refractory chronic GVHD.

One of the obstacles to chronic GVHD research is the lack of standardized response criteria. The National Institute of Health (NIH) has recommended response criteria at a Consensus Conference. These need to be validated. We recently completed and reported a trial of pentostatin in treating steroid-refractory chronic GVHD. During the trial, we prospectively collected percent body-surface-area (BSA) involvement of rash, superficial sclerosis and deep sclerosis. Here, we compare cutaneous responses using the NIH scale and the Hopkins scale. The two scales produced similar overall response rates but different domain response rates. There was 80% agreement in overall response at the final treatment evaluation, but only a 64% agreement for fasciitis/non-moveable sclerosis. There was more disparity in the measurement of sclerosis than in that of erythema, which highlights the difficulty of quantifying sclerosis. For sclerosis, the Hopkins scale, which used skin softening, was more predictive of early response as compared with the NIH scale, which focused on percent BSA. Early assessment of skin softening may be important if trying to detect the activity of a particular agent in chronic GVHD. Further validation of the NIH scale is ongoing, which should produce a clinically useful and predictive scale.

Chronic graft-versus-host disease: implications of the National Institutes of Health consensus development project on criteria for clinical trials.

Chronic graft-versus-host disease (GVHD) has been a difficult problem to address and clinical research in this area lags behind other innovations in hematopoietic stem cell transplantation (HCT). Recently the international transplant community has focused more on chronic GVHD. This new focus is well represented by the development of the National Institutes of Health sponsored chronic GVHD consensus project, which has unified the transplant community's approach to chronic GVHD through the activities of focused working groups. From December 2005 through May 2006, a series of consensus documents have been published addressing the areas of diagnosis and staging, histopathology, strategies for the development and validation of biomarkers, response criteria, ancillary therapy and supportive care and the design of clinical trials. This paper summarizes and discusses these reports, focusing specifically on diagnosis and scoring and response criteria. Although these documents represent a huge effort by the research community, they must be prospectively implemented and validated. These new criteria should advance the standards and uniformity of chronic GVHD clinical research. The ultimate success of this project is dependent on whether these recommendations move the field forward. This is an opportunity for the transplant community to unite and make a significant impact in chronic GVHD.

Oral PUVA and topical steroids for treatment of oral manifestations of chronic graft-vs.-host disease.

BACKGROUND: Oral manifestations of chronic graft-vs.-host disease (cGVHD) can significantly affect the quality of life and severity often does not correlate with systemic manifestations. We evaluated the use of topical corticosteroids and the intraoral application of psoralen-UVA (PUVA) for treatment of oral manifestations of cGVHD. METHODS: Overall, 18 patients with oral manifestations of cGVHD were treated with either intraoral PUVA (n=7) or with topical corticosteroids (n=16). Four patients received intraoral PUVA after failure of topical steroids and one patient was treated with topical corticosteroids after failing treatment with intraoral PUVA. A glass fiber extension of an UVA source was used for manual intraoral application. Treatment with topical corticosteroids consisted of 0.1 mg/ml dexamethasone mouth wash four times a day in combination with antifungal prophylaxis. RESULTS: Four patients showed complete local response (CR) due to intraoral PUVA, two improved and one did not respond. Topical corticosteroids resulted in nine patients in CR, two improved and five did not respond. CONCLUSION: Intraoral PUVA as well as topical corticosteroids are effective in treatment of oral manifestations of oral GVHD with few side-effects and improve quality of life in patients with cGVHD.

Phase I study of escalating doses of low-dose-rate, locoregional irradiation preceding Cytoxan-TBI for patients with chemotherapy-resistant non-Hodgkin's or Hodgkin's lymphoma.

