Josh Wright

Guidelines for the management of the acute painful crisis in sickle cell disease

Severe acute pain is the commonest manifestation of sickle cell disease (SCD) requiring hospital admission in Europe and the USA. Although the pain itself is not directly lifethreatening, inappropriate treatment leads to unnecessary suffering and potentially fatal complications, related both to the disease and the treatment, and repeated admissions with pain are associated with a higher mortality rate (Platt et al, 1994). There are thought to be more than 10 000 patients with SCD in the UK (Streetly et al, 1997), the majority of these live in London. Whereas some hospitals see large numbers of patients with SCD and have established protocols and experienced staff, most hospitals will see only a few patients each year. These guidelines aim to provide advice on a basic, minimum standard of care for patients with acute painful crises and SCD, and pay particular attention to adequate analgesia and monitoring for life-threatening complications.

Is routine molecular screening for common α-thalassaemia deletions necessary as part of an antenatal screening programme?

Antenatal sickle and thalassaemia screening programmes are now established in most high prevalence areas in England. Although screening reliably detects β-thalassaemia trait, in many cases, results state that α-thalassaemia trait cannot be excluded. The detection of couples at risk of a child with hydrops fetalis is one of the aims of the national programme. We, therefore, performed polymerase chain reaction (PCR) for the common α-thalassaemia gene deletions to assess the usefulness of this technique in routine screening practice. Between August 2001 and August 2002, of the 5092 women booked at the antenatal clinic, 425 were found to have a mean corpuscular haemoglobin (MCH) <27 pg in the absence of β-thalassaemia trait; 189 (44.5%) had an MCH <25 pg. All 425 patients underwent PCR analysis for the common deletions: –SEA (South-East Asian), –MED (Mediterranean), −α 20.5, –FIL (Filipino), −α 3.7 and −α 4.2 genotypes. In total, 130 (31%) women were positive for α-thalassaemia deletion; 86 (24.7%) were heterozygous for −α 3.7, 19 (4.4%) were homozygous for −α 3.7, 12 (2.8%) were heterozygous for −α 4.2, 1 (0.2%) was homozygous for −α 4.2, 11 (2.6%) were heterozygous for –SEA and one (0.2%) was heterozygous for the –MED genotype. Although the detection rate for α +-thalassaemia was high, a strategy of selective screening using MCH <25 pg and ethnic group (SEA, Middle East or Eastern MED) would have identified all individuals heterozygous for α 0-thalassaemia. Routine molecular screening for all forms of α-thalassaemia trait is unjustified in antenatal screening.

Anti‐Fy3 in sickle cell disease: a difficult transfusion problem

human fetus and neonate. Acta Paediatrica, 91(Suppl. 438), 54–65. Peterec, S.M., Brennan, S.A., Rinder, H.M., Wnek, J.L. & Beardsley, D.S. (1996) Reticulated platelet values in normal and thrombocytopenic neonates. Journal of Pediatrics, 129, 269–274. Saigo, K., Sakota, Y., Masuda, Y., Matsunaga, K., Takenokuchi, M., Nishimura, K., Sugimoto, T., Sakurai, K., Hashimoto, M., Yanai, T., Hayakawa, A., Takeshima, Y., Nomura, T., Kubota, Y. & Kumagai, S. (2008) Automatic detection of immature platelets for decision making regarding platelet transfusion indications for pediatric patients. Transfusion and Apheresis Science, 38, 127–132. Sola, M.C., Calhoun, D.A., Hutson, A.D. & Christensen, R.D. (1999) Plasma thrombopoietin concentrations in thrombocytopenic and non-thrombocytopenic patients in a neonatal intensive care unit. British Journal of Haematology, 104, 90–92.

Remission of human immunodeficiency virus-related lymphoma in association with immune reconstitution on anti-retroviral therapy, without chemotherapy.

