International Consensus Report Research Articles

ITP and international guidelines: What do we know, what do we need?

In the last decade, rituximab and thrombopoietin-receptor agonists (TPO-ra) have been introduced into the traditional armamentarium of Immune Thrombocytopenia (ITP), consisting in corticosteroids as initial treatment and splenectomy in those not responding or relapsing. A variety of immunosuppressive treatments were reserved for patients not responsive to splenectomy. These advancements have been incorporated in two international current guidelines: the first, produced by an international group of expert clinicians (International Consensus Report, ICR); the second, by a selected group of hematologists and methodologists with expertise in systematic reviews and guideline development, mainly from United States, without direct connection with pharmaceutical companies. This latter guideline was endorsed by the American Society of Hematology (ASH). A new standardized terminology has also been adopted, with a more clear definition of primary vs secondary ITP and a clear distinction between the different phases of the disease-newly diagnosed, persistent, chronic (after 12 months from diagnosis). Both guidelines structure their suggestions on first, second and third-line treatments, with less attention to the different phases of the disease and its severity. There is a substantial agreement in proposing the initial treatment with oral corticosteroids and TPO-ra as third-line approach in patients unsuccessfully splenectomized in whom these agents appear to have the more favorable therapeutic profile. As to the second-line approach in patients failing corticosteroids, rituximab and TPO-ra could be valid alternatives to splenectomy but, unfortunately, the international guidelines fail to offer a consistent approach. Whereas ICR considers splenectomy at the same level of many other second-line treatments including rituximab and TPO-ra, ASH guideline definitely recommends reserving TPO-ra and rituximab to patients failing or with a contra-indication to splenectomy. As new data are being accumulated on long-term outcomes and toxicity of TPO-ra and the role of rituximab is being better defined for particular patients as second-line therapy, it will be possible to revisit the pros and cons of these options vs each other and splenectomy which, although less and less popular, maintains the highest curative potential, with an acceptable toxicity. The thrombotic risk in ITP should also be better defined and taken into account in guiding the treatment in the individual patients. Hopefully, new studies will be based more on clinical outcomes than on platelet count increase. The ultimate lesson of the insufficient evidence and disagreement among experts is that management of ITP should be tailored to the individual patients.

Management of Primary Immune Thrombocytopenia, 2012: A Survey of Oklahoma Hematologists-Oncologists

BackgroundManagement options for patients with primary immune thrombocytopenia (ITP) have increased, and treatment of patients with ITP has changed during the past 10 years. MethodsTo document current practice and to determine how current practice is related to recommendations of 2 recent practice guidelines for ITP, an international Consensus report and an American society of Hematology (ASH) guideline, the authors surveyed practicing hematologistsoncologists in Oklahoma. Surveys were specific for children or adults. Each survey had 3 questions describing patients with a new diagnosis and patients who had not achieved remission with initial treatment. Questions were adapted from the clinical scenarios of the ASH guideline. ResultsTwelve (92%) Oklahoma pediatric hematologistsoncologists responded; 82 (81%) Oklahoma adult hematologistsoncologists responded. For a child with a new diagnosis of ITP, a platelet count of 8000/μL and minor bleeding, 5 (42%) hematologistsoncologists selected observation without drug treatment (recommended by both guidelines). For an adult with a platelet count of 9000/μL who had failed to respond to initial treatment with corticosteroids and IVIg, 32 (39%) selected splenectomy (recommended by the ASH guideline); 30 (37%) selected rituximab and 13 (16%) selected thrombopoietin-receptor agonists (both recommended by the International Consensus report). Hematologists-oncologists who had more years in practice were more likely to select splenectomy (P = 0.047). ConclusionsIn a time of changing management for patients with ITP, these data document reported current management in Oklahoma and provide a basis for serial comparisons across time and for comparisons with other regions and comparison of management with patient outcomes.

