St Helier Hospital

Abstract The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-19 1,2 , host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases 3–7 . They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.

The guideline group was selected to be representative of UK-based medical experts, experienced district general hospital haematologists and a patient representative. MEDLINE and EMBASE were searched systematically for publications in English from 2004 to 2008 using key word aplastic anaemia. The writing group produced the draft guideline which was subsequently revised by consensus by members of the General Haematology Task Force of the British Committee for Standards in Haematology. The guideline was then reviewed by 59 practising UK haematologists, the BCSH (British Committee for Standards in Haematology) and the British Society for Haematology Committee and comments incorporated where appropriate. Criteria used to quote levels and grades of evidence are as outlined in appendix 3 of the Procedure for Guidelines Commissioned by the BCSH (http://www.bcshguidelines.com/process1.asp#App3) and given at the end of this Guideline as Appendix I. The objective of this guideline is to provide healthcare professionals with clear guidance on the diagnosis and management of patients with acquired aplastic anaemia. The guidance may not be appropriate to patients with inherited aplastic anaemia and in all cases individual patient circumstances may dictate an alternative approach. Because aplastic anaemia is a rare disease, many of the statements and comments are based on review of the literature and expert or consensus opinion rather than on clinical studies or trials. A previous guideline on the diagnosis and management of aplastic anaemia was published in this journal (Marsh et al, 2003). This guideline is an update of the 2003 guideline and is to replace the 2003 guideline (Marsh et al, 2003). Aplastic anaemia (AA) is a rare but heterogeneous disorder. The majority (70–80%) of these cases are categorised as idiopathic because their primary aetiology is unknown. In a subset of cases, a drug or infection can be identified that precipitates the bone marrow failure/aplastic anaemia, although it is not clear why only some individuals are susceptible. In approximately 15–20% of patients the disease is constitutional/inherited, where the disease is familial and/or presents with one or more other somatic abnormalities. Careful history and clinical examination is important to help exclude rarer inherited forms. A detailed drug and occupational exposure history should always be taken. Any putative drug should be discontinued and should not be given again to the patient. Any possible association of aplastic anaemia with drug exposure should be reported to the Medicines and Healthcare products Regulatory Agency (MHRA) using the Yellow card Scheme. All patients presenting with aplastic anaemia should be carefully assessed to: confirm the diagnosis and exclude other possible causes of pancytopenia with hypocellular bone marrow. classify the disease severity using standard blood and bone marrow criteria. document the presence of associated paroxysmal nocturnal haemoglobinuria (PNH) and cytogenetic clones. Small PNH clones, in the absence of haemolysis, occur in up to 50% of patients with aplastic anaemia and abnormal cytogenetic clones occur in up to 12% of patients with aplastic anaemia in the absence of myelodysplatic syndrome (MDS). exclude a possible late onset inherited bone marrow failure disorder. A multidisciplinary team (MDT) approach to the assessment and management of newly presenting patients is recommended. A specialist centre with expertise in aplastic anaemia should be contacted soon after presentation to discuss a management plan for the patient. Best supportive care Prophylactic platelet transfusions should be given when the platelet count is <10 × 109/l (or <20 × 109/l in the presence of fever). There is no evidence to support the practice of giving irradiated blood components except for patients who are undergoing bone marrow transplantation (BMT). We would recommend empirically that this practice is extended to patients receiving immunosuppressive therapy. Transfusion of irradiated granulocyte transfusions may be considered in patients with life-threatening neutropenic sepsis. The routine use of recombinant human erythropoietin (rHuEpo) in aplastic anaemia is not recommended. A short course of granulocyte colony-stimulating factor (G-CSF) may be considered for severe systemic infection that is not responding to intravenous antibiotics and anti-fungal drugs, but should be discontinued after 1 week if there is no increase in the neutrophil count. Prophylactic antibiotic and antifungal drugs should be given to patients with neutrophil count <0·5 × 109/l. Intravenous amphotericin should be introduced into