In the developed world, the incidence of human immunodeficiency virus (HIV)-related non-Hodgkin lymphoma (NHL) has significantly declined since the introduction of effective anti-retroviral therapy (ART).[1,2] Patients developing lymphoma while on ART have significantly improved outcomes, comparable with those for lymphoma in non-HIV populations.[3] Commencement of anti-retroviral drugs is essential for successful lymphoma management in treatment naı̈ve individuals found to be HIV positive at diagnosis.[4] Cytotoxic chemotherapy in HIV positive patients causes a fall in CD4 count of 50%, rendering them at increased risk of opportunistic infection and may slow the immune re-constitution seen with ART.[5] While inducing profound cell mediated immunodeficiency, HIV infection also leads to immune activation and a chronic inflammatory state which, along with Epstein Barr virus (EBV) and other infective etiologies, may contribute to the pathogenesis of lymphoma. Immunologically, there are parallels with other immunodeficiency states in which lymphoma may arise, such as post-solid organ or stem cell transplant and inherited immunodeficiency. EBV plays a significant role in lymphomagenesis, whatever the underlying nature of immune deficiency.[6,7] Primary management of the EBV driven post-transplant lymphoproliferative disorders (PTLD) involve attempts at restoring immune function. CD4 and CD8 positive T cells are essential for controlling primary and reactivated EBV, thus PTLD is treated either by reduction of immunosuppression, immunotherapy with anti-CD20 antibody which targets the EBV containing lymphocytes or the administration of specific cytotoxic T lymphocytes.[8] ART has its effects by reducing HIV replication, restoring T-cell numbers and function along with cellular and humoral immune responses. However, it is sometimes associated with significant toxicity, especially when patients have acquired immune deficiency syndrome (AIDS) defining infections, where potentially life threatening immune reconstitution disease or immune reconstitution inflammatory syndrome may be activated, unmasking opportunistic infection or malignancy.[9,10] It is therefore possible that severely immunosuppressed patients with detection of HIV infection at the time of diagnosis of lymphoma could respond to immune reconstitution without the need for conventional chemotherapy regimens, in a similar manner to patients with PTLD. In this retrospective UK wide case series, we report the successful management of nine patients with different lymphoma subtypes treated with ART alone. Selected lymphoma specialists throughout UK were contacted via email to report patients diagnosed with lymphoma who had responded to ART alone. Centers were asked to provide anonymized information including demographics, histological subtype, stage, HIV viral load, CD4 count, antiretroviral regimen, progression and clinical outcomes. Central pathology review was not possible, however, all the patients were managed in centers with lymphoma and HIV expertise and in keeping with Improving Outcome Guidance had been discussed in multidisciplinary meetings with lymphoma and HIV specialists. Tissue specimens were assessed by histopathologists with special expertise in the diagnostics of lymphoma.

Specialist integrated haematological malignancy diagnostic services: an Activity Based Cost (ABC) analysis of a networked laboratory service model

Aims Specialist Integrated Haematological Malignancy Diagnostic Services (SIHMDS) were introduced as a standard of care within the UK National Health Service to reduce diagnostic error and improve clinical outcomes. Two broad models of service delivery have become established: ‘co-located’ services operating from a single-site and ‘networked’ services, with geographically separated laboratories linked by common management and information systems. Detailed systematic cost analysis has never been published on any established SIHMDS model. Methods We used Activity Based Costing (ABC) to construct a cost model for our regional ‘networked’ SIHMDS covering a two-million population based on activity in 2011. Results Overall estimated annual running costs were £1 056 260 per annum (£733 400 excluding consultant costs), with individual running costs for diagnosis, staging, disease monitoring and end of treatment assessment components of £723 138, £55 302, £184 152 and £94 134 per annum, respectively. The cost distribution by department was 28.5% for haematology, 29.5% for histopathology and 42% for genetics laboratories. Costs of the diagnostic pathways varied considerably; pathways for myelodysplastic syndromes and lymphoma were the most expensive and the pathways for essential thrombocythaemia and polycythaemia vera being the least. Conclusions ABC analysis enables estimation of running costs of a SIHMDS model comprised of ‘networked’ laboratories. Similar cost analyses for other SIHMDS models covering varying populations are warranted to optimise quality and cost-effectiveness in delivery of modern haemato-oncology diagnostic services in the UK as well as internationally.

Bone marrow transplants from peripheral blood

EDITOR, - Reinfusion of peripheral blood stem cells to repopulate the bone marrow after myeloablative chemotherapy is being increasingly used to intensify treatment for haematological and other malignancies.1 We could find no published data on the practicalities of returning the cells to the patient through a central venous line. One method is to inject …

Central nervous system prophylaxis in patients with diffuse large B cell lymphoma, are we treating ourselves? A response to the recent BCSH Guideline