Conflicts of Interest and Clinical Recommendations

The growing influence of practice guidelines has increased concern for potential sources of bias. Two recent guidelines for primary immune thrombocytopenia (ITP) provided a unique opportunity for a systematic comparison of different methods of practice guideline development. One guideline (International Consensus Report [ICR]) was supported by pharmaceutical companies that produce products for ITP. The ICR panel members were selected for expertise in ITP; 16 (73%) reported associations with pharmaceutical companies. The other guideline was sponsored by the American Society of Hematology (ASH); panel members were selected for lack of conflicts and for expertise in guideline development as well as for ITP. Discrepancies were conspicuous when the guidelines addressed treatment. In contrast to the ASH guideline, the ICR gave stronger recommendations for agents manufactured by companies from which the ICR or its panel members received support. These data provide direct evidence that differences in financial support and methods of evidence evaluation can influence recommendations.

Immune Thrombocytopenia Nomenclature, Consensus Reports, and Guidelines: What Are the Consequences for Daily Practice and Clinical Research?

New insights into the pathophysiology and the natural history of immune thrombocytopenia (ITP) and new therapeutical approaches have emerged in the last 10 years that have made necessary the update of previous guidelines. An important step towards the harmonization on both the definition of the disease and the phases of the disease, the objectives of treatment, and the criteria of response to be used in clinical trials has been first made possible throughout the International Working group on ITP. This important step has been followed by an international consensus report and the updated American Society of Hematology (ASH) guidelines focused on the investigation and management of ITP taking into account the data from the most recent clinical trials in the field. In this article, the consequences and translation that these guidelines may have or not on daily practice and on future clinical trials are discussed and the few controversies are pointed out. Whereas these guidelines are helpful for the investigation of ITP and for the harmonization of clinical trials, some area of uncertainties do remain for the best management of ITP and especially the choice of the best second-line strategy in persistent ITP is still far from being consensual.

Treatment of patients diagnosed with primary immune thrombocytopenia at the Hematology Department of the University Medical Centre Ljubljana

Background: Primary immune thrombocytopenia (ITP) is an autoimmune disorder resulting from antibody- and T-cell-mediated destruction of the platelets and suppression of platelet production in the bone marrow. According to the International Consensus report, in order to be diagnosed with ITP, patient is required to have isolated thrombocytopenia with a platelet count below 100 × 109/L, with no other obvious cause for this condition and no other disease that could cause secondary immune thrombocytopenia. Methods: We retrospectively analysed patients who were treated de novo for ITP at the Departement of Hematology of the University Medical Centre Ljubljana (UMC) between the period from 1 January 2008 to 31 December 2012. We excluded those who did not meet the criteria for diagnosis of ITP. Afterwards we analyzed the type and response to treatment and the incidence of bleeding. Splenecomised patients were analysed separately. Results: In the four-year period we treated 153 patients diagnosed with ITP. 113/153 were included in the study, while 40/153 (26 %) were excluded. Bleeding incidents were recorded in 47/113 (41.5 %), but none of them were life threatening or fatal. 14/113 (12.4 %) were treated by splenectomy. Conclusions: Since ITP is a diagnosis of exclusion, many patient do not meet all the criteria for firm diagnosis. Considering low platelet counts, life threathening or even fatal bleedings are rare. Corticosteroids are standard first-line treatment. Nevertheless, many patients do not need any treatment at the time of diagnosis. At our centre splenectomy is often used as a second line treatment. In patients with refractory ITP or those who are not good candidates for splenectomy, we also use thrombopoetin receptors agonists or rituximab.

Management of Primary Immune Thrombocytopenia, 2012: A Survey of Oklahoma Hematologists-Oncologists