the febrile neutropenia regimen early if fevers persist despite broad spectrum antibiotics. Iron chelation therapy should be considered when the serum ferritin is >1000 μg/l. Definitive treatment Infection or uncontrolled bleeding should be treated first before giving immunosuppressive therapy. This also applies to patients scheduled for BMT, although it may sometimes be necessary to proceed straight to BMT in the presence of severe infection as a BMT may offer the best chance of early neutrophil recovery. Haemopoietic growth factors such as rHuEpo or G-CSF should not be used on their own in newly diagnosed patients in an attempt to ‘treat’ the aplastic anaemia. Prednisolone should not be used to treat patients with aplastic anaemia because it is ineffective and encourages bacterial and fungal infection. Allogeneic BMT from a human leucocyte antigen (HLA)-identical sibling donor is the initial treatment of choice for newly diagnosed patients if they have severe or very severe aplastic anaemia, are <40 years old and have an HLA-compatible sibling donor. There is no indication for using irradiation-based conditioning regimens for patients undergoing HLA-identical sibling BMT for aplastic anaemia. The recommended source of stem cells for transplantation in aplastic anaemia is bone marrow. Immunosuppressive therapy is recommended for (i) patients with non-severe aplastic anaemia who are transfusion dependent (ii) patients with severe or very severe disease who are >40 years old and (iii) younger patients with severe or very severe disease who do not have an HLA-identical sibling donor. The standard immunosuppressive regimen is a combination of antithymocyte globulin (ATG) and ciclosporin. ATG must only be given as an in-patient. Ciclosporin should be continued for at least 12 months after achieving maximal haematological response, followed by a very slow tapering, to reduce the risk of relapse. The routine use of long term G-CSF, or other haemopoietic growth factors, after ATG and ciclosporin, is not recommended outside the setting of prospective clinical trials. Matched unrelated donor (MUD) BMT may be considered when a patient has severe aplastic anaemia, has no matched sibling donor but a matched unrelated donor, is <50 years old (or 50–60 years old with good performance status), and has failed at least one course of ATG and ciclosporin. The optimal conditioning regimen for MUD BMT is uncertain, but currently a fludarabine, non-irradiation-based regimen is favoured for younger patients. There is a high risk (around 33%) of relapse of aplastic anaemia in pregnancy. Supportive care is the mainstay of treatment in pregnancy and the platelet count should be maintained >20 × 109/l, if possible. It is safe to use ciclosporin in pregnancy. Aplastic anaemia is defined as pancytopenia with a hypocellular bone marrow in the absence of an abnormal infiltrate and with no increase in reticulin. For a comprehensive update on the pathophysiology, the reader is directed to a recent review (Young et al, 2006). These guidelines will focus specifically on idiosyncratic acquired aplastic anaemia, and will not refer to the inevitable and predictable aplasia that occurs after chemotherapy and/or radiotherapy. The incidence of acquired aplastic anaemia in Europe and North America is around 2 per million population per year (Issaragrisil et al, 2006; Montanéet al, 2008). The incidence is 2–3 times higher in East Asia. There is a biphasic age distribution with peaks from 10 to 25 years and >60 years. There is no significant difference in incidence between males and females (Heimpel, 2000). Congenital aplastic anaemia is very rare, the commonest type being Fanconi anaemia, which is inherited as an autosomal recessive disorder in most cases. Patients with aplastic anaemia most commonly present with symptoms of anaemia and skin or mucosal haemorrhage or visual disturbance due to retinal haemorrhage. Infection is a less common presentation. There is no lymphadenopathy or hepatosplenomegaly (in the absence of infection) and these findings strongly suggest another diagnosis (Gordon-Smith, 1991). In children and young adults, the findings of short stature, café au lait spots and skeletal anomalies should alert the clinician to the possibility of a congenital form of aplastic anaemia, Fanconi anaemia, although Fanconi anaemia can sometimes present in the absence of overt clinical signs. Patients with Fanconi anaemia most commonly present between the ages of 3 and 14 years but can occasionally present later in their 30s [up to 32 years in males and 48 years in females reported by Young & Alter, (1994)]. The findings of leucoplakia, nail dystrophy and pigmentation of the skin are characteristic of another inherited form of aplastic anaemia, dyskeratosis congenita, with a median age at presentation of 7 years (range 6 months to 26 years) (Dokal, 2000; Walne & Dokal, 2009). Some affected patients may have none of these clinical features and the diagnosis is made later after failure to respond to immunosuppressive therapy (Vulliamy & Dokal, 2006). A preceding history of jaundice, usually 2–3 months before, may indicate a post-hepatitic aplastic anaemia (Gordon-Smith, 1991; Young & Alter, 1994). Many drugs and chemicals have been implicated in the aetiology of aplastic anaemia, but for only very few is there reasonable evidence for an association from case control studies, and even then it is usually impossible to prove causality (Baumelou et al, 1993; Young & Alter, 1994; Heimpel, 1996; Kauffmann et al, 1996; Issaragrissil et al, 1997), (see Table I). A careful drug history should be obtained, detailing all drug exposures for a period beginning 6 months and ending 1 month prior to presentation (Heimpel, 1996; Kauffmann et al, 1996). If at presentation the patient is taking several drugs which may have been implicated in aplastic anaemia, even if the evidence is based on case report(s) alone, then all the putative drugs should be discontinued and the patient should not be re-challenged with the drugs at a later stage after recovery of the blood counts. The MHRA should be informed using the Yellow Card Scheme on every occasion that a patient presents with aplastic anaemia where there is a possible drug association (website: http://www.yellowcard.gov.uk). Similarly, a careful occupational history of the patient may reveal exposure to chemicals or pesticides that have been associated with aplastic anaemia, as summarised in Table II. Aplastic anaemia is a rare disorder. Most cases are idiopathic, but careful history and clinical examination is important to identify rarer inherited forms. Although most cases of aplastic anaemia are idiopathic, a careful drug and occupational exposure history should be taken. Any putative drug should be discontinued and should not be given again to the patient. Any possible association of aplastic anaemia with drug exposure should be reported to the MHRA using the Yellow card Scheme. The following investigations are required to (i) confirm the diagnosis (ii) exclude other possible causes of pancytopenia with a hypocellular bone marrow (iii) exclude inherited aplastic anaemia (iv) screen for an underlying cause of aplastic anaemia and (v) document or exclude a co-existing abnormal cytogenetic clone or a PNH clone. See Table III for a summary of investigations required for the diagnosis of aplastic anaemia. The full blood count (FBC) typically shows pancytopenia although usually the lymphocyte count is preserved. In most cases the haemoglobin level, neutrophil and platelet counts are all uniformly depressed, but in the early stages isolated cytopenia, particularly thrombocytopenia, may occur. Anaemia is accompanied by reticulocytopenia, and macrocytosis is commonly noted. Careful examination of the blood film is essential to exclude the presence of dysplastic neutrophils and abnormal platelets, blasts and other abnormal cells, such as hairy cells (as seen in hairy cell leukaemia). The monocyte count may be depressed but the absence of monocytes should alert the clinician to a possible diagnosis of hairy cell leukaemia. In aplastic anaemia, anisopoikilocytosis is common and neutrophils may show toxic granulation. Platelets are reduced in number and mostly of small size. Fetal haemoglobin (HbF) should be measured pre-transfusion in children as this is an important prognostic factor in paediatric myelodysplastic syndrome (MDS) which may feature in the differential diagnosis of pancytopenia in children. Both a bone marrow aspirate and trephine biopsy are required. Bone marrow aspiration and biopsy may be performed in patients with severe thrombocytopenia without platelet support, providing that adequate surface pressure is applied (Kelsey et al, 2003). Fragments are usually readily obtained from the aspirate. Difficulty obtaining fragments should raise the suspicion of a diagnosis other than aplastic anaemia. The fragments and trails are hypocellular with prominent fat spaces and variable amounts of residual haemopoietic cells. Erythropoiesis is reduced or absent, dyserythropoiesis is very common and often marked, so this alone should not be used to make a diagnosis of MDS. Megakaryocytes and granulocytic cells are reduced or absent; dysplastic megakaryocytes and granulocytic cells are not seen in aplastic anaemia. Lymphocytes, macrophages, plasma cells and mast cells appear prominent. In the early stages of the disease, one may also see prominent haemophagocytosis by macrophages, as well as background eosinophilic staining representing interstitial oedema. A trephine is crucial to assess overall cellularity, to assess the morphology of residual haemopoietic cells and to exclude an abnormal infiltrate. In most cases the trephine is hypocellular