Comparisons of statistical distributions for cluster sizes in a developing pandemic.

BACKGROUND: We consider cluster size data of SARS-CoV-2 transmissions for a number of different settings from recently published data. The statistical characteristics of superspreading events are commonly described by fitting a negative binomial distribution to secondary infection and cluster size data as an alternative to the Poisson distribution as it is a longer tailed distribution, with emphasis given to the value of the extra parameter which allows the variance to be greater than the mean. Here we investigate whether other long tailed distributions from more general extended Poisson process modelling can better describe the distribution of cluster sizes for SARS-CoV-2 transmissions. METHODS: We use the extended Poisson process modelling (EPPM) approach with nested sets of models that include the Poisson and negative binomial distributions to assess the adequacy of models based on these standard distributions for the data considered. RESULTS: We confirm the inadequacy of the Poisson distribution in most cases, and demonstrate the inadequacy of the negative binomial distribution in some cases. CONCLUSIONS: The probability of a superspreading event may be underestimated by use of the negative binomial distribution as much larger tail probabilities are indicated by EPPM distributions than negative binomial alternatives. We show that the large shared accommodation, meal and work settings, of the settings considered, have the potential for more severe superspreading events than would be predicted by a negative binomial distribution. Therefore public health efforts to prevent transmission in such settings should be prioritised.

A stochastic model for MRSA transmission within a hospital ward incorporating environmental contamination.

Methicillin-resistant Staphylococcus aureus (MRSA) transmission in hospital wards is associated with adverse outcomes for patients and increased costs for hospitals. The transmission process is inherently stochastic and the randomness emphasized by the small population sizes involved. As such, a stochastic model was proposed to describe the MRSA transmission process, taking into account the related contribution and modelling of the associated microbiological environmental contamination. The model was used to evaluate the performance of five common interventions and their combinations on six potential outcome measures of interest under two hypothetical disease burden settings. The model showed that the optimal intervention combination varied depending on the outcome measure and burden setting. In particular, it was found that certain outcomes only required a small subset of targeted interventions to control the outcome measure, while other outcomes still reported reduction in the outcome distribution with up to all five interventions included. This study describes a new stochastic model for MRSA transmission within a ward and highlights the use of the generalized Mann-Whitney statistic to compare the distribution of the outcome measures under different intervention combinations to assist in planning future interventions in hospital wards under different potential outcome measures and disease burden.

A study to investigate dose escalation of doxorubicin in ABVD chemotherapy for Hodgkin lymphoma incorporating biomarkers of response and toxicity.

BACKGROUND: Myelotoxicity during initial cycles of chemotherapy for Hodgkin lymphoma is associated with better outcome, supporting the concept of individualised dosing based on pharmacodynamic end points to optimise results. This study was performed to identify the maximum tolerated dose (MTD) of doxorubicin within cycles 1-3 ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine). Circulating biomarkers of response (nucleosomal DNA, nDNA) and epithelial toxicity (Cytokeratin 18, CK18) were also measured. METHODS: Dose escalation of doxorubicin in cycles 1-3 ABVD supported by pegfilgrastim was performed on a six-patient cohort basis (35, 45 and 55 mg m(-2)) with doxorubicin reduced to 25 mg m(-2) or omitted in cycles 4-6 to maintain cumulative exposure of 103-130% standard ABVD. BVD was given at standard doses throughout. Six additional subjects were recruited at the MTD. RESULTS: Twenty-four subjects were recruited. Dose-limiting toxicities (DLTs) of grade 3 neuropathy, pneumonitis, palmar-plantar erythema and neutropenic infection were observed at 55 mg m(-2), so 45 mg m(-2) was declared the MTD. In patients who subsequently experienced DLT at any time, large increases in CK18 were seen on day 3 of cycle 1 ABVD. CONCLUSION: Escalated ABVD incorporating doxorubicin at 45 mg m(-2) in cycles 1-3 can be delivered safely with pegfilgrastim support. Circulating cell death biomarkers may assist in the development of future individualised dosing strategies.

Incurable, invisible and inconclusive: watchful waiting for chronic lymphocytic leukaemia and implications for doctor-patient communication.