Abstract 1094 IntroductionWith the availability of multiple new agents, management of patients with primary immune thrombocytopenia (ITP) has changed substantially since the initial practice guideline for ITP was developed by the American Society of Hematology (ASH). To document current practice and to determine how current practice is related to recommendations of 2 recent guidelines for ITP, an International Consensus report (ICR), 2010, and an updated ASH guideline, 2011, we surveyed practicing hematologists-oncologists in Oklahoma. MethodsSeparate surveys were developed for children and adults. Each survey had 3 clinical scenarios; each scenario had 5–7 management choices. Hematologists-oncologists were instructed to select 1 management choice. Questions were adapted from the clinical scenarios of the ASH guideline. Additionally, data were collected for [1] number of years in practice; [2] site of practice, (either University of Oklahoma Medical Center or community); and [3] the estimated number of patients with ITP seen each year. Oklahoma hematologists-oncologists were identified by searching the Oklahoma Board of Medical Licensure and the Oklahoma Osteopathic Association websites for all active physicians certified in adult/pediatric hematology/oncology as of 12/31/2011. Exclusion criteria were: physicians whose careers were devoted to full-time research/administration. Data was collected between 1/31/2012–3/15/2012. Only the stronger grades of recommendations by the ICR and ASH guidelines were used for comparison to the hematologists-oncologists’ responses. Comparison of treatment responses to the number of years in practice was selected a priori, because it was hypothesized that hematologists-oncologists with fewer years in practice may more readily accept newer treatments while hematologists-oncologists with more years in practice may prefer more traditional management. Chi-square or Fisher’s exact test were used to determine if treatment responses differed by number of years in practice. SAS version 9.2 was used; alpha was set at 0.05. ResultsAll 13 (100%) Oklahoma pediatric hematologists-oncologists responded. For a child with a new diagnosis of ITP, a platelet count of 8,000/μL, and minor bleeding, 5 (38%) pediatric hematologists-oncologists selected observation without drug treatment (recommended by both guidelines). Because of the small number of pediatric hematologists-oncologists, no comparison of their responses to years in practice was performed. Eighty-three (82%) adult hematologists-oncologists responded. For an adult with a platelet count of 9,000/μL who had failed to respond to initial treatment with corticosteroids and IVIg, 32 (39%) selected splenectomy (recommended by ASH guideline); 31 (37%) selected rituximab and 13 (16%) selected thrombopoietin (TPO)-receptor agonists (both recommended by ICR). There was not a statistically significant difference between the number of years in practice for those who selected splenectomy versus all other treatment options (p = 0.07). DiscussionAlthough both recent guidelines recommended that children with no/mild bleeding may be managed with observation regardless of the platelet count, only 5 (38%) pediatric hematologists-oncologists selected observation in this scenario. The practice guidelines have different recommendations for second-line treatment in adults: the ICR recommends TPO-receptor agonists and rituximab but not splenectomy; the ASH guideline recommends splenectomy but not TPO-receptor agonists or rituximab. For this clinical scenario, 39% of hematologists-oncologists selected splenectomy, 37% selected rituximab and 16% selected TPO-agents. These different choices and recommendations reflect the changing clinical practice. Although not statistically significant, the hematologists-oncologists who had been in practice for >20 years appeared to be more likely to select splenectomy (p=0.07), consistent with greater acceptance of newer treatments by younger hematologists-oncologists. Although these data may not be generalizable, the high survey response rate provides confidence that these data accurately reflect the judgment, if not the actual practice, of Oklahoma hematologists-oncologists. ConclusionThese observations provide an estimate of actual current clinical practice for management of patients with ITP. Disclosures:Off Label Use: Rituximab for primary immune thrombocytopenia (ITP). George:Alexion, Inc.: Consultancy; Baxter, Inc.: Consultancy; Amgen, Inc.: Consultancy, PI for clinical trial involving romiplostim, PI for clinical trial involving romiplostim Other, Research Funding. Terrell:Amgen, Inc.: Consultancy; Baxter, Inc.: Consultancy.

