Allogeneic hematopoietic stem cell transplantation and norovirus gastroenteritis: a previously unrecognized cause of morbidity.

BACKGROUND: A retrospective study of the clinical, epidemiologic, and virologic features of norovirus gastroenteritis in 12 adult allogeneic hematopoietic stem cell transplant (HSCT) recipients. METHODS: Norovirus infection was diagnosed by reverse-transcriptase polymerase chain reaction. Strains were genotyped by nucleic acid sequence of the most highly conserved region of the norovirus gene encoding the capsid S (shell) domain. RESULTS: Ten of 12 patients presented with vomiting of short duration, but diarrhea was present in all. The median time from onset to norovirus diagnosis was 1 month (range, 0.25-6.0 months). Eleven patients were receiving immunosuppression when norovirus infection was diagnosed: 8 for graft-versus-host disease (GVHD) in an organ other than gut, 1 for previous gut GVHD, and 2 for presumed gut GVHD that proved to be norovirus gastroenteritis. Six patients required enteral or parenteral nutrition for severe weight loss. In 10 patients, diarrhea lasted a median of 3 months (range, 0.5-14 months) and virus was shed at a high level throughout. The remaining 2 patients died after 4 months of diarrhea (one died of unrelated complications, and the other died of malnutrition). The noroviruses found were GII (untyped), GII-3, GII-4, and GII-7 in 1, 1, 9, and 1 patients, respectively. Eleven of the 12 patients had acquired their infection in the community. Phylogenetic analysis of the GII-4 strains demonstrated that all differed. CONCLUSIONS: Noroviruses are a hitherto unsuspected cause of prolonged morbidity and mortality in adults after allogeneic HSCT. The use of reverse-transcriptase polymerase chain reaction to detect high viral load levels in feces distinguishes norovirus gastroenteritis from gut GVHD.

Superiority of reduced-intensity allogeneic transplantation over conventional treatment for relapse of Hodgkin's lymphoma following autologous stem cell transplantation.

This study compares outcome of reduced-intensity conditioned transplant (RIT) with outcome of conventional non-transplant therapy in patients with Hodgkin's lymphoma relapsing following autograft. There were 72 patients in two groups who had relapsed, and received salvage therapy with chemotherapy+/-radiotherapy. One group (n=38) then underwent alemtuzumab-containing RIT. The second group-historical controls (n=34), relapsing before the advent of RIT-had no further high-dose therapy. This group was required to respond to salvage therapy and live for over 12 months post-relapse, demonstrating potential eligibility for RIT, had this been available. Overall survival (OS) from diagnosis was superior following RIT (48% at 10 years versus 15%; P=0.0014), as was survival from autograft (65% at 5 years versus 15%; P< or =0.0001). For the RIT group, OS at 5 years from allograft was 51%, and in chemoresponsive patients was 58%, with current progression-free survival of 42%. Responses were seen in 8 of 15 patients receiving donor lymphocyte infusions (DLI) for relapse/progression, with durable remission in five patients at median follow-up from DLI of 45 months (28-55). These data demonstrate the potential efficacy of RIT in heavily pre-treated patients whose outlook with conventional therapy is dismal, and provide evidence of a clinically relevant graft-versus-lymphoma effect.

A second autologous transplant may be efficacious in selected patients with Hodgkin's lymphoma relapsing after a previous autograft.

Treatment options for patients who relapse following autologous transplantation for Hodgkin's lymphoma are limited. There are anecdotal reports of lengthy remissions following second autologous procedures, although treatment-related toxicity can be significant. We report a single centre experience of second autologous transplant performed in seven highly selected patients, who relapsed following initial high-dose therapy. They were all young and had slow tempo disease, which was still sensitive to conventional dose chemotherapy. All received BEAM conditioning for the first transplant, and six of the seven received BEAM for the second. All six of these patients regenerated successfully and with no delay, the final patient dying during the procedure following alternative conditioning. Only one case of presumed carmustine-related pneumonitis was seen, which responded rapidly to corticosteroid therapy. Four patients have subsequently relapsed, of whom three have died at 29, 33, and 38 months postprocedure. One is alive with active disease at 68 months, and the final two are alive and in continuing complete remission at 104 and 68 months.

The effect of low-dose aciclovir on reactivation of varicella zoster virus after allogeneic haemopoietic stem cell transplantation.

Patients undergoing haemopoietic stem cell transplants (HSCT) are at high risk of varicella zoster virus (VZV) reactivation, with a significant incidence of dissemination. This study reports a retrospective analysis of 247 allogeneic HSCT recipients receiving anti-viral prophylaxis with low-dose oral aciclovir 400 mg/day, administered until immunosuppression was discontinued and the CD4(+) cell count exceeded 200/mm(3). Viral reactivation was successfully suppressed by aciclovir prophylaxis, with only one case of breakthrough infection. The cumulative incidence of zoster infection at 1 year post transplant was 2% and at 5 years 34%. In all, 64 patients discontinued prophylaxis. Zoster developed in 26 of these, giving a cumulative incidence of infection at 1 year after stopping aciclovir of 39% and at 3 years 44%. Infection occurred in a localised dermatomal distribution in 93% of cases. This supports previous findings that aciclovir prophylaxis prevents early VZV reactivation, although the long-term incidence is not affected as infection occurs once prophylaxis is discontinued. Such infection, however, is mild and localised. This study does not support the idea that use of such low-dose aciclovir regimens reduces the zoster incidence by permitting subclinical reactivation during prophylaxis, and therefore the re-establishment of protective anti-viral immunity.