Patients with chronic lymphocytic leukaemia (CLL) find it hard to accept a diagnosis of an incurable cancer for which no treatment is recommended and which may not cause symptoms for many years. We used qualitative interviews with 12 people with CLL managed by watchful waiting, drawn from a maximum variation sample of 39 adults with leukaemia, to explore accounts of watchful waiting and implications for clinical management. Patients with CLL recalled being given little information about the condition and wanted to know more about how it might affect them in the future. The invisibility of CLL meant that some chose not to disclose the diagnosis to others. Check-ups sometimes felt cursory, causing dissatisfaction. As symptoms increased, lifestyle adaptations became essential, well before treatment was warranted. Patients with CLL on watchful waiting experience levels of depression, anxiety and quality of life similar to those in active treatment; our qualitative approach has illuminated some of the reasons for the negative psychological impacts. We relate our findings to perceptions of the illness state, doctor-patient communication, and work pressure. We recommend that specialists could better support patients by acknowledging psychological impacts of CLL, actively listening to patients' concerns, and meeting their needs for information.

A sequential Monte Carlo approach to derive sampling times and windows for population pharmacokinetic studies.

Here we present a sequential Monte Carlo approach that can be used to find optimal designs. Our focus is on the design of population pharmacokinetic studies where the derivation of sampling windows is required, along with the optimal sampling schedule. The search is conducted via a particle filter which traverses a sequence of target distributions artificially constructed via an annealed utility. The algorithm derives a catalog of highly efficient designs which, not only contain the optimal, but can also be used to derive sampling windows. We demonstrate our approach by designing a hypothetical population pharmacokinetic study, and compare our results with those obtained via a simulation method from the literature.

Estimation of parameters for macroparasite population evolution using approximate bayesian computation.

We estimate the parameters of a stochastic process model for a macroparasite population within a host using approximate Bayesian computation (ABC). The immunity of the host is an unobserved model variable and only mature macroparasites at sacrifice of the host are counted. With very limited data, process rates are inferred reasonably precisely. Modeling involves a three variable Markov process for which the observed data likelihood is computationally intractable. ABC methods are particularly useful when the likelihood is analytically or computationally intractable. The ABC algorithm we present is based on sequential Monte Carlo, is adaptive in nature, and overcomes some drawbacks of previous approaches to ABC. The algorithm is validated on a test example involving simulated data from an autologistic model before being used to infer parameters of the Markov process model for experimental data. The fitted model explains the observed extra-binomial variation in terms of a zero-one immunity variable, which has a short-lived presence in the host.

Assessment of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukaemia (the LRF CLL4 Trial): a randomised controlled trial.

BACKGROUND: Previous studies of patients with chronic lymphocytic leukaemia reported high response rates to fludarabine combined with cyclophosphamide. We aimed to establish whether this treatment combination provided greater survival benefit than did chlorambucil or fludarabine. METHODS: 777 patients with chronic lymphocytic leukaemia requiring treatment were randomly assigned to fludarabine (n=194) or fludarabine plus cyclophosphamide (196) for six courses, or chlorambucil (387) for 12 courses. The primary endpoint was overall survival, with secondary endpoints of response rates, progression-free survival, toxic effects, and quality of life. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number NCT 58585610. FINDINGS: There was no significant difference in overall survival between patients given fludarabine plus cyclophosphamide, fludarabine, or chlorambucil. Complete and overall response rates were better with fludarabine plus cyclophosphamide than with fludarabine (complete response rate 38%vs 15%, respectively; overall response rate 94%vs 80%, respectively; p<0.0001 for both comparisons), which were in turn better than with chlorambucil (complete response rate 7%, overall response rate 72%; p=0.006 and 0.04, respectively). Progression-free survival at 5 years was significantly better with fludarabine plus cyclophosphamide (36%) than with fludarabine (10%) or chlorambucil (10%; p<0.00005). Fludarabine plus cyclophosphamide was the best combination for all ages, including patients older than 70 years, and in prognostic groups defined by immunoglobulin heavy chain gene (V(H)) mutation status and cytogenetics, which were tested in 533 and 579 cases, respectively. Patients had more neutropenia and days in hospital with fludarabine plus cyclophosphamide, or fludarabine, than with chlorambucil. There was less haemolytic anaemia with fludarabine plus cyclophosphamide (5%) than with fludarabine (11%) or chlorambucil (12%). Quality of life was better for responders, but preliminary analyses showed no significant difference between treatments. A meta-analysis of these data and those of two published phase III trials showed a consistent benefit for the fludarabine plus cyclophosphamide regimen in terms of progression-free survival. INTERPRETATION: Fludarabine plus cyclophosphamide should now become the standard treatment for chronic lymphocytic leukaemia and the basis for new protocols that incorporate monoclonal antibodies.