throughout but sometimes it is patchy, with hypocellular and cellular areas. Thus, a good quality trephine of at least 2 cm is essential. A ‘hot spot’ in a patchy area may explain why sometimes the aspirate is normocellular. Care should be taken to avoid tangential biopsies as subcortical marrow is normally ‘hypocellular’. Focal hyperplasia of erythroid or granulocytic cells at a similar stage of maturation may be observed. Sometimes lymphoid aggregates occur, particularly in the acute phase of the disease or when the aplastic anaemia is associated with systemic autoimmune disease, such as rheumatoid arthritis or systemic lupus erythematosus. The reticulin is not increased and no abnormal cells are seen. Increased blasts are not seen in aplastic anaemia, and their presence either indicates a hypocellular MDS or evolution to leukaemia (Marin, 2000; Tichelli et al, 1992; Bennett & Orazi, 2009). To define aplastic anaemia there must be at least two of the following (i) haemoglobin <100 g/l (ii) platelet count <50 × 109/l (iii) neutrophil count <1·5 × 109/l (International Agranulocytosis and Aplastic Anaemia Study Group, 1987). The severity of the disease is graded according to the blood count parameters and bone marrow findings as summarised in Table IV (Camitta et al, 1975; Bacigalupo et al, 1988). However, because of routine and more accurate automated reticulocyte counting, this will over-estimate the level of reticulocyte count used in the historical Camitta criteria (Camitta et al, 1975) for defining disease severity. The assessment of disease severity is important in treatment decisions but has less prognostic significance today in terms of correlation with response to ATG treatment (Scheinberg et al, 2009). Patients with bi-or tri-lineage cytopenias that are less severe than this are not classified as aplastic anaemia. However, they should have their blood counts monitored to determine whether they will develop aplastic anaemia with time. Liver function tests should be performed to detect antecedent hepatitis, but in post-hepatitic aplastic anaemia the serology is most often negative for all the known hepatitis viruses. The onset of aplastic anaemia occurs 2–3 months after an acute episode of hepatitis and is more common in young males (Brown et al, 1997). Blood should be tested for hepatitis A antibody, hepatitis B surface antigen, hepatitis C antibody and Epstein–Barr virus (EBV). Cytomegalovirus (CMV) and other viral serology should be assessed if BMT is being considered. Parvovirus causes red cell aplasia but not aplastic anaemia. Human immunodeficiency virus (HIV) is not a recognised cause of aplastic anaemia, but it can cause isolated cytopenias. We would recommend that prior to a diagnosis of aplastic anaemia, appropriate investigations to exclude alternative aetiologies of cytopenias (B12, red cell folate and HIV) should be performed. Vitamin B12 and folate levels should be measured to exclude megaloblastic anaemia which, when severe, can present with pancytopenia. If a deficiency of B12 or folate is documented, this should be corrected before a final diagnosis of aplastic anaemia is confirmed. Bone marrow aplasia due to vitamin deficiency is exceedingly rare. The occurrence of pancytopenia in systemic lupus erythematosus may (i) be autoimmune in nature occurring with a cellular bone marrow or (ii) be associated with myelofibrosis or rarely (iii) occur with a hypocellular bone marrow. Blood should be tested for anti-nuclear antibody and anti-DNA antibody in all patients presenting with aplastic anaemia. Paroxysmal nocturnal haemoglobinuria should be excluded by performing flow cytometry (Dacie & Lewis, 2001; Parker et al, 2005). The Ham test and sucrose lysis test have been abandoned by most centres as diagnostic tests for PNH. Analysis of glycosylphosphatidylinositol (GPI)-anchored proteins, such as CD55 and CD59 by flow cytometry, is a sensitive and quantitative test for PNH enabling the detection of small PNH clones which occur in up to 50% of patients with aplastic anaemia, the proportion depending on the sensitivity of the flow cytometric analysis used (Dunn et al, 1999; Socie et al, 2000; Sugimori et al, 2005). Such small clones are most easily identified in the neutrophil and monocyte lineages in aplastic anaemia and will be detected by flow cytometry and not by the Ham test. If the patient has had a recent blood transfusion, the Ham test may be negative whereas a population of GPI-deficient red cells may still be detected by flow cytometry. However, the clinical significance of a small PNH clone in aplastic anaemia as detected by flow cytometry remains uncertain. Such clones can remain stable, diminish in or is important is the presence of a significant PNH clone with clinical or evidence of should be for to exclude which is a feature of PNH. of associated with PNH should be with the reticulocyte