PURPOSE: In patients in whom bone marrow transplantation (BMT) fails, recurrence often occurs at sites known to have contained disease before initiating BMT. The purpose of this study was to find the maximal tolerable dose of locoregional irradiation (LRT) between 1000 and 2000 cGy that could be integrated with our Cytoxan-total body irradiation (TBI) BMT conditioning regimen in the treatment of lymphoma. METHODS AND MATERIALS: Patients had Hodgkin's or non-Hodgkin's lymphoma in chemotherapy-refractory relapse. All patients received LRT to a maximum of three sets of fields encompassing either all current or all previously known sites of disease. Cytoxan-TBI consisted of cyclophosphamide 50 mg/kg daily for 4 days followed by TBI of 1200 cGy given in four fractions. RESULTS: Twenty-one patients were enrolled. Radiation Therapy Oncology Group Grade 3 in-field acute toxicity was observed in 1 patient at each dose level up to 1500 cGy and in 3 of 6 patients receiving 2000 cGy. Clinically evident late toxicities were limited to hypothyroidism and one second malignancy occurring outside the LRT fields. CONCLUSION: Low-dose-rate, LRT with concurrent Cytoxan-TBI before BMT has acceptable rates of in-field toxicity for doses up to 1500 cGy in five fractions. This regimen safely permits the use of a total combined radiation dose of up to 2700 cGy during 2 weeks, with encouraging in-field response rates in treatment-refractory patients.

High incidence of graft failure in children receiving CD34+ augmented elutriated allografts for nonmalignant diseases.

T-cell depletion of the marrow graft using counterflow centrifugal elutriation reduces the risk of graft-versus-host disease (GVHD). However, because of high rates of graft failure and relapse, elutriation alone has not improved survival. We have carried out a phase II clinical trial in 54 pediatric patients to determine if CD34+ selection to rescue pluripotent stem cells from the small lymphocyte fraction improves engraftment. The processed grafts contained a mean of 5.5 x 10(7) cells/kg IBW, 4.7 x 10(6) CD34+ cells/kg IBW, and 6.3 x 10(5) CD3+cells/kg IBW. Patients achieved an ANC >500 at a median of 16 days and platelet count >20 000 at a median of 28 days. The incidence of clinically significant GVHD was 19%. In total, 10 patients enrolled in this study experienced graft failure, with eight of the 14 patients transplanted for nonmalignant indications failing to engraft stably. Graft failure was statistically significantly associated with nonmalignant diagnosis (P<0.001), but was not associated with CMV seropositivity, donor gender, or cell counts of the allograft. We conclude that although time to engraftment is similar to that seen with unmanipulated grafts, graft failure remains a significant problem in patients with hereditary, nonmalignant diseases. Future efforts will seek to preserve the benefits of elutriation with CD34+ selection by increasing immune ablation of the preparative regimen and/or increasing posttransplant immune suppression.

Thalidomide-induced neuropathy.

BACKGROUND: Thalidomide is effective for the treatment of some refractory dermatologic and oncologic diseases. Toxic neuropathy limits its use, as embryopathy can be avoided by contraceptive measures. OBJECTIVE: To describe the clinical, electrophysiologic, and pathologic features of thalidomide-induced peripheral neuropathy. METHODS: Clinical and electrophysiologic examinations were performed in seven patients with thalidomide-induced peripheral neuropathy. Thalidomide was used for graft-vs-host disease, pyoderma gangrenosum, and discoid lupus with dosages ranging from 100 to 1,200 mg/day for 5 to 16 months (cumulative dosages of 24 to 384 g). RESULTS: All seven patients had clinical and electrophysiologic evidence of a sensory more than motor, axonal, length-dependent polyneuropathy that presented as painful paresthesias or numbness. Sural nerve biopsies, done in three patients, showed evidence of Wallerian degeneration and loss of myelinated fibers. The symptoms, signs, and electrophysiologic data correlated with total cumulative dose of thalidomide. CONCLUSIONS: Thalidomide induces a dose-dependent sensorimotor length-dependent axonal neuropathy; it should be judiciously used with close neurologic monitoring.

Endoscopic findings predict the histologic diagnosis in gastrointestinal graft-versus-host disease.

