Family studies of warts, hypogammaglobulinemia, immunodeficiency, myelokathexis syndrome.

PURPOSE OF REVIEW: WHIM syndrome (warts, hypogammaglobulinemia, immunodeficiency, myelokathexis, or WHIMs) is a very rare autosomal dominant immunodeficiency disorder attributable to mutations in CXCR4. We reviewed clinical manifestations in 24 patients in 9 families to expand understanding of this syndrome. RECENT FINDINGS: Warts, cellulitis and respiratory infections are common in patients with WHIMs. Less commonly these patients have congenital heart disease, human papilloma virus-associated malignancies (cervical and vulvular) and lymphomas. Hearing loss because of recurrent otitis media is another important complication. Treatment with granulocyte colony-stimulating factor is controversial; this review indicates that it is effective to prevent and treat infections based upon long-term observations of patients enrolled in the Severe Chronic Neutropenia International Registry. Understanding the natural history and diversity of this syndrome are important for ongoing clinical trials of novel agents to treat WHIMs. SUMMARY: WHIM syndrome has diverse manifestations; some features occur consistently in almost all patients, for example, neutropenia, lymphocytopenia and mild hypogammaglobulinemia. However, the clinical consequences are quite variable across patient cohorts and within families. Each complication is important as a cause for morbidity and a source for patient and family concerns.

Early viral reactivation despite excellent immune reconstitution following haploidentical Bone marrow transplant with post-transplant cytoxan for sickle cell disease.

BACKGROUND: Haploidentical bone marrow transplant (haplo-BMT) offers near universal donor availability as a curative modality for individuals with severe sickle cell disease (SCD). However, the required intense immunodepletion is associated with increased infectious complications. A paucity of data exists on immune reconstitution following haplo-BMT for SCD. METHODS: A multi-institution learning collaborative was developed in the context of a phase II clinical trial of a non-myeloablative, related haplo-BMT with post-transplant cyclophosphamide for SCD. We report results from a cohort of 23 patients for whom immune reconstitution data up to one year were available. RESULTS: Median age was 14.8 years. Out of 23, 18 participants received pre-conditioning with azathioprine, hydroxyurea, and hypertransfusions. 70% (16/23) of participants had multiple indications for haplo-BMT. We observed excellent immune reconstitution of CD4, CD8, CD19, and CD56 cellular subsets by 6 months post transplant. Engraftment rate and event-free survival in this cohort were 100% and 96%, respectively. 70% (16/23) of patients had at least one viral reactivation or infection, including CMV 35% (8/23), HHV-6 22% (5/23), and polyoma virus 17% (4/23), with no cases of post-transplant lymphoproliferative disease. CONCLUSION: Further prospective studies are needed to better characterize immune reconstitution and the immunologic basis for increased viral reactivation following haplo-BMT with post-transplant cyclophosphamide for SCD.

Unrelated Donor Transplantation in Children with Thalassemia using Reduced-Intensity Conditioning: The URTH Trial.

Allogeneic hematopoietic stem cell transplantation (HSCT) can cure transfusion-dependent thalassemia (TDT). In a multicenter trial we investigated the efficacy of reduced-intensity conditioning (RIC) before unrelated donor (URD) HSCT in children with TDT. Thirty-three children, ages 1 to 17 years, received bone marrow (BM) or umbilical cord blood (UCB) allografts. Median time to neutrophil engraftment was 13 days (range, 10 to 25) and 24 days (range, 18 to 49) and platelet engraftment 23 days (range, 12 to 46) and 50 days (range, 31 to 234) after BM and UCB allografts, respectively. With a median follow-up of 58 months (range, 7 to 79), overall and thalassemia-free survival was 82% (95% CI, .64% to .92%) and 79% (95% CI, .6% to .9%), respectively. The cumulative incidence of grades II to IV acute graft-versus-host disease (GVHD) after BM and UCB allografts was 24% and 44%; the 2-year cumulative incidence of chronic extensive GVHD was 29% and 21%, respectively; 71% of BM and 91% of UCB recipients discontinued systemic immunosuppression by 2 years. Six patients who had Pesaro risk class 2 (n = 5) and class 3 (n = 1) died of GVHD (n = 3), viral pneumonitis (n = 2) and pulmonary hemorrhage (n = 1). Outcomes after this RIC compared favorably with URD HSCT outcomes for TDT and supported engraftment in 32 of 33 patients. Efforts to reduce GVHD and infectious complications are being pursued further.

Realism in evidence based medicine: interpreting the randomised controlled trial.

Realism is emerging as a paradigm for research and explanation in the natural and social sciences. A realist framework is elaborated and applied to the four possible situations that may generate the observations of randomised, controlled trials. It is demonstrated that by using two realist concepts "mechanism" and "context" a number of misinterpretations of such trials from within the dominant empiricist paradigm may be rectified. Evidence based medicine should adopt realism to temper a misleading empiricism, this will involve relegating statistical arguments to their proper subsidiary place and adopting an adequate theory of causation.

Skill mix, doctors and nurses: substitution or diversification?

This commentary surveys the current arguments for and against modifying the work of doctors and nurses by placing the main viewpoints - substitution and diversification - within the policy background, particularly that of the UK. We discuss the forces for modification: cost effectiveness, professional development, quality improvement and pragmatic management and how each provides a stand-point for evaluation of the issues. Policy makers and managers in the health sector should be aware of the rather fragmented evidence base for doctor-nurse substitution and should consider skill mix changes only when they are clear about: purpose, evidence base, acceptable risks, accountability and quality assurance. Doctor-nurse substitution is not necessarily cost effective, nor is it unfailingly a gain in nurse professionalism or in quality of care. Of the management perspectives available - advocacy, skepticism or pragmatism - the current evidence and policy base favours pragmatism over evaluations of the rightness or wrongness of a general policy.

A test-and-treat policy does not save endoscopy workload in a non-referral hospital.

AIM: To assess the impact that a test-and-treat policy with open-access urea breath testing (UBT) has had on the referral rates for endoscopy in a district hospital. Additionally, we examined for any change in the proportion of serious pathology detected endoscopically after adopting the policy. METHODS: Analysis of data on all open-access endoscopy referrals in a 12-month period before (October 1994 to September 1995) and 2 years after (October 1997 to September 1998) the introduction of the UBT service. This was compared with the same service in our sister hospital, which had not provided a UBT service. Results of patients attending the UBT service during the period of study were also examined. RESULTS: A total of 798 patients attended for endoscopy (18% aged < 40 years, 82% aged > 40 years) in the pre-UBT year compared with 1905 patients (16% aged < 40 years, 84% aged > 40 years) in the post-UBT year. The standardized referral ratios were significantly higher for both age groups in the post-UBT year: 210 in the < 40 years group (95% CI 187 to 235) and 244 in the > 40 years group (95% CI 233 to 257). Six per cent of the < 40 years group in the post-UBT year had serious pathology compared with 7% pre-UBT (P < 0.1). However, the proportion of serious pathology decreased from 37 to 27% in the > 40 years group (P < 0.01). The total number of open-access endoscopies had increased steadily over the 3 years, despite the introduction of the UBT service. This trend was mirrored in our sister hospital. A total of 457 patients attended the UBT service during the 12 months. Of these, 24.5% were Helicobacter pylori positive, with a 66.3% eradication rate. CONCLUSIONS: A test-and-treat policy has not saved endoscopy workload in this non-referral hospital. We feel that results from centres with an H. pylori interest cannot be generalized for the vast majority.