serum serum and analysis of the bone marrow should be although this may be in a very hypocellular bone marrow and often are In this one should in analysis for and 7 in It was that the presence of an abnormal cytogenetic clone a diagnosis of MDS and not aplastic anaemia, but it is that abnormal cytogenetic clones may be present in up to 12% of patients with aplastic anaemia at diagnosis et al, Tichelli et al, 1996; et al, 2006). The presence of abnormal at presentation in should alert to the of MDS. cytogenetic clones may also the course of the disease et al, 2000). The management of a patient with aplastic anaemia who has an abnormal cytogenetic clone is in blood should be tested for and or C to identify or exclude Fanconi anaemia. This should be performed in all patients who are BMT of Fanconi anaemia patients should also be For all other it is to an age for Fanconi anaemia because the age at diagnosis may sometimes occur in the and rarely in the of may be excluded by a known but there are many to be identified (Vulliamy et al, Walne & Dokal, 2009). with this is not currently as a routine clinical A is at presentation to exclude infection and for with of the are no as all young patients should have blood to exclude a diagnosis of Fanconi anaemia. the findings of an and/or raise the possibility of a haematological disorder as the cause of the pancytopenia. In younger abnormal or are features of Fanconi anaemia. The investigations should exclude causes of a hypocellular bone marrow with pancytopenia other than aplastic anaemia. These leukaemia can sometimes be to from aplastic anaemia. The following features of MDS are not in aplastic dysplastic cells of the granulocytic and blasts in the blood or marrow et al, et al, 2001; Bennett & Orazi, 2009). In trephine in reticulin associated with residual of suggest hypocellular MDS rather than aplastic anaemia. The presence of abnormal of is to in this because small of granulocytic cells may be seen in the bone marrow in aplastic anaemia when dyserythropoiesis is very common in aplastic anaemia. acute leukaemia occurs in of cases of usually months of the bone marrow In to aplastic anaemia, the neutropenia is usually more than the thrombocytopenia and sometimes there is an increase in reticulin the hypocellular bone marrow may help confirm the should not be in severe aplastic anaemia in children in case they to have For all paediatric cases of aplastic anaemia, a morphology review is the of the for rare haematological cell leukaemia presents with pancytopenia but the is a feature of this disorder. It is usually or impossible to aspirate on bone marrow In to the interstitial infiltrate of hairy cells with their characteristic in the bone marrow there is always increased reticulin. cells that are typically and Although is a common in hairy cell it may be in of cases. either or and myelofibrosis may sometimes present with pancytopenia and a hypocellular bone marrow. The bone marrow biopsy should be very carefully for of cells or which may be seen in only a small of the are often prominent in aplastic anaemia, should be performed. is usually accompanied by and the absence of an in the presence of marrow should alert one to studies and studies will help to confirm the diagnosis of can sometimes present with pancytopenia and a hypocellular bone this is seen more commonly with bone marrow marrow and and are often in infection. are more in where they are often by The bone marrow aspirate should be for if is et al, or may be associated with pancytopenia. The bone marrow may show and with of fat cells as well as haemopoietic cells, and increased which a on et al, The may also be seen as on an aspirate. Some of fat may also be seen in aplastic anaemia, early in aplastic anaemia can present with an isolated thrombocytopenia, and pancytopenia Such patients can be as autoimmune thrombocytopenia but bone marrow examination in aplastic anaemia shows with reduced or which is not seen in A recent comprehensive review on aplastic anaemia in children in more that may present with pancytopenia and a hypocellular bone marrow in children & A approach is recommended to and develop a treatment should also be given to review of blood and bone marrow by a specialist if there are features or where there is the All patients presenting with aplastic anaemia should be carefully assessed to: confirm the diagnosis and exclude other possible causes of pancytopenia with hypocellular bone marrow classify the disease severity using standard blood and bone marrow criteria document the presence of associated PNH and cytogenetic clones exclude a possible late onset inherited bone marrow failure disorder A approach to the assessment is recommended and also to an appropriate management plan for the patient. If there is the diagnosis and/or management of the case for specialist and/or review of the blood and bone