Multivariate Markov process models for the transmission of methicillin-resistant Staphylococcus aureus in a hospital ward.

Methicillin-resistant Staphylococcus Aureus (MRSA) is a pathogen that continues to be of major concern in hospitals. We develop models and computational schemes based on observed weekly incidence data to estimate MRSA transmission parameters. We extend the deterministic model of McBryde, Pettitt, and McElwain (2007, Journal of Theoretical Biology 245, 470-481) involving an underlying population of MRSA colonized patients and health-care workers that describes, among other processes, transmission between uncolonized patients and colonized health-care workers and vice versa. We develop new bivariate and trivariate Markov models to include incidence so that estimated transmission rates can be based directly on new colonizations rather than indirectly on prevalence. Imperfect sensitivity of pathogen detection is modeled using a hidden Markov process. The advantages of our approach include (i) a discrete valued assumption for the number of colonized health-care workers, (ii) two transmission parameters can be incorporated into the likelihood, (iii) the likelihood depends on the number of new cases to improve precision of inference, (iv) individual patient records are not required, and (v) the possibility of imperfect detection of colonization is incorporated. We compare our approach with that used by McBryde et al. (2007) based on an approximation that eliminates the health-care workers from the model, uses Markov chain Monte Carlo and individual patient data. We apply these models to MRSA colonization data collected in a small intensive care unit at the Princess Alexandra Hospital, Brisbane, Australia.

The role of prognostic factors in assessing 'high-risk' subgroups of patients with chronic lymphocytic leukemia.

The management of chronic lymphocytic leukemia (CLL) has historically relied on 'watchful waiting' and palliative approaches to therapy. However, the course of disease is highly variable and a substantial proportion of patients with early-stage CLL develop rapidly progressive disease requiring therapy. In recent decades, numerous clinical and biological prognostic markers that are predictive of decreased survival outcomes, disease progression and/or resistance to therapy, and that may play a role in defining the subgroups of patients with 'high-risk' CLL have been identified. At the same time, highly effective treatment modalities have become available with the advent of chemoimmunotherapy combinations and allogeneic stem cell transplantation. Thus, we are approaching an era when patients with CLL may potentially benefit from individualized risk assessments based on prognostic markers and when specific therapies may be offered to the subgroup of patients with high-risk disease. This review provides a brief overview of newer biological prognostic markers, discusses the challenges associated with identifying the subgroup of patients with high-risk CLL and further aims to provide recommendations on how prognostic markers may be used to assess high-risk subgroups in different clinical situations in CLL.

Characterizing an outbreak of vancomycin-resistant enterococci using hidden Markov models.

BACKGROUND: Antibiotic-resistant nosocomial pathogens can arise in epidemic clusters or sporadically. Genotyping is commonly used to distinguish epidemic from sporadic vancomycin-resistant enterococci (VRE). We compare this to a statistical method to determine the transmission characteristics of VRE. METHODS AND FINDINGS: A structured continuous-time hidden Markov model (HMM) was developed. The hidden states were the number of VRE-colonized patients (both detected and undetected). The input for this study was weekly point-prevalence data; 157 weeks of VRE prevalence. We estimated two parameters: one to quantify the cross-transmission of VRE and the other to quantify the level of VRE colonization from sporadic sources. We compared the results to those obtained by concomitant genotyping and phenotyping. We estimated that 89% of transmissions were due to ward cross-transmission while 11% were sporadic. Genotyping found that 90% had identical glycopeptide resistance genes and 84% were identical or nearly identical on pulsed-field gel electrophoresis (PFGE). There was some evidence, based on model selection criteria, that the cross-transmission parameter changed throughout the study period. The model that allowed for a change in transmission just prior to the outbreak and again at the peak of the outbreak was superior to other models. This model estimated that cross-transmission increased at week 120 and declined after week 135, coinciding with environmental decontamination. SIGNIFICANCE: We found that HMMs can be applied to serial prevalence data to estimate the characteristics of acquisition of nosocomial pathogens and distinguish between epidemic and sporadic acquisition. This model was able to estimate transmission parameters despite imperfect detection of the organism. The results of this model were validated against PFGE and glycopeptide resistance genotype data and produced very similar results. Additionally, HMMs can provide information about unobserved events such as undetected colonization.