Squamous cell carcinoma and junctional epidermolysis bullosa

Squamous cell carcinoma and junctional epidermolysis bullosa

Long Term Follow up of Patients with Immune Thrombocytopenia Receiving Rituximab

Abstract 4675 Introduction:Rituximab has been used in the management of chronic immune thrombocytopenia (ITP) with promising results. The risk of losing response, however, is yet to be determined with long term follow up. Method:We retrospectively analyzed 32 consecutive patients (20 females, 12 males) with ITP (including 6 patients with secondary ITP) treated with rituximab in two tertiary care hospitals in Oman between May 2006 and May 2011. Response criteria were based on the International Consensus report (Rodeghiero F et al. Blood 2009). Result:The median age at diagnosis was 25 years (range, 4 – 58). Clinical presentation ranged from mild echymosis to more severe central nervous system bleeding. Patients received a median of one line of therapy before rituximab (range, 1–4), including 3 patients who failed splenectomy. Patients received intravenous rituximab using 375 mg/m2 once weekly for 4 weeks. The median time from diagnosis to receiving rituximab was 21 months (range, 1– 177). Only one patient was positive for Hepatitis C virus, but no hepatitis B or HIV positive in this cohort. Anti nuclear antibody was positive in 34% (10/29) of patients. The median hemoglobin and platelet counts at diagnosis were 12 g/dl (range, 5–16) and 11×109/L (range, 1–60) respectively. The median follow up time after rituximab was 26 months (95% confidence interval: 11–40). The overall cumulative response rate was 59% (partial response of 15% and complete response of 44%). The median time to respond was 30 days (Standard error [SE] 49) with a response rate of 44% at 4 weeks (95% Confidence interval: 29–62%). The multivariable Cox model analysis (variables include: age at diagnosis, gender, number of previous therapies and primary vs. secondary) revealed none of the variables included to be statistically significant. The cumulative rate of loss of response was 32% (6/19) with a median time to lose response of 54 months (SE, 0.03). In patients who lost response, the median time to lose response was 17 months (SE, 14). Of the 6 patients who lost response, 4 received a second course of rituximab and all 4 achieved a full response. No major side effects to rituximab were reported during the follow up. Conclusion:Rituximab is an effective and a well tolerated second line therapy for ITP. The response to rituximab can be maintained for a long duration with a high rate of response after retreatment. None of the pretreatment variables studied carried a significant predictive value for response. The study was limited by the small sample size and further larger prospective studies are recommended. Disclosures:Off Label Use: Rituximab was used in our study as a second line for the management of chronic immune thrombocytopenia.

Improving Live Donor Kidney Transplant Guidelines: More Evidence Required

The availability of clinical guidelines on living donor kidney transplantation has undoubtedly aided clinical decision-making in this area and hopefully helped to minimize adverse outcomes and unintended harm to living donors. Several countries, including the United Kingdom, the United States, Canada, Australia, and countries in continental Europe, have published guidelines that cover the screening and follow-up of living kidney donors. In addition, in 2005, the Transplantation Society produced an international consensus report from the Amsterdam Forum that includes medical guidelines for living donation. The intention of guidelines is to synthesize available evidence into recommendations for best practice. Where evidence is poor or lacking, it is replaced by aspiration or opinion, either of an individual or, more often, a group of clinicians with experience in the area in question. How do the various guidelines compare? In this issue of Transplantation, Tong et al. (1) report a carefully undertaken and comprehensive comparison of the scope, quality, and consistency of the published guidelines on the screening of potential living donors and donor follow-up. They evaluated nine published guidelines, including those from the Amsterdam Forum, using the Appraisal of Guidelines Research and Evaluation (AGREE) instrument (2). This appraisal instrument examines the quality of the guidelines, both in terms of the evidence used and the way it is reported, and provides a benchmark for producing high-quality guidelines. The quality of guidelines assessed was variable. Reassuringly, many of the recommendations made in the different published guidelines were consistent. However, in several areas, the guidelines differed in their recommendations, particularly with respect to the medical contraindications to donation. For example, the acceptable thresholds stated for hypertension, obesity, glucose metabolism, and cardiovascular disease were not consistent across the different guidelines, although some of these differences may reflect the different populations for which they were written. Tong et al. also make the important observation that although the published guidelines are consistent in emphasizing the importance of assessing the potential donors' psychological state, they failed to provide adequate guidance on how and with what tools psychological state should be assessed. Many of the recommendations made in the guidelines examined were based on limited evidence, and this reflects the relative lack of good long-term data on which to base such guidance. Given the lack of available high-quality evidence in many areas, it is not perhaps surprising that there should sometimes be a lack of consensus. This should serve, however, as a very timely reminder of the need to improve the evidence base for evaluating potential living donors. This requires much better long-term follow-up data than is currently available, and this need is particularly pressing in view of the trend toward accepting living donors which may in previous years have been declined on the basis of comorbid conditions. Living kidney donation is a major undertaking for donor and recipient. The donor agrees to undergo surgery in the belief that the risks are defined and are minimized. They have a right to understand fully the short- and long-term risks of donation that they are exposing themselves to, especially where comorbidity makes them less than ideal donors. There are many barriers to achieving long-term follow-up, in addition to the cost and workload involved. The donor may live some distance from the transplant unit, and may be ambivalent about participating in long-term follow-up, or may not wish to be reminded about their surgery and that there may be long-term sequelae. Similarly, long-term studies are not appealing to research funding bodies or researchers because the results by definition will be a long time coming and as such are not useful for career progression. Nevertheless, it is important that more effort is made by the medical community to follow-up, and when necessary give appropriate support to, living donors. Perhaps the most important message from the study of Tong et al. is that there is a need for more effort to be made in gathering long-term data on living donors. Their call for mandatory submission of registry data, along with improved long-term monitoring by healthcare providers, and appropriate education and support to maintain a healthy lifestyle should be supported. Tong et al. conclude that there is an urgent need to ensure that guidelines for living donation are consistent, evidence-based, and comprehensive to promote best outcome. Most transplant clinicians would agree, but the key to this is a better evidence base than is currently available. A major focus on improving the evidence base in living donor assessment and long-term outcome is required without delay. Other clinical practice guidelines should adopt the same rigorous approach recommended for living kidney donor guidelines if they are to be accurate, useful, and appropriate.