marrow morphology at a specialist is with red cell and platelet transfusions is essential for patients with aplastic anaemia to a safe blood count. It is recommended to platelet transfusions when the platelet count is <10 × 109/l (or <20 × 109/l in the presence of C level IV rather than giving only in response to bleeding (Kelsey et al, 2003). of bleeding is in an individual patient. usually is more common in patients who have <10 × 109/l platelets, retinal or However, haemorrhage may be the first in patients who have none of these other bleeding (Gordon-Smith, 1991). For and platelet must be given to appropriate levels as recommended by BCSH and a platelet count to that level has been A common in patients with aplastic anaemia, with leukaemia is that they may develop to present in red cell and platelet transfusions by or This can in platelet as well as an increased risk of after BMT et al, leucocyte of all of red cells and in the UK is to reduce the risk of et al, 2000). In a centre the incidence of was reported to be 50% in patients with aplastic anaemia who had blood products prior to the of leucocyte in the UK with only 12% for patients who only leucocyte blood products et al, 1997). Patients who to platelet transfusions should be for However, other causes of platelet such as infection and drugs, should be If a patient to donor in platelet should be

PURPOSE: Early mortality in multiple myeloma (MM) is usually attributed to combined effects of active disease and comorbid factors. We have studied early deaths in a series of large multicenter trials to assess direct causes of death, their predictability, and whether current management strategies have reduced their frequency. PATIENTS AND METHODS: A total of 3,107 newly diagnosed patients entered onto United Kingdom Medical Research Council MM trials from 1980 to 2002 were studied. Trial files, final clinical summaries, and postmortem reports were analyzed. RESULTS: Death within 60 days of trial entry occurred in 299 patients (10%). Logistic regression modeling identified beta 2-microglobulin, performance status, and age as the most important predictors of early death, but only with 61% sensitivity and 73% specificity. Forty-five percent of deaths were attributable to infection, which was often associated with bone pain (particularly thoracic pain) and delay in presenting to medical care. Neutropenia was present at diagnosis in only 11 of the 135 deaths from infection. Renal failure was present in 28% of early deaths and was linked to light-chain MM, hypercalcemia, dehydration, and nonsteroidal anti-inflammatory drugs. There was no time related reduction in the percentage or nature of early deaths in 1,550 patients older than 65 years receiving similar therapy between 1982 and 2002. CONCLUSION: A tenth of patients die within 60 days of diagnosis of MM. Infection and renal failure are the main direct causes of early mortality, which cannot be accurately predicted by presenting prognostic features. All patients should be considered at high risk of death during induction therapy.

Intravenous immunoglobulin (IVIg) is a potential alternative treatment for anti-neutrophil cytoplasm antibody (ANCA)-associated systemic vasculitis (AASV) with less toxicity than conventional immunosuppressive agents. This randomized, placebo-controlled trial aimed to investigate the efficacy of a single course of IVIg (total dose 2 g/kg) in previously-treated AASV with persistent disease activity in whom there was an intention to escalate therapy. Vasculitic activity was monitored by the Birmingham vasculitis activity score (BVAS), C-reactive protein (CRP) and ANCA levels. Treatment response was defined as a reduction in BVAS of more than 50% after 3 months, and there was an intention to keep doses of concurrent immunosuppressive drugs unchanged during this period; follow-up continued to 12 months. Seventeen patients were randomized to receive IVIg and 17 to receive placebo. Treatment responses were found in 14/17 and 6/17 of the IVIg and placebo groups, respectively (p=0.015, OR 8.56, 95%CI 1.74-42.2). Following infusion of trial medication, greater falls in CRP were seen at 2 weeks (p=0.02) and 1 month (p=0.04) in the IVIg group. No differences were observed between ANCA levels or cumulative exposure to immunosuppressive drugs, and after 3 months there were no differences in CRP levels or disease activity between the IVIg and placebo groups. Seventeen adverse effects occurred after IVIg and six after placebo: they were mostly mild, although reversible rises in serum creatinine occurred in four from the IVIg group. A single course of IVIg reduced disease activity in persistent AASV, but this effect was not maintained beyond 3 months; mild, reversible side-effects following IVIg were frequent. IVIg is an alternative treatment for AASV with persistent disease activity after standard therapy.