BACKGROUND AND STUDY AIMS: Graft-versus-host disease (GvHD) of the gastrointestinal tract is a major cause of morbidity and mortality after allogeneic bone marrow transplantation (BMT). Whether endoscopic findings predict the histologic diagnosis of GvHD in the gastrointestinal tract remains controversial. We performed a study to determine the diagnostic accuracy of macroscopic endoscopy findings in the diagnosis of acute and chronic histologically proven gastrointestinal GvHD (GI-GvHD). PATIENTS AND METHODS: Endoscopic images from the intestinal mucosa of post-BMT patients were blindly graded as positive or negative for GI-GvHD and compared with corresponding histological findings, which were used as the gold standard. RESULTS: 44 BMT patients were referred for 96 endoscopic evaluations. Using 162 endoscopy-biopsy pairs, a positive association between endoscopic grading and histologic grading of GI-GvHD (odds ratio [OR] = 11.97, 95% CI 3.86, 37.16) was observed. Endoscopic diagnosis correctly predicted histologic diagnosis in both acute and chronic GI-GvHD (OR = 9.3 vs. 23.1, P = 0.31). CONCLUSIONS: The diagnostic accuracy of endoscopy was high in both acute and chronic histologically proven GI-GvHD. Accurate diagnosis of GI-GvHD might be obtained with mucosal biopsies from either the upper or lower gastrointestinal tract. Endoscopy may play a significant role in establishing early diagnosis and treatment for GI-GvHD in patients following BMT, but histologic evaluation of the gastrointestinal mucosa is needed to confirm the final diagnosis.

Bone marrow transplantation in Shwachman-Diamond syndrome.

Shwachman-Diamond syndrome is a rare autosomal recessive disorder characterized by exocrine pancreatic dysfunction, metaphyseal dysostosis and bone marrow dysfunction with a predilection towards severe hematologic complications. Allogeneic bone marrow transplantation has been used as a therapeutic approach for SDS patients with serious hematologic abnormalities with mixed results. There is some concern that these patients may be more susceptible to early (<100 days) transplant-related complications than other transplant groups. We report a patient who received a matched allogeneic transplant without developing serious early transplant-related complications, but eventually died from relapse of his disease. Although experience is limited, a review of the reported cases suggests patients with SDS may be transplanted without significant short-term morbidity and mortality.

Nonmyeloablative bone marrow transplantation from partially HLA-mismatched related donors using posttransplantation cyclophosphamide.

Cyclophosphamide (Cy) is a potent immunosuppressive agent that is selectively toxic to lymphocytes proliferating in response to recent antigen stimulation. In animal models, both graft rejection and GVHD after histoincompatible BMT can be inhibited by the posttransplantation administration of high-dose Cy. Therefore, a phase I clinical trial was undertaken to determine the minimal conditioning, including posttransplantation Cy, that permits the stable engraftment of partially HLA-mismatched marrow (up to 3 HLA antigens) from first-degree relatives. Thirteen patients (median age, 53 years) with high-risk hematologic malignancies received conditioning with fludarabine, 30 mg/m2 per day from days -6 to -2, and TBI, 2 Gy on day -1. All patients received Cy, 50 mg/kg on day 3, mycophenolate mofetil from day 4 to day 35, and tacrolimus from day 4 to day > or = 50. Three patients in cohort 1 received no additional conditioning, and 2 experienced graft rejection. Ten patients in cohort 2 received identical conditioning with the addition of Cy 14.5 mg/kg on days -6 and -5. Sustained donor cell engraftment occurred in 8 of these patients, with a median time to absolute neutrophil count > 500/microL of 15 days (range, 13-16 days) and to unsupported platelet count > 20,000/microL of 14 days (range, 0-26 days). All patients with engraftment achieved > or = 95% donor chimerism within 60 days of transplantation. Two patients with myelodysplastic syndrome rejected their grafts but experienced autologous neutrophil recovery at 24 and 44 days. Histologic acute GVHD developed in 6 patients (grade II in 3 patients, grade III in 3 patients) at a median of 99 days (range, 38-143 days) after transplantation and was fatal in 1 patient. At a median follow-up of 191 days (range, 124-423 days), 6 of 10 patients in cohort 2 were alive, and 5 were in complete remission of their disease, including both patients with graft rejection. These data demonstrate that partially HLA-mismatched bone marrow can engraft rapidly and stably after nonmyeloablative conditioning that includes posttransplantation Cy. Clinically significant antitumor responses occur, even among patients who reject their donor grafts.