Chronic adult primary immune thrombocytopenia (ITP) in the Asia-Pacific region

Patients with primary immune thrombocytopenia (ITP) from the Asia-Pacific region often exhibit characteristics distinct from those of patients from the West. Moreover, as the region itself is heterogeneous, the ITP landscape among individual Asia-Pacific countries can be diverse. The recently released international consensus report on ITP places new emphasis on ITP, but does not address the unique ITP landscape in the Asia-Pacific region, which is home to 60% of the world's population. In an attempt to characterize how the ITP landscape differs between the West and the Asia-Pacific region, an expert panel with representatives from Northeast Asia, Southeast Asia, and Australia was convened. Important differences were identified between the guidance provided in the international consensus report and experience in the Asia-Pacific region, namely diagnostic practices, incidence and approach to ITP secondary to H. pylori infection, systemic lupus erythematosus-related ITP, the use of bone marrow examination, initial treatment strategies, and the role of splenectomy, rituximab, and thrombopoietin receptor agonists.

Sorafenib and bevacizumab combination targeted therapy in advanced neuroendocrine tumor: A phase II study of the Spanish Neuroendocrine Tumor Group (GETNE0801).

4113 Background: Sorafenib (S) and bevacizumab (B) as single agents have shown efficacy in NETs phase II trials. S+B combination has shown manageable toxicity in phase I trials in solid tumors. The aim of this study was to evaluate the efficacy and toxicity of the STI's combination in NETs. Methods: Phase II, controled clinical trial, carried out in 10 centers in Spain. Eligibility criteria: measurable, non-resectable, histologically confirmed moderately or well-differentiated NETs; 1 prior chemotherapy treatment allowed; ECOG PS 0–2. Duration of treatment: 6 months. Pts received S 200 mg bid (days 1 to 5 of each week) and B 5mg/Kg once every 2 weeks (day 1 of week 1). Efficacy results were calculated with intention to treat sample (n=41). Results: 44 pts were enrolled, 59.1% men. Median age was 60 years (range 32–76) and ECOG PS was 1 for 54.5% of pts. Carcinoid tumors: 31 pts and islet cell carcinoma (ICC): 13 pts were evaluated. Histology grade was well-differentiated in 95.5% of pts. Target lesions of pts at baseline were mainly in the liver (86.4%) and lymphatic nodes (31.8%). ORR (RECIST 1.1) was 9.8% and DCR 95.1%. PR was documented in 3 pts with carcinoid tumors and 1 PR with ICC. Estimated PFS was a median of 12.4 months (95%CI: 9.4-16.2) and a PFS rate at 6 months of 90.9% (30/33). A total of 8 pts finished the study prematurely: 6 due to adverse events and 2 due to consent withdraw. Most common grade 3-4 toxicities were hand-foot syndrome (20.5%) and asthenia (15.9%). No major response was observed with Chromogranin/5-HIAA analysis. Conclusions: This is the first study of targeted STI's combination in advanced NETs. The final results of the combination of low-dose sorafenib + bevacizumab showed a potential clinical benefit, albeit with moderate toxicities. Further studies should be confirm the real value of the targeted combination therapies in this setting, according to International Consensus Report (Kulke M, et al; JCO published online on January 24, 2011).