Cognitive function during insulin-induced hypoglycemia in humans: short-term cerebral adaptation does not occur.

It has been suggested that cerebral adaptation may occur in response to short-term hypoglycemia. This was examined in the present study by measuring serial changes in cognitive function and symptoms after 60 min of continuous hypoglycemia. Hypoglycemia was induced with a hyperinsulinemic glucose clamp on two separate occasions in 24 non-diabetic human subjects. Cognitive function was assessed using the following cognitive test battery: Paced Auditory Serial Addition Test (PASAT), Rapid Visual Information Processing (RVIP), Trail-Making B (TMB), Digit Symbol Substitution Test (DSST) and Four Choice Reaction Time (CRT). In condition A the blood glucose was maintained at 4.5 mmol/l throughout. On two separate occasions (condition B and condition C) the blood glucose was stabilised at 4.5 mmol/l for 30 min, lowered to 2.5 mmol/l for 60 min and restored to 4.5 mmol/l for 30 min. In each condition the cognitive test battery was performed immediately after stabilisation of blood glucose at 4.5 mmol/l and the subsequent battery was repeated at different time intervals: condition A--after a further 40 min of euglycemia; condition B--after 5 min of hypoglycemia; condition C--after 40 min of hypoglycemia. Acute hypoglycemia induced a significant deterioration in cognitive function which was manifest in all tests except TMB (P < 0.05), but performance ability did not differ between conditions B and C. Symptom scores, assessed by a scaled questionnaire, increased significantly during hypoglycemia (P < 0.001) but no differences were detected between the scores at 30 min and 60 min.(ABSTRACT TRUNCATED AT 250 WORDS)

Beta 2-agonists and running economy in prepubertal boys.

Asthmatic athletes (adults and junior) have competed successfully at the highest level for many years assisted by pre-event medication with beta 2-agonists. To examine the impact of beta 2-agonists upon submaximal running economy (oxygen consumption at a given submaximal work load), we studied 10 nonasthmatic boys (age, 10.4 +/- 0.48 years, mean +/- SD). They each completed submaximal (speeds, 7.2, 8.0 and 8.8 km/hr) and peak treadmill running protocols preceded by treatment with beta 2-agonist (terbutaline, 500 micrograms via nebuhaler) or placebo in a randomized, crossover single-blind study. No significant differences were found between running economy and heart rate during the submaximal exercise tests or between peak oxygen consumption (VO2), peak respiratory exchange ratio, peak heart rate (HR), or total running time during the peak VO2 test. Pretreatment with terbutaline did produce small but nonsignificant increases in aerobic fractional utilization (percent peak VO2 on drug: 65.9%, 72.6%, and 76.7% vs. placebo: 65.1%, 70%, and 75.5%), at the three submaximal work loads. Respiratory exchange ratio (RER) values were elevated throughout the submaximal tests (on drug: 0.94, 0.93, and 0.94 vs placebo: 0.91, 0.92, and 0.91, P < 0.05). No significant differences were found between drug and placebo for minute ventilation (VE) and ventilatory equivalent for oxygen (VE/VO2), at both submaximal and peak exercise intensities.(ABSTRACT TRUNCATED AT 250 WORDS)

Mesangiocapillary glomerulonephritis with dense "deposits" in the basement membranes of the kidney.

Amongst 125 patients with mesangiocapillary glomerulonephritis (MCGN), 19 showed continuous intramembranous dense "deposits" (IDD). Most were children or young adults. Two patients had partial lipodystrophy. Eleven had a consistently low plasma concentration of C3; only three, however, had an initial low plasma concentration of C4, which rose and then remained normal in two. Tests for the C3 nephritic factor were positive in thirteen patients, and plasma C1q was normal in 8 out of 11 cases investigated. Ten out of twelve (seven of them with low plasma C3) showed C3 deposition by immunofluorescence in the glomerular tuft. This was also demonstrated in some instances in Bowman's capsule and tubular basement membranes. Stains for IgG, IgA, C4 and C1q were negative in all, whereas stains for IgM and fibrin were weakly positive in the glomeruli of three and eight cases repectively. Eight patients went into terminal renal failure over an average of thirty-three months and required hemodialysis or transplantation. MCGN with IDD is an uncommon pattern of renal response to injury, which involves activation of the alternate pathway of the complement system and has a poor short term prognosis. The association with partial lipodystrophy and C3-splitting activity suggests a primary complement abnormality.

Wellington coroner autopsy cases 1970-89: acute deaths due to drugs, alcohol and poisons.