Weight loss and malnutrition in patients with chronic graft-versus-host disease.

It is well known that weight loss occurs in patients with chronic graft-versus-host disease. However, the severity and frequency of weight loss in this population have not been adequately described. Recent data suggest that a body-mass index (BMI) below 21.9 is an independent risk factor for mortality. In our analysis we have shown that out of 93 patients with cGVHD, 43% are malnourished as evidenced by a BMI less than 21.9 and 14% are severely malnourished (BMI less than 18.5). In addition, there is a clear trend showing that patients with active, ongoing cGVHD have lower BMIs (P = 0.02). Furthermore, we show that many symptoms thought to contribute to weight loss in patients with cGVHD, such as odynophagia and oral sensitivity, are not related to weight loss in our population. We conclude that, in all likelihood, unknown causes still exist that are responsible for weight loss in this group of patients. Elevated resting energy expenditure and elevated serum tumor necrosis factor-alpha are potential contributors to weight loss that will be tested in future studies. We also conclude that treating cGVHD aggressively may help reverse weight loss and malnutrition, which may be independent risk factors for mortality in this population.

Risk factors for post-stem cell transplant sinusitis.

An understanding of the factors that place the post-transplant patient at increased risk for sinusitis would help identify patients likely to develop disease and possibly allow for interventions that would decrease the incidence or severity of sinus disease. This retrospective study investigates the ability of screening paranasal sinus computed tomographic scans (CTs), clinical history, and potential risk factors for sinusitis, including history of tobacco use, history of allergies or asthma, IgG level, history of sinusitis, remission status and acute graft-versus-host disease (GVHD) to predict post-transplant sinusitis. Medical records and sinus CTs of 100 allogeneic bone marrow recipients were reviewed. There was no increased risk of developing sinusitis post SCT for patients with significant disease on screening CT, symptoms at time of transplant, a history of tobacco use, asthma or allergies, low IgG level, history of sinusitis or for patients at high risk of relapse. Patients with GVHD were 4.3 times more likely than patients without GVHD to develop sinusitis post transplant (95% CI: 1.7-11.0, P = 0.002). Acute GVHD places patients at greater risk of developing sinus infections.

Long-term results of blood and marrow transplantation for Hodgkin's lymphoma.

PURPOSE: To evaluate the long-term outcome after allogeneic (allo) and autologous (auto) blood or marrow transplantation (BMT) in patients with relapsed or refractory Hodgkin's lymphoma (HL). PATIENTS AND METHODS: We analyzed the outcome of 157 consecutive patients with relapsed or refractory HL, who underwent BMT between March 1985 and April 1998. Patients

A high-dose pulse steroid regimen for controlling active chronic graft-versus-host disease.