Allogeneic Platelet MHC Class I Antigens Prevent CD61 Specific Cytotoxic T Cell (CTL)-Mediated Immune Thrombocytopenia (ITP).

AbstractAbstract 3686In the International Consensus Report (Rodeghiero et al. Blood 2009;113:2386-2393), platelet transfusions are only recommended in patients with auto-immune thrombocytopenia (ITP) as an adjunctive therapy for life-threatening bleeding. However, the clinical evidence of post-transfusion increments in ITP suggests that in some cases of ITP, platelet transfusions may be a useful prophylactic therapy. To understand the importance of platelet transfusion in this setting, we utilized our murine model of ITP that demonstrates both antibody- and CTL-mediated thrombocytopenia. BALB/c CD61 knockout (KO) mice were immunized by transfusions of three different platelet populations that were either single antigen positive (e.g. CD61+ or MHC class I+) or double antigen positive (CD61+/MHC class I+). Splenocytes from the immune KO mice were either not depleted (ND) or depleted of CD19+ B cells and then transferred into SCID mice and the development of thrombocytopenia and bleeding diathesis was monitored. When ND splenocytes from MHC class I+ immune KO mice were transferred, no thrombocytopenia or bleeding was observed. In contrast, transfer of ND splenocytes from CD61+ immune mice induced a significant thrombocytopenia with a bleeding mortality of 40% within 3 weeks post-transfer; depletion of B cells was used to analyze CD8+ T cell- mediated thrombocytopenia and these depleted splenocytes also induced thrombocytopenia and bleeding. In addition, compared with healthy mice, the bone marrow of the transferred mice showed elevated numbers of megakaryocytes with some of them appearing to be apoptotic. On the other hand, when splenocytes from the double immunized (CD61+/MHC class I+) mice were transferred, the CD8+ T cell- mediated thrombocytopenia and bleeding mortality was not observed. In addition to preventing the thrombocytopenia and bleeding, histological analysis of the bone marrow showed normal numbers of megakaryocytes. These results suggest that both antibody- and CD8+ T cell-mediated immune thrombocytopenia exist and that when anti-CD61 specific CD8+ T cells interacted with allogeneic MHC antigens on platelets they were prevented from inducing CD8+ T cell-mediated thrombocytopenia. Thus, allogeneic MHC platelet transfusions may be responsible for inhibiting CD8+ T cell-mediated thrombocytopenia and may be a therapeutic option for those patients who suffer from cell-mediated ITP. Disclosures:No relevant conflicts of interest to declare.

Coincidence of Immune Thrombocytopenia, Intracranial Hemorrhage and Graft-versus-Host Disease in an 11-Year-Old Girl

Primary immune thrombocytopenia (ITP) in children is usually self-limiting and harmless but can, rarely, result in life-threatening complications. The case of an 11-year-old girl with ITP is presented who developed recurrent intracranial hemorrhages followed by cerebral infarctions. The clinical course was complicated by a graft-versus-host disease involving several organs. Treatment was performed according to the current international consensus report of 2010 with glucocorticoids, immunoglobulin G, anti-D-immunoglobulin and additionally embolisation of the splenic artery. The girl survived. Reliable predictors, preventive measures for life-threatening complications in ITP and more information about the effectiveness and side-effects of the recommended treatment are urgently needed.