BACKGROUND: There is increasing evidence that lack of facilities, equipment, and expertise in district hospitals across many low- and middle-income countries constitutes a major barrier to accessing surgical care. However, what is less clear, is the extent to which people perceive barriers when trying to access surgical care. METHODS: PubMed and EMBASE were searched using key words ("access" and "surgery," "barrier" and "surgery," "barrier" and "access"), MeSH headings ("health services availability," "developing countries," "rural population"), and the subject heading "health care access." Articles were included if they were qualitative and applied to illnesses where the treatment is primarily surgical. RESULTS: Key barriers included difficulty accessing surgical services due to distance, poor roads, and lack of suitable transport; lack of local resources and expertise; direct and indirect costs related to surgical care; and fear of undergoing surgery and anesthesia. CONCLUSIONS: The significance of cultural, financial, and structural barriers pertinent to surgery and their role in wider health care issues are discussed. Immediate action to improve financial and geographic accessibility along with investment in district hospitals is likely to make a significant impact on overcoming access and barrier issues. Further research is needed to identify issues that need to be addressed to close the gap between the care needed and that provided.

Serum levels of interleukin-10 (IL-10) are elevated in a proportion of patients with untreated chronic hepatitis C, and this may compromise the host immune response to the virus. The capacity for IL-10 production varies according to the genetic composition of the IL-10 locus. We examined the inheritance of 3 biallelic polymorphisms in the IL-10 gene promoter in patients with chronic hepatitis C and their association with response to treatment with interferon alfa (IFN-alpha). After adjusting for potential confounding variables, a highly significant relationship was found between inheritance of the IL-10 promoter -592*A and -819*T alleles or the ATA haplotype and response to IFN-alpha therapy (P =.016). Response to treatment was also associated with viral genotype 3a, a low viral load, and less fibrosis on liver biopsy. Following in vitro stimulation of peripheral blood mononuclear cells, the IL-10 promoter haplotypes, GCC, ACC, and ATA, were associated with high, intermediate, and low IL-10 production, respectively. These findings indicate that heterogeneity in the promoter region of the IL-10 gene has a role in determining the initial response of chronic hepatitis C to IFN-alpha therapy. Patients who are genetically predisposed to high IL-10 production have a poor response to IFN-alpha and may benefit from additional treatment strategies designed to enhance a T-helper type 1 (Th1) response.

By 21 March 2020 infections related to the novel coronavirus SARS-CoV-2 had affected people from 177 countries and caused 11,252 reported deaths worldwide. Little is known about risk, presentation and outcomes of SARS-CoV-2 (COVID-19) infection in kidney transplantation recipients, who may be at high-risk due to long-term immunosuppression, comorbidity and residual chronic kidney disease. Whilst COVID-19 is predominantly a respiratory disease, in severe cases it can cause kidney and multi-organ failure. It is unknown if immunocompromised hosts are at higher risk of more severe systemic disease. Therefore, we report on seven cases of COVID-19 in kidney transplant recipients (median age 54 (range 45-69), three females, from a cohort of 2082 managed transplant follow-up patients) over a six-week period in three south London hospitals. Two of seven patients presented within three months of transplantation. Overall, two were managed on an out-patient basis, but the remaining five required hospital admission, four in intensive care units. All patients displayed respiratory symptoms and fever. Other common clinical features included hypoxia, chest crepitation, lymphopenia and high C-reactive protein. Very high D dimer, ferritin and troponin levels occurred in severe cases and likely prognostic. Immunosuppression was modified in six of seven patients. Three patients with severe disease were diabetic. During a three week follow up one patient recovered, and one patient died. Thus, our findings suggest COVID-19 infection in kidney transplant patients may be severe, requiring intensive care admission. The symptoms are predominantly respiratory and associated with fever. Most patients had their immunosuppression reduced and were treated with supportive therapy. By 21 March 2020 infections related to the novel coronavirus SARS-CoV-2 had affected people from 177 countries and caused 11,252 reported deaths worldwide. Little