Corticosteroids remain essential for controlling active chronic graft-versus-host disease (cGVHD). However, the optimum dose and administration schedule is unknown. We have reviewed our results in 61 patients with severe refractory cGVHD who were treated with a high-dose pulse steroid regimen (PS) consisting of methylprednisolone at 10 mg/kg per day for 4 consecutive days, with subsequent tapering doses. After 4 days, all patients received a course of additional immunosuppressive therapy. The median age of the 56 patients who were evaluable for response was 32 years (range, 0.2-57 years). Patients had failed a median of 2 (range, 1-5) treatments prior to the PS. The median follow-up for 45 surviving patients after PS was 1.5 years. The probability of survival at 1 year and 2 years after PS was 88% (95% confidence interval [CI], 76%-95%) and 81% (95% CI, 65%-91%), respectively. Twenty-seven patients (48%) showed a major response to PS with substantial improvement of cGVHD manifestations, including softening of the skin, increased range of motion, and improved performance status; 15 patients (27%) showed a minor response, defined as improvement in some but not all symptoms of cGVHD. Of the 42 responders, 21 (50%) had progression of their cGVHD afterwards. The median time to progression was 1.9 years. The probability of progression at 1 and 2 years after PS was 36% (95% CI, 23%-53%) and 54% (95% CI, 38%-71%), respectively. The probability of progression at 1 year was 25% (95% CI, 12%-47%) and 55% (95% CI, 32%-81%) for patients who had major and minor response, respectively (hazard ratio, 2.13). Ten of the 42 responders (24%) were able to discontinue all systemic immunosuppressive treatments. The probability of discontinuation at 1 and 2 years after PS was 9% (95% CI, 3%-25%) and 27% (95% CI, 15%-48%), respectively. The treatment was well tolerated with no serious adverse events. Our results suggest that PS is a well-tolerated regimen for achieving rapid clinical response in the majority of patients with cGVHD who failed on multiple previous therapies. Further studies are warranted to maintain the efficacy of this regimen by combining with new active agents in cGVHD.

Acute bleeding complications in patients after bone marrow transplantation.

Acute bleeding is a frequent complication that commonly associates with increased morbidity after bone marrow transplantation. Except for diffuse alveolar hemorrhage and cerebral hemorrhage, bleeding is infrequently recorded as a direct cause of death. Yet outcome analyses showed that bleeding from any reviewed site was associated with reduced survival. Reduced survival was correlated with bleeding intensity and the number of bleeding sites. These data point to the need to monitor all manifestations of bleeding, as bleeding may identify patients at risk for bone marrow transplantation toxicity. Until recently, prophylactic platelet transfusions were commonly given at a trigger of 20 x 10(9)/L. Whereas bleeding is more likely to occur when platelet counts drop to low levels, most bleeding episodes were recorded with platelet counts greater than 20 x 10(9)/L, suggesting causes other than profound thrombocytopenia in the pathogenesis of bleeding. Given that a trigger of 10 x 10(9)/L has become accepted for prophylactic platelet transfusions, care should be taken to ensure that parameters other than the incidence of bleeding have not been adversely affected.

Mycophenolate mofetil for the prevention and treatment of graft-versus-host disease following stem cell transplantation: preliminary findings.

The therapeutic benefits of allogeneic stem cell transplantation in patients with hematologic disorders are limited by the significant morbidity and mortality of graft-versus-host disease (GVHD). Current agents for the prevention and treatment of GVHD have limited efficacy and often result in toxic side-effects. Mycophenolate mofetil (MMF) is a new immunosuppressant with a selective mechanism of action. When employed following solid organ transplantation, MMF reduces the incidence and severity of acute rejection episodes. By selectively targeting activated lymphocytes, the active metabolite of MMF, mycophenolic acid (MPA), appears to augment the actions of standard immunosuppressant agents without adding overlapping toxicities. Studies of combination regimens that include MMF report that this agent permits a dose reduction of cyclosporine, tacrolimus, or corticosteroid, without increasing the incidence of acute rejection in solid organ transplants. Reports on the efficacy of MMF following stem cell transplantation in animal studies were mixed. However, the use of a non-myeloablative conditioning regimen with a post-graft immunosuppressive regimen of MMF and cyclosporine was able to sustain stable mixed chimeras in 60% to 80% of dogs who received hematopoietic grafts from DLA-identical littermates. MMF has demonstrated activity in preliminary clinical trials for GVHD prophylaxis, and treatment of acute or chronic GVHD. Larger clinical trials are warranted to determine the optimum dose and route of MMF administration for GVHD, as well as the comparative safety and efficacy of MMF-containing regimens.