The neglected hepatitis C virus genotypes 4, 5 and 6: an international consensus report

Abstract Hepatitis C virus (HCV) genotypes 4, 5 and 6 represent >20% of all HCV cases worldwide. HCV-4 is mainly seen in Egypt, where it represents 90% of all HCV cases. Antischistosomal therapy was the main cause of contamination there, followed by procedures performed by informal providers and traditional healers such as dental care, wound treatment, circumcision, deliveries, excision and scarification. It is also highly prevalent in sub-Saharan Africa and in the Middle East. In Europe, its prevalence has recently increased particularly among intravenous drug users and in immigrants. HCV-5 is mainly found in South Africa, where it represents 40% of all HCV genotypes, but four pockets of HCV-5 were found in France, Spain, Syria and Belgium and sporadic cases were found elsewhere. The mode of transmission is mainly iatrogenic and transfusion. HCV-6 is found in Hong Kong, Vietnam, Thailand and Myanmar and also in American and Australian from Asian origin. The response to treatment in HCV-4 is intermediate between HCV-1 and HCV-2 and HCV-3. A sustained viral response is achieved in 43-70% with pegylated interferon and ribavirin. It is higher in Egyptians than Europeans and Africans and is negatively related to insulin resistance and to the severity of fibrosis. It increases to >80% with 24 weeks of therapy only if a rapid virological response is achieved. In HCV-5, a sustained virological response is achieved in >60% with 48 weeks of therapy. HCV-6 is also considered an easy-to-treat genotype, leading to a response in 60-85% of cases.

The classification of inherited epidermolysis bullosa (EB): Report of the Third International Consensus Meeting on Diagnosis and Classification of EB

Since publication in 2000 of the Second International Consensus Report on Diagnosis and Classification of Epidermolysis Bullosa, many advances have been made to our understanding of this group of diseases, both clinically and molecularly. At the same time, new epidermolysis bullosa (EB) subtypes have been described and similarities with some other diseases have been identified. We sought to arrive at a new consensus of the classification of EB subtypes. We now present a revised classification system that takes into account the new advances, as well as encompassing other inherited diseases that should also be included within the EB spectrum, based on the presence of blistering and mechanical fragility. Current recommendations are made on the use of specific diagnostic tests, with updates on the findings known to occur within each of the major EB subtypes. Electronic links are also provided to informational and laboratory resources of particular benefit to clinicians and their patients. As more becomes known about this disease, future modifications may be needed. The classification system has been designed with sufficient flexibility for these modifications. This revised classification system should assist clinicians in accurately diagnosing and subclassifying patients with EB.

Commentary: Asthma time trends—mission accomplished?

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Occupational rhinitis: diagnostic criteria, relation to lower airway symptoms and IgE sensitization in bakery workers

Conclusions. The use of different diagnostic criteria has considerable consequences for the prevalence estimates of occupational rhinitis. There is a strong relationship between occupational rhinitis and lower airway symptoms. Storage mites appear to be important occupational allergens in Norwegian bakeries. Objectives. To study the consequences of various diagnostic criteria on the prevalence of occupational rhinitis, assess the prevalence of IgE sensitization and explore the relationships between upper and lower airway symptoms and between symptoms and IgE sensitization. Material and methods. A total of 197 employees in 6 bakeries were interviewed and completed a questionnaire. A skin prick test was performed, total and specific IgE were determined and a histamine release test was performed for relevant allergens. The criteria for the diagnosis of occupational rhinitis were based on the 1994 International Consensus Report on Rhinitis. Results. The prevalence of occupational rhinitis varied between 23% and 50%, depending on the criteria used. The occurrence of nasal symptoms was found to precede the development of lower airway symptoms. Occupational rhinitis, both IgE- and non-IgE-mediated, was associated with asthma symptoms. The most frequent causes of sensitization (20%) were different species of storage mites. Storage mite sensitization was related to occupational rhinitis and work exposure.

Psychiatric morbidity in a neurology-based memory clinic: the effect of systematic psychiatric evaluation.

