Gianotti-Crosti syndrome associated with cytomegalovirus antigenemia after bone marrow transplantation

Gianotti-Crosti syndrome (GCS) is characterized by a distinctive self-limiting acral papular or papulovesicular eruption associated with an underlying viral illness. It has not been previously reported in patients post-bone marrow transplantation. We report a 6-year-old Japanese boy who underwent allogeneic bone marrow transplantation from an unrelated donor for acute lymphoblastic leukemia (ALL) in second remission. He had clinical and histopathologic findings characteristic of GCS and evidence of subclinical infection with cytomegalovirus (CMV) detected by CMV antigenemia assay. It is likely that CMV is the causative agent for the GCS in this case.     

Intravitreal sustained-release ganciclovir implantation to control cytomegalovirus retinitis in AIDS

Immunoglobulin (Ig) heavy chain class switch recombination occurs mainly by joining two switch (S) regions, segments of tandemly repeated DNA sequences that lie upstream of heavy chain constant region genes. The products of this recombination event are a chromosomal DNA joint and a 'looped-out' circular DNA joint. Although a previous study showed that 40% of chromosomal joints in the mu gene switch region (S mu) are found in the flanking regions of S mu, which do not contain typical S mu region repeats [1], other studies revealed that almost all recombination sites on looped-out circular DNA are found within S regions [2-4]. To resolve this discrepancy, we have isolated and sequenced 164 DNA fragments containing recombination joints from both chromosomal and looped-out DNA of a single cell line, the murine B lymphoma line CH12F3, which switches from IgM to IgA production with a high frequency upon cytokine stimulation [5]. The recombination sites were distributed almost evenly in the S mu region and its flanking regions, suggesting that the final joining of DNA ends may not necessarily take place in S regions. In contrast, there were few joining sites in the exon located 5' of the switch region (the I mu exon), suggesting that the 3' end of the I mu exon might be the upstream border of the recombination joint.     

Use of neuroendocrine hormones to promote reconstitution after bone marrow transplantation

A survey of the previous literature and the data shown here indicate that neuroendocrine hormones such as growth hormone and prolactin may be of potential clinical use after bone marrow transplantation (BMT) to promote hematopoietic and immune recovery. The amounts of hormones used in our model do not promote weight gain suggesting that their lymphohematopoietic actions were independent of their anabolic effects. While the hormones may not produce the same extent of immune/hematopoietic effects when compared to conventional hematopoietic and immune stimulating cytokines (i.e. IL-2 or G-CSF), their pleiotropic effects and limited toxicity after systemic administration makes them attractive to test in the post-BMT setting. However, more work needs to be performed to understand the mechanism(s) of their action, particularly with regard to T-cell function and development.     

Treatment of cytomegalovirus retinitis with an intraocular sustained-release ganciclovir implant. A randomized controlled clinical trial

BACKGROUND AND METHODS: We performed a randomized controlled clinical trial to assess the safety and efficacy of a 1 microgram/h ganciclovir implant for the treatment of newly diagnosed cytomegalovirus (CMV) retinitis in patients with the acquired immunodeficiency syndrome (AIDS). Patients with previously untreated peripheral CMV retinitis were randomly assigned either to immediate treatment with the ganciclovir implant or to deferred treatment. Standardized fundus photographs were taken at 2-week intervals and analyzed in a masked fashion. The study end point was progression of retinitis based on the photographic assessment. RESULTS: Twenty-six patients (30 eyes) were enrolled. The median time to progression of retinitis was 15 days in the deferred treatment group (n = 16) vs 226 days in the immediate treatment group (n = 14) (P < .00001, log-rank test). During the study, 39 primary implants and 12 exchange implants were placed in immediate-treatment eyes, deferred-treatment eyes that progressed, or contralateral eyes that developed CMV retinitis. Postoperative complications in the total series included seven late retinal detachments and one retinal tear without detachment. Final visual acuity was 20/25 or better in 34 of 39 eyes. The estimated risk of developing CMV retinitis in the fellow eye was 50% at 6 months. Biopsy-proven visceral CMV disease developed in eight (31%) of 26 patients. The median survival was 295 days. CONCLUSION: The ganciclovir implant is effective for the treatment of CMV retinitis. Patients with unilateral CMV retinitis treated with the implant are likely to develop CMV retinitis in the fellow eye, and some patients will develop visceral CMV disease.     

Successful treatment of severe cytomegalovirus retinitis with foscarnet and intraocular injection of ganciclovir in a myelosuppressed unrelated bone marrow transplant patient

PURPOSE: To compare U.S. medical student Match results in 1996 for 19 categorical residency positions by specialty with those of the overall Match reported by the National Resident Matching Program (NRMP). METHOD: Data for the numbers of "active" senior U.S. student applicants (those who submitted rank lists), the numbers of U.S. seniors matched, and the numbers of unfilled positions for 19 specialties were obtained from a variety of sources. Chi-square analysis was performed to compare Match results for each independent specialty with the overall Match results. The level for statistical significant was set at p < .005. RESULTS: Eight specialties were identified as significantly more competitive than the overall Match process for both the percentage of U.S. seniors who successfully matched in that specialty and the ratio of unmatched U.S. senior applicants to unfilled categorical positions. Five specialties were identified as significantly less competitive for these two measures. Six specialties showed no significant difference in the percentages of U.S. students matching, but for three of these specialties there were more unmatched students than unfilled categorical positions. CONCLUSION: U.S. medical student Match results for categorical residency positions for different specialties vary significantly from the overall Match process. This information can be used in counseling senior medical students on their specialty selection and the residency application process.     