Results of the randomized phase IIB ADMIRE trial of FCR with or without mitoxantrone in previously untreated CLL.

ADMIRE was a multicenter, randomized-controlled, open, phase IIB superiority trial in previously untreated chronic lymphocytic leukemia. Conventional front-line therapy in fit patients is fludarabine, cyclophosphamide and rituximab (FCR). Initial evidence from non-randomized phase II trials suggested that the addition of mitoxantrone to FCR (FCM-R) improved remission rates. Two hundred and fifteen patients were recruited to assess the primary end point of complete remission (CR) rates according to International Workshop on Chronic Lymphocytic Leukemia criteria. Secondary end points were progression-free survival (PFS), overall survival (OS), overall response rate, minimal residual disease (MRD) negativity and safety. At final analysis, CR rates were 69.8 FCR vs 69.3% FCM-R (adjusted odds ratio (OR): 0.97; 95% confidence interval (CI): (0.53-1.79), P=0.932). MRD-negativity rates were 59.3 FCR vs 50.5% FCM-R (adjusted OR: 0.70; 95% CI: (0.39-1.26), P=0.231). During treatment, 60.0% (n=129) of participants received granulocyte colony-stimulating factor as secondary prophylaxis for neutropenia, a lower proportion on FCR compared with FCM-R (56.1 vs 63.9%). The toxicity of both regimens was acceptable. There are no significant differences between the treatment groups for PFS and OS. The trial demonstrated that the addition of mitoxantrone to FCR did not increase the depth of response. Oral FCR was well tolerated and resulted in impressive responses in terms of CR rates and MRD negativity compared with historical series with intravenous chemotherapy.

Analysis of VH gene sequences using two web-based immunogenetics resources gives different results, but the affinity maturation status of chronic lymphocytic leukaemia clones as assessed from either of the resulting data sets has no prognostic significance.

Some cellular and molecular features of chronic lymphocytic leukaemia (CLL) cells that are associated with prognosis may reflect the context within which their progenitors encountered antigen. It follows that the nature of antigen drive in CLL could influence the clinical course and we were prompted to assess the impact, if any, of affinity maturation (an antigen-driven process) on prognosis. Statistical models for assessing affinity maturation status are typically applied to V(H) gene sequence data analysed using a web-based resource like IMGT or VBASE. Since these resources differ with respect to some key relevant features, we evaluated a cohort of CLL cases by applying statistical models to V(H) data derived from both IMGT and VBASE. Important differences between the resulting data sets became apparent. These resulted from database variance and because IMGT and VBASE define complementarity-determining and framework regions (CDRs, FRs) in different ways. Thus, the numbers of mutations identified and their distribution between CDRs/FRs varied between the data sets for the majority of clones. Consequently, two different but overlapping sets of cases with evidence of affinity maturation were defined. Notwithstanding their differences, no significant associations of affinity maturation status with CD38 expression, p53 functional status or survival were identifiable in either data set.

Role of poly(ADP-ribosyl)ation in the killing of chronic lymphocytic leukemia cells by purine analogues.

Although the nucleoside analogues fludarabine and chlorodeoxyadenosine have become important therapeutic agents in chronic lymphocytic leukemia (CLL), their effectiveness is limited by drug resistance. Because such resistance is likely to result from impaired drug-induced apoptosis, it is clearly important to understand the mechanisms involved in this process. Whereas p53 can contribute to the nucleoside-induced killing of CLL cells, recent work from this laboratory and elsewhere has shown that such killing can also occur by p53-independent mechanisms. Because poly(ADP-ribose) polymerase (PARP)-mediated NAD+/ATP depletion has been implicated in the nucleoside-induced killing of normal resting lymphocytes, we postulated that this mechanism might account for the p53-independent component of nucleoside cytotoxicity in CLL. To address this question, we used 3-aminobenzamide (3AB) at a concentration (200 microM) known to produce selective inhibition of poly(ADP-ribosyl)ation in intact cells and examined nucleoside-induced killing using a number of different end points (cell membrane disruption, cell shrinkage, mitochondrial depolarization, exposure of phosphatidyl serine, morphological changes, DNA fragmentation, and PARP-1 cleavage). In 27 of the 30 cases of CLL examined, 3AB delayed nucleoside-induced cell membrane disruption without inhibiting other manifestations of cytotoxicity. This indicates that PARP activity, rather than contributing to the induction of cell killing, was accelerating cell membrane disruption during the late stages of apoptosis. This novel observation has important implications for previous studies of PARP-mediated cytotoxicity. However, in cells from one CLL patient, 3AB inhibited all manifestations of nucleoside cytotoxicity; this was the only case in the study known to have a p53 gene defect affecting both alleles. This indicates that PARP activity can occasionally be central to nucleoside-induced killing and that such PARP-mediated killing is p53 independent.