Deutsch, Y.E., Tadmor, T., Podack, E.R. & Rosenblatt, J.D. (2011) CD30: an important new target in hematologic malignancies. Leukemia & Lymphoma, 52, 1641–1654. Gruss, H.J., D€ olken, G., Brach, M.A., Mertelsmann, R. & Herrmann, F. (1993) The significance of serum levels of soluble 60 kDa receptors for tumor necrosis factor in patients with Hodgkin’s disease. Leukemia, 7, 1339–1343. Herbeck, R., Teodorescu Br̂ınzeu, D., Giubelan, M., Laz ar, E., Dema, A. & Ionit a, H. (2011) Bcell transcription factors Pax-5, Oct-2, BOB.1, Bcl-6, and MUM1 are useful markers for the diagnosis of nodular lymphocyte predominant Hodgkin lymphoma. Romanian Journal of Morphology and Embryology, 52, 69–74. Hu, S., Xu-Monette, Z.Y., Balasubramanyam, A., Manyam, G.C., Visco, C., Tzankov, A., Liu, W.M., Miranda, R.N., Zhang, L., Montes-Moreno, S., Dybkær, K., Chiu, A., Orazi, A., Zu, Y., Bhagat, G., Richards, K.L., Hsi, E.D., Choi, W.W., Han van Krieken, J., Huang, Q., Huh, J., Ai, W., Ponzoni, M., Ferreri, A.J., Zhao, X., Winter, J.N., Zhang, M., Li, L., Møller, M.B., Piris, M.A., Li, Y., Go, R.S., Wu, L., Medeiros, L.J. & Young, K.H. (2013) CD30 expression defines a novel subgroup of diffuse large B-cell lymphoma with favorable prognosis and distinct gene expression signature: a report from the International DLBCL Rituximab-CHOP Consortium Program Study. Blood, 121, 2715– 2724. Li, Y.J., Li, Z.M., Rao, H.L., Xia, Y., Huang, H.Q., Xia, Z.J., Li, S., Li, W.Y. & Jiang, W.Q. (2012) CD20-negative de novo diffuse large B-cell lymphoma in HIV-negative patients: a matched case-control analysis in a single institution. Journal of Translational Medicine, 10, 84. Marafioti, T., Hummel, M., Foss, H.D., Laumen, H., Korbjuhn, P., Anagnostopoulos, I., Lammert, H., Demel, G., Theil, J., Wirth, T. & Stein, H. (2000) Hodgkin and Reed-Sternberg cells represent an expansion of a single clone originating from a germinal center B-cell with functional immunoglobulin gene rearrangements bu defective immunoglobulin transcription. Blood, 95, 1443–1450. Metkar, S.S., Naresh, K.N., Manna, P.P., Srinivas, V., Advani, S.H. & Nadkarni, J.J. (2000) Circulating levels of TNF alpha and TNF receptor superfamily members in lymphoid neoplasia. American Journal of Hematology, 65, 105–110. Salles, G., Bienvenu, J., Bastion, Y., Barbier, Y., Doche, C., Warzocha, K., Gutowski, M.C., Rieux, C. & Coiffier, B. (1996) Elevated circulating levels of TNFalpha and its p55 soluble receptor are associated with an adverse prognosis in lymphoma patients. British Journal of Haematology, 93, 352–359. Stein, H., Mason, D.Y., Gerdes, J., O’Connor, N., Wainscoat, J., Pallesen, G., Gatter, K., Falini, B., Delsol, G. & Lemke, H. (1985) The expression of the Hodgkin’s disease associated antigen Ki-1 in reactive and neoplastic lymphoid tissue: evidence that Reed-Sternberg cells and histiocytic malignancies are derived from activated lymphoid cells. Blood, 66, 848–858. Valsami, S., Pappa, V., Rontogianni, D., Kontsioti, F., Papageorgiou, E., Dervenoulas, J., Karmiris, T., Papageorgiou, S., Harhalakis, N., Xiros, N., Nikiforakis, E. & Economopoulos, T. (2007) A clinicopathological study of B-cell differentiation markers and transcription factors in classical Hodgkin’s lymphoma: a potential prognostic role of MUM1/IRF4. Haematologica, 92, 1343– 1350.

Authors' response to Dong-Zhi Li's letter: 'Routine molecular screening for common alpha-thalassaemia deletions is necessary as part of an antenatal screening programme'

We thank Dr Li for his comments. Screening for a thalassaemia remains a difficult issue without a perfect solution. The aim of our research was primarily to assess the National Health Service (NHS) sickle and thalassaemia programme recommendation on screening for pregnancies at risk of Bart’s hydrops. Such events are very unusual in the UK population as opposed to the considerably higher risk in southern China. Secondly, we wished to assess the type and prevalence of a globin deletions seen within our local population hence the application of universal a deletion screening for patients with low Mean Corpuscular Haemoglobin (MCH) regardless of partner testing. We accept that there may be more cost efficient strategies. In fact, the ‘at risk ethnic origin/low MCH’ NHS screening programme approach is very similar to that adopted by Dr Li. Pregnant patients from an at-risk ethnic group with low MCH undergo partner testing as a first step. If the couple are both deemed to be at risk of carrying a thalassaemia then they will undergo multiplex PCR testing for a deletions. Regarding the second point of double heterozygotes for a and b thalassaemia; although we did not clearly state this within the paper, we can confirm that it is the practice of the authors and the NHS sickle and thalassaemia screening programme to look for ‘silent’ a deletions in individuals with b thalassaemia trait in at risk ethnic groups. Of course no available strategy takes into account mutational forms of alpha thalassaemia, which may interact with a deletions to cause fetal hydrops.