To estimate the prevalence of psychiatric morbidity and the effect of systematic psychiatric evaluation in patients referred to a memory clinic in a neurological setting. Descriptive case-series study in consecutive referrals to a memory clinic. An outpatient multidisciplinary memory clinic in a neurological setting. An index group of 100 consecutive patients (aged 60-89) referred for diagnostic evaluation of cognitive symptoms during a period of 8 months and a reference group of 686 consecutive patients (aged 60-98) referred during a previous period of 54 months. In the index group, a systematic psychiatric evaluation was performed in addition to the neurological evaluation and routine investigations. In the reference group, patients had the same basic evaluation, but psychiatric evaluation was optional and was performed in 21% of the patients. Prevalence of primary psychiatric morbidity in the index and reference groups according to international clinical criteria and multidisciplinary consensus report and three key psychiatric symptoms: delusions, hallucinations, and affective symptoms in the index group. Twenty-three percent of patients in the index group had a primary psychiatric disease. A primary psychiatric disease was diagnosed in 8% of patients in the reference group (P<.001). One or more psychiatric symptoms were identified in 72% of all patients in the index group. Psychiatric conditions and symptoms are frequent in elderly patients with cognitive symptoms, including those referred to a neurological memory clinic. The data provide evidence for a multispecialty and multidisciplinary approach to the diagnosis and management of patients with possible dementia.

Comparative Study of Different Inhaler Devices in Asthmatic Children

The inhaler is an important drug delivery system in the treatment of asthma, but inhaler technique is often inadequate. We assessed technique in children diagnosed with asthma, comparing the performance of three devices. In a cross-sectional survey, 523 children (271 boys, 252 girls, ages 5 to 12 years; mean+/-SD 7.53+/-1.79 years) demonstrated inhalation technique according to Netherlands Asthma Foundation criteria during a first visit to a primary care clinic in Abha, Saudi Arabia. Patients used the device with which they were most familiar (either pMDI, Turbuhaler or Diskus). Two hundred children (38% of total population) used a pMDI, while 323 (62% of total population) used one of the dry powder inhalers 173 (58%) the Turbuhaler and 150 (47%) the Diskus. Only 49 children (25% of the total population) completed the assessment without making a mistake. The remaining 474 (75% of the total population) performed one or more manuevers poorly. Only 80 children who used an MDI (40% of those using the device) completed 50% or more of the maneuvers correctly compared with 111 (69% of those using the device) and 100 (67% of those using the device) of those using the Turbuhaler and Diskus, respectively (P=0.001 for comparison of MDI with dry powder inhalers). Children whose mothers had intermediate school or higher education performed better than those whose mothers had less education (P=0.001). The father's education had no bearing on performance with the inhaler. The inhaler technique of most asthmatic children is poor, but technique is better in children who use a dry powder compared a metered-dose inhaler. The level of the mother's education is positively associated with better inhalation technique in the child.

Allergic bronchial asthma: airway inflammation and hyperresponsiveness.

The international consensus report on diagnosis and treatment of asthma was published in 1992 (Clin Exp Allergy 22: 1-72). According to the report, asthma is a chronic inflammatory disorder of the airways in which many cells play a role, including mast cells and eosinophils. Airway inflammation causes various symptoms of asthma which are usually associated with widespread but variable airflow obstruction and causes an associated increase in airway responsiveness to a variety of stimuli. The definition of asthma, provided in this report, is an epoch-making revision of the conventional recognition of asthma based on respiratory physiology and does not contradict the empirical knowledge that asthma responds well to steroid therapy. One reason, which led airway inflammation to be understood as a major factor in the pathophysiology of asthma is the technological advance and the widespread use of bronchoscopes. The use of bronchoscopy as a research tool has markedly improved the understanding of the pathology of asthma. It became also possible to link biopsy findings to autopsy findings in patients who died of asthma. However, it is relatively difficult to repeat a biopsy of the airway mucosal membranes in individual asthmatic patients. Here, animal models of asthma play a significant role. Findings from animal models can provide a clue for the development of new anti-asthmatic drugs. This paper will deal with the paradigm of allergic asthma and focus on recent topics of interleukin (IL)-4 and IL-5, which seem to play a central role in allergic asthma. The causative relationship between airway inflammation and hyperresponsiveness will be discussed.