Sampling methods for exploring between-subject variability in cardiac electrophysiology experiments.

Between-subject and within-subject variability is ubiquitous in biology and physiology, and understanding and dealing with this is one of the biggest challenges in medicine. At the same time, it is difficult to investigate this variability by experiments alone. A recent modelling and simulation approach, known as population of models (POM), allows this exploration to take place by building a mathematical model consisting of multiple parameter sets calibrated against experimental data. However, finding such sets within a high-dimensional parameter space of complex electrophysiological models is computationally challenging. By placing the POM approach within a statistical framework, we develop a novel and efficient algorithm based on sequential Monte Carlo (SMC). We compare the SMC approach with Latin hypercube sampling (LHS), a method commonly adopted in the literature for obtaining the POM, in terms of efficiency and output variability in the presence of a drug block through an in-depth investigation via the Beeler-Reuter cardiac electrophysiological model. We show improved efficiency for SMC that produces similar responses to LHS when making out-of-sample predictions in the presence of a simulated drug block. Finally, we show the performance of our approach on a complex atrial electrophysiological model, namely the Courtemanche-Ramirez-Nattel model.

Genomic disruption of the histone methyltransferase SETD2 in chronic lymphocytic leukaemia.

Histone methyltransferases (HMTs) are important epigenetic regulators of gene transcription and are disrupted at the genomic level in a spectrum of human tumours including haematological malignancies. Using high-resolution single nucleotide polymorphism (SNP) arrays, we identified recurrent deletions of the SETD2 locus in 3% (8/261) of chronic lymphocytic leukaemia (CLL) patients. Further validation in two independent cohorts showed that SETD2 deletions were associated with loss of TP53, genomic complexity and chromothripsis. With next-generation sequencing we detected mutations of SETD2 in an additional 3.8% of patients (23/602). In most cases, SETD2 deletions or mutations were often observed as a clonal event and always as a mono-allelic lesion, leading to reduced mRNA expression in SETD2-disrupted cases. Patients with SETD2 abnormalities and wild-type TP53 and ATM from five clinical trials employing chemotherapy or chemo-immunotherapy had reduced progression-free and overall survival compared with cases wild type for all three genes. Consistent with its postulated role as a tumour suppressor, our data highlight SETD2 aberration as a recurrent, early loss-of-function event in CLL pathobiology linked to aggressive disease.

A complementary role of multiparameter flow cytometry and high-throughput sequencing for minimal residual disease detection in chronic lymphocytic leukemia: an European Research Initiative on CLL study.

In chronic lymphocytic leukemia (CLL) the level of minimal residual disease (MRD) after therapy is an independent predictor of outcome. Given the increasing number of new agents being explored for CLL therapy, using MRD as a surrogate could greatly reduce the time necessary to assess their efficacy. In this European Research Initiative on CLL (ERIC) project we have identified and validated a flow-cytometric approach to reliably quantitate CLL cells to the level of 0.0010% (10(-5)). The assay comprises a core panel of six markers (i.e. CD19, CD20, CD5, CD43, CD79b and CD81) with a component specification independent of instrument and reagents, which can be locally re-validated using normal peripheral blood. This method is directly comparable to previous ERIC-designed assays and also provides a backbone for investigation of new markers. A parallel analysis of high-throughput sequencing using the ClonoSEQ assay showed good concordance with flow cytometry results at the 0.010% (10(-4)) level, the MRD threshold defined in the 2008 International Workshop on CLL guidelines, but it also provides good linearity to a detection limit of 1 in a million (10(-6)). The combination of both technologies would permit a highly sensitive approach to MRD detection while providing a reproducible and broadly accessible method to quantify residual disease and optimize treatment in CLL.

Sleep deprivation and the physiological response to exercise under steady-state conditions in untrained subjects.