Strategies for the prevention of cytomegalovirus disease after marrow transplantation

The purposes of this review are to examine the epidemiology of disease due to cytomegalovirus (CMV) in recipients of autologous and allogeneic marrow transplants and to compare different antiviral regimens used for the prevention of such disease in recipients of allogeneic marrow transplants, with an emphasis on ganciclovir. In seven studies, ganciclovir reduced the incidence of CMV infection and disease after allogeneic marrow transplantation. In one study mortality after transplantation was reduced because of a decreased rate of CMV-related death among ganciclovir-treated patients. Ganciclovir was effective when given to all CMV-seropositive patients (prophylaxis) or to patients who were considered at high risk for CMV disease on the basis of a positive surveillance culture (early treatment). The effectiveness of ganciclovir for the prevention of CMV infection and disease is limited by drug-induced neutropenia. Experience with other antiviral agents, such as foscarnet, has been limited. Initial studies of the adoptive transfer of CMV-specific CD8+ cytotoxic T cells have been conducted. In short, ganciclovir is currently effective for the prevention of CMV disease in allogeneic marrow transplant recipients, but its usefulness is limited by neutropenia. Future studies must be aimed at confining the toxicity of ganciclovir to patients at the highest risk for CMV disease.     

Reimmunization after allogeneic bone marrow transplantation

BACKGROUND/AIMS: Patients with cirrhosis and ascites show high plasma concentrations of endothelin. The aim of the current study was to investigate whether this feature is a compensatory response to effective hypovolemia or a consequence of systemic endotoxemia. METHODS: Protocols 1 and 2 assess the effect of acute changes in effective blood volume on plasma endothelin, and protocol 3 investigates the relationship between plasma endotoxin and endothelin in patients with cirrhosis and ascites. Protocol 1 included nine healthy subjects and 26 patients with cirrhosis studied during supine rest, upright tilt (which decreases effective blood volume) and cycloergometric exercise (which activates vasoactive systems by a baroreceptor independent mechanism). Protocol 2 included six patients studied before and 1 and 3 h after the intravenous administration of a plasma expander. In protocol 3, the plasma levels of endothelin and endotoxin were measured in 17 non-infected patients with cirrhosis and also in four patients with spontaneous bacterial peritonitis at diagnosis and following resolution of infection. RESULTS: Plasma endothelin was 3-5 times higher in patients with cirrhosis than in healthy volunteers. In healthy subjects, upright tilt and exercise were associated with a significant activation of the renin-aldosterone and sympathetic nervous systems and an increase in plasma endothelin. In patients with cirrhosis, upright tilt and exercise were associated with a significant increase and plasma volume expansion with a marked suppression of the renin-aldosterone and sympathetic nervous systems. However, in these patients none of these maneuvers affected plasma endothelin levels. In the patients with cirrhosis in protocol 3, there was no correlation between plasma endotoxin and endothelin. Resolution of peritonitis was associated with a marked fall in plasma endotoxin and no changes in plasma endothelin. CONCLUSIONS: These findings suggest that mechanisms other than effective hypovolemia or systemic endotoxemia are involved in the increased plasma endothelin of cirrhosis with ascites.     

Prophylactic ganciclovir treatment reduces fungal as well as cytomegalovirus infections after heart transplantation

Cytomegalovirus (CMV) infection is associated with an increased incidence of other opportunistic infections in organ transplant recipients. Whether this is related to immunomodulating effects of CMV or independent of CMV but associated with a host risk factor common to both infections is unclear. The purpose of this study was to determine whether the reduction in CMV infections seen with prophylactic ganciclovir treatment after heart transplantation is associated with a reduced incidence of other opportunistic infections. Of 149 patients prospectively enrolled in a multicenter, randomized, double-blind, placebo-controlled trial of ganciclovir to prevent CMV disease, 74 patients enrolled at this center (33 control and 41 ganciclovir-treated) were retrospectively identified. All received prophylactic OKT-3 and standard 3 drug maintenance immunosuppressive therapy. Actuarial survival and rejection rates and incidence of opportunistic infections (bacterial, fungal, and protozoal) for the 2 treatment groups were determined and compared using Cox-Mantel analysis. CMV disease occurred 2.5 times more frequently in the control group. There were no significant differences in survival or rejection rates nor in bacterial or protozoal infection incidence between the 2 groups. Bacterial infections occurred in 54% of control and 39% of ganciclovir-treated patients (P = 0.18). There were significantly fewer fungal infections in the ganciclovir-treated group (7% vs. 27%, P = 0.0071). CMV and fungal infections were both significantly reduced in patients who received ganciclovir prophylaxis. This suggests that active CMV disease may be causally associated with the development of opportunistic fungal infections.     