Coronal autopsy reports attributing deaths to drugs or poisonings were examined for the period 1970-89. There were 239 deaths of which 69% were suicide, 23% were accidental, 4% therapeutic misadventure, and 4% of uncertain category. 10.4% of deaths were due solely to alcohol and alcohol was found in another 13% of deaths from other drugs and poisons [corrected]. Twenty-seven percent of deaths were attributed to carbon monoxide poisoning. Five percent of deaths were due to poisons. Prescription drugs were the cause of deaths in 54% with the principle drug classes being opioids (14%), tricyclic antidepressants (12%), barbiturates (11%), hypnosedatives (8%). Prescribers need to be aware of the interactions of such drugs with alcohol, and to consider safer alternative drugs for those at risk of overdose or drug misuse.

Classification of glomerulonephritis.

A classification of glomerulonephritis which is being used as a basis for the New Zealand National Study of Glomerulonephritis is presented, together with comments about the salient pathological features of each type of glomerular disease.

Outcome of second allogeneic transplants using reduced-intensity conditioning following relapse of haematological malignancy after an initial allogeneic transplant.

Disease relapse following an allogeneic transplant remains a major cause of treatment failure, often with a poor outcome. Second allogeneic transplant procedures have been associated with high TRM, especially with myeloablative conditioning. We hypothesized that the use of reduced-intensity conditioning (RIC) would decrease the TRM. We performed a retrospective national multicentre analysis of 71 patients receiving a second allogeneic transplant using RIC after disease relapse following an initial allogeneic transplant. The majority of patients had leukaemia/myelodysplasia (MDS) (N=57), nine had lymphoproliferative disorders, two had myeloma and three had myeloproliferative diseases. A total of 25% of patients had unrelated donors. The median follow-up was 906 days from the second allograft. The predicted overall survival (OS) and TRM at 2 years were 28 and 27%, respectively. TRM was significantly lower in those who relapsed late (>11 months) following the first transplant (2 years: 17 vs 38% in early relapses; P=0.03). Two factors were significantly associated with a better survival: late relapse (P=0.014) and chronic GVHD following the second transplant (P=0.014). These data support our hypothesis that the second RIC allograft results in a lower TRM than using MA. A proportion of patients achieved a sustained remission even when relapsing after a previous MA transplant.

Role of allogeneic transplantation in low-grade lymphoma and chronic lymphocytic leukemia.

PURPOSE OF REVIEW: Indolent lymphoproliferative disorders are incurable with conventional chemotherapy. Exploring the potential of allogeneic transplantation to eradicate disease has therefore been of interest for some time. This review reports on recent developments in this field to evaluate the current status of stem cell transplantation in the management of these conditions. RECENT FINDINGS: Most recent studies examine the application of reduced intensity regimens in follicular non-Hodgkin's lymphoma and chronic lymphocytic leukemia. Interest is particularly focused on assessing the potency of the allogeneic graft-versus-malignancy effect, whether achieved by T cells infused at the time of transplant, or by the administration of exogenous donor lymphocytes at relapse or progression following transplant. Furthermore, the discovery of molecular/genetic factors that permit identification of patients with poor prognosis chronic lymphocytic leukemia has led to interest in identifying whether the allogeneic effect can overcome the impact of these factors. SUMMARY: Encouraging evidence is accumulating for the efficacy of reduced intensity transplantation in indolent lymphoproliferative disorders. Allogeneic graft-versus-malignancy effects can be demonstrated and durable responses to donor lymphocytes are being reported. More follow-up is required, however, before the curative potential of allogeneic transplantation can be assessed. The appropriate timing of transplant and the choice of regimen remains unclear.

Use of 18F-FDG positron emission tomography following allogeneic transplantation to guide adoptive immunotherapy with donor lymphocyte infusions.

Fluorine-18 fluorodeoxyglucose positron emission tomography ((18)F-FDG PET) provides valuable prognostic information in the management of lymphoma patients. However, the utility of (18)F-FDG PET following allografting is unclear. We analysed the use of (18)F-FDG PET after allogeneic reduced-intensity transplantation (RIT) performed in our institution. Between June 1998 and January 2002, 55 patients underwent RIT for either Hodgkin or non-Hodgkin lymphoma. At least one (18)F-FDG PET scan was performed during the post-transplant period (median five studies) in 15 (27.2%) of these 55 patients. PET scans were performed after re-staging computed tomography (CT) and were categorised depending on (18)F-FDG uptake. The first PET scan was informative in 11 of 15 patients (73%) and influenced the administration of donor lymphocyte infusions (DLI) in nine: leading to earlier DLI administration in two patients, earlier dose escalation in one, withholding of DLI administration in five and dose reduction in one. In addition, subsequent monitoring with (18)F-FDG PET scans documented a graft-versus-lymphoma effect in five patients (median post-DLI follow-up 33 months, range 13-36 months). These preliminary data suggest that (18)F-FDG PET has a role in guiding DLI administration and monitoring the immunotherapeutic effect in patients after allogeneic transplantation. This retrospective pilot study forms the basis for a prospective study to clarify the utility of (18)F-FDG PET/CT in these patients.