Seven physically untrained subjects underwent 72 h total sleep deprivation, followed a baseline day. Daily, at 0400 and 1600 h, subjects pedalled on a bicycle ergometer under individually set work loads of 40, 60, and 80% VO2max. This was not a study oriented towards endurance but towards capacity, requiring steady-state measurement. From assessments of heart rate, VO2 and VCO2 were calculated: VO2max, gross mechanical efficiency, VO2 at a heart rate of 150, and respiratory quotient. To assess possible training effects, a control group underwent identical procedures except that they slept at night and had the morning measure delayed until 0830 h. A series of statistical models were applied to the data, which centered on quantifying the inherent underlying variability, to estimate the level any main effect had to reach to become significant. the analysis showed that the noise level was small enough for any real effect of importance to have been detected, with a reasonably large probability. No statistically significant effects were found for any of the parameters with respect to conditions, days, and time. The main significant outcome was with mechanical efficiency, which displayed greater variability during sleep deprivation. Both groups displayed similar trends in training effects. It was concluded that the physiological ability to do work of the type and duration used here was not adversely affected by 72 h of sleep loss.

Homotypic interactions protect chronic lymphocytic leukaemia cells from spontaneous death in vitro.

Chronic lymphocytic leukaemia (CLL) cells are long-lived in vivo but undergo spontaneous apoptosis when cultured in vitro. Since CLL cells associate intimately with one another at sites of tissue involvement, we examined the hitherto unproven possibility that homotypic interactions between the malignant cells might reduce their propensity to undergo spontaneous cell death. In a series of experiments in which highly pure CLL-cell populations were cultured on a non-adherent surface, cell viability was found to increase markedly with the level of crowding at the bottom of the culture vessel. The effect was observed among unevenly distributed cells within a single culture vessel and did not require direct cell-cell contact. This indicates that cell survival was being regulated in an autocrine fashion by locally acting soluble products. Conditioned medium from crowded CLL cells enhanced the survival of autologous non-crowded cells, indicating that at least some of the autocrine survival factors produced by CLL cells could accumulate in the extracellular environment. In addition, the survival of non-crowded CLL cells was markedly enhanced by co-culturing them with an excess of autologous fixed cells. This protective effect of direct cell-cell contact was mediated by specific surface structures since it was abrogated by pre-treating the fixed cells with neuraminidase. Our results provide the first direct demonstration that the survival of cultured CLL cells is enhanced by homotypic interactions. We speculate that these protective effects may contribute to the accumulation of CLL cells in vivo, and that further elucidation of the underlying mechanisms may lead to novel therapeutic strategies.

Thrombotic microangiopathy following bone marrow transplantation.

Thrombotic microangiopathy (TMA) is a well-recognised disorder which may occur in up to 6% of patients following bone marrow transplantation (BMT). Reported cases of post-BMT TMA vary widely in their reported clinical features, severity and response to therapy. Several factors are important in the aetiology, including cyclosporin A (CsA), graft-versus-host disease, irradiation, intensive conditioning chemotherapy and infection. A unifying pathogenetic mechanism is suggested, wherein these factors may interact to produce post-BMT TMA. On the basis of differences in clinical features and prognosis, we propose the classification of post-BMT TMA into four distinctive although overlapping subtypes: multifactorial fulminant TMA, conditioning-associated haemolytic-uraemic syndrome, CsA-associated nephrotoxicity with microangiopathic haemolytic anaemia (MAHA) and CsA-associated neurotoxicity with MAHA. Treatment of post-BMT TMA, especially of the poor-prognosis multifactorial fulminant subtype, is currently unsatisfactory, although occasional cases may respond to plasma exchange.

Vogt-Koyanagi-Harada syndrome complicating allogeneic bone marrow transplantation.

Vogt-Koyanagi-Harada (VKH) syndrome is an uncommon acute ophthalmological disorder, characterised by bilateral serous retinal detachment with diffuse choroiditis, in association with specific extra-ocular manifestations. We describe a patient with unequivocal VKH syndrome arising 49 days after matched unrelated donor bone marrow transplantation (BMT) performed as treatment for severe aplastic anaemia. The visual symptoms and retinal changes responded well to corticosteroids. The haematological relevance of VKH syndrome is to distinguish it from retinitis due to cytomegalovirus, which requires different therapy and has a far worse visual prognosis.