Reactivated fulminant hepatitis B virus replication after bone marrow transplantation: clinical course and possible treatment with ganciclovir

A female chronic hepatitis B virus carrier (HBV-DNA negative) suffered from simultaneous hepatitis B virus and cytomegalovirus reactivation after in vivo T cell depletion preceding transplantation of an in vitro T cell depleted marrow graft for treatment of acute leukaemia. Interstitial pneumonia developing after bone marrow transplantation was successfully treated with ganciclovir (day 13 until day 46). The initially unnoticed extensive hepatitis B virus replication finally led to clinical hepatitis (day 85) and liver failure (day 96). Liver transplantation was performed, but the patient died from septicaemia. Retrospective analysis of hepatitis B virus DNA revealed that the HBV replication started immediately after T cell depletion and was completely suppressed during ganciclovir administration. Screening for HBV-DNA seems to be mandatory in comparable cases, and antiviral chemotherapy should be seriously considered.     

Sequential respiratory syncytial virus and cytomegalovirus pneumonia following bone marrow transplantation

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

Filgrastim for the treatment of leukemia relapse after bone marrow transplantation

The absence of an effective therapy for most patients with leukemia who relapse after allogeneic BMT has generated interest in new strategies. We present our experience on the use of filgrastim 5 micrograms/kg/day s.c., in four patients with leukemia (three with AML and one with CLL) who relapsed after allogeneic transplantation. One patient with AML achieved CR after 55 days of treatment. No response was observed in the remaining three. The patient who responded developed extensive chronic GVHD but relapsed 10 months later. In one of the unresponsive patients a dramatic increase in bone marrow infiltration and WBC count followed administration of filgrastim. We conclude that filgrastim can occasionally induce CR in leukemic patients who relapse after BMT.     

Femoral head osteonecrosis after bone marrow transplantation

Thirty-five patients with bilateral osteonecrosis of the femoral head after bone marrow transplantation were reviewed retrospectively. The median age at the time of transplantation was 26 years. The first symptoms occurred within 2 years of transplantation. At presentation, 18 of the patients reported pain in both hips, 17 had symmetric radiographic lesions, and 39 of the hips had collapsed. Medical treatment was indicated initially. At the final examination before surgery (median, 3.5 years), 31 patients had bilateral hip pain, 22 patients had symmetric radiographic lesions, and 56 of the hips had collapsed. Fifty-seven of the hips required surgery, including one open drainage, four core decompressions, six cup arthroplasties, and 46 primary total hip replacements. Six hips (four core decompressions; two cups) later underwent total hip replacement revision, and a deep infection developed in one. By considering the requirement of a total hip replacement as a failure of conservative treatment, the rate of survival of the femoral head was 30% 5 years after the transplant. There was no significant difference between the Ficat grades, except for Grade 0, which showed a higher survival rate. The study of the specific features of the osteonecrosis may lead to the recommendation of primary total hip arthroplasty after failure of the medical treatment.     

Use of studies on genome polymorphism in follow up after allogenic bone marrow transplantation

The study of structures polymorphic in size found in the human genom (the VNTR loci) enables us to differentiate two individuals or--after bone marrow transplantation--to detect the simultaneous presence of two genoms in patients' blood or marrow. The existence of mixed chimerism may influence the therapy. The authors have screened 54 patients, transplanted in their Institute, and their donors by determination of four polymorphic loci. Informative marker was found in 43 cases. The bone marrow transplantation immunotherapy of 29 patients could be followed over 2-36 months. To increase the sensitivity of the polymerase chain reaction method used, the authors introduced the blotting/hybridization steps using isotop labeled repetitive sequences. The results are presented in comparison with literature data.     

Chronic progressive radiation myelopathy after bone marrow transplantation

CAPL is a cancer-related gene shown to be overexpressed during tumor metastasis formation. A CAPL antisense oligodeoxynucleotide (ODN), GX-1, and a random control ODN (CTRL1) were 3'-conjugated to MAG3, labeled with technetium-99m, purified, and the biodistribution of the radiolabeled conjugates in normal mice was studied. A 99mTc-MAG3-GX-1 complex of >97% radiochemical purity was obtained and the product was stable for >6 h as determined by reversed phase high performance liquid chromatography (HPLC). Biodistribution studies of the 99mTc-MAG3-ODNs in groups of four normal mice, sacrificed 5 min and 60 min after injection, demonstrated that the radiolabeled ODNs were distributed in an unspecific manner. The excretion route was mainly urinary. At 60 min, 55.2% of the injected dose of 99mTc-MAG3-GX-1 and 72.4% of 99mTc-MAG3-CTRL1 was found in the urine. This finding is clearly different from previously reported data on tritiated 20-mer phosphodiester ODNs, as well as the unconjugated 99mTc-MAG3 chelate, suggesting that 99mTc-MAG3 coupled to the 3'-end of ODNs has an influence on the biodistribution of the oligo, and possibly has a protective function to enzymatic degradation in vivo.