is known about risk, presentation and outcomes of SARS-CoV-2 (COVID-19) infection in kidney transplantation recipients, who may be at high-risk due to long-term immunosuppression, comorbidity and residual chronic kidney disease. Whilst COVID-19 is predominantly a respiratory disease, in severe cases it can cause kidney and multi-organ failure. It is unknown if immunocompromised hosts are at higher risk of more severe systemic disease. Therefore, we report on seven cases of COVID-19 in kidney transplant recipients (median age 54 (range 45-69), three females, from a cohort of 2082 managed transplant follow-up patients) over a six-week period in three south London hospitals. Two of seven patients presented within three months of transplantation. Overall, two were managed on an out-patient basis, but the remaining five required hospital admission, four in intensive care units. All patients displayed respiratory symptoms and fever. Other common clinical features included hypoxia, chest crepitation, lymphopenia and high C-reactive protein. Very high D dimer, ferritin and troponin levels occurred in severe cases and likely prognostic. Immunosuppression was modified in six of seven patients. Three patients with severe disease were diabetic. During a three week follow up one patient recovered, and one patient died. Thus, our findings suggest COVID-19 infection in kidney transplant patients may be severe, requiring intensive care admission. The symptoms are predominantly respiratory and associated with fever. Most patients had their immunosuppression reduced and were treated with supportive therapy. The novel coronavirus 2019 (or coronavirus disease 2019 [COVID-19]) infection, which originated in the city of Wuhan, in Hubei province, China, in December 2019 shares close similarities in its genomic structure with the severe acute respiratory syndrome coronavirus (SARS-CoV) that caused the SARS global pandemic in 2003 and the Middle East respiratory syndrome (MERS) epidemic in 2012 (MERS-CoV), and even closer similarities to bat SARS-like betacoronavirus (bat-SL-CoVZC45 betacoronavirus and bat-SL-CoVZXC21).1Wu F. Zhao S. Yu B. et al.A new coronavirus associated with human respiratory disease in China.Nature. 2020; 579: 265-269Crossref PubMed Scopus (7720) Google Scholar,2Lu R. Zhao X. Li J. et al.Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding.Lancet. 2020; 395: 565-574Abstract Full Text Full Text PDF PubMed Scopus (8314) Google Scholar Between December 31, 2019, and March 27, 2020, 532,692 COVID-19 cases and 24,077 deaths worldwide have been identified as being caused by a newly identified enveloped RNA virus named SARS-CoV-2.3Johns Hopkins University of Medicine—Coronavirus Resource CenterCoronavirus COVID-19 global cases by the Center for Systems Science and Engineering (CSSE) at Johns Hopkins University. March 27, 2020.https://coronavirus.jhu.edu/map.htmlDate accessed: March 27, 2020Google Scholar In the United Kingdom, between January 31, 2020, and March 20, 2020, 3983 cases were identified with 177 (4% of tested patients) deaths.4UK Government. Number of coronavirus (COVID-19) cases and risk in the UK 2020. Available at: https://www.gov.uk/government/publications/covid-19-track-coronavirus-cases. Accessed April 14, 2020.Google Scholar Due to widespread nature, COVID-19 was declared as a pandemic by World Health Organization on March 11, 2020, and 176 countries are affected as of March 27, 2020.3Johns Hopkins University of Medicine—Coronavirus Resource CenterCoronavirus COVID-19 global cases by the Center for Systems Science and Engineering (CSSE) at Johns Hopkins University. March 27, 2020.https://coronavirus.jhu.edu/map.htmlDate accessed: March 27, 2020Google Scholar The SARS pandemic was reported to affect both pediatric and adult kidney transplant recipients in Hong Kong, with less severe disease in the pediatric population.5Chiu M.C. Suggested management of immunocompromised kidney patients suffering from SARS.Pediatr Nephrol. 2003; 18: 1204-1205Crossref PubMed Scopus (16) Google Scholar One liver transplant patient died with the SARS-CoV infection in 2003.6Kumar D. Tellier R. Draker R. et al.Severe Acute Respiratory Syndrome (SARS) in a liver transplant recipient and guidelines for donor SARS screening.Am J Transplant. 2003; 3: 977-981Crossref PubMed Scopus (122) Google Scholar The MERS coronavirus infection had a variable impact on kidney transplant recipients. In 1 report of 2 kidney transplant patients, one died of progressive respiratory disease and acute kidney injury while the other survived.7AlGhamdi M. Mushtaq F. Awn N. Shalhoub S. MERS CoV infection in two renal transplant recipients: case report.Am J Transplant. 2015; 15: 1101-1104Crossref PubMed Scopus (84) Google Scholar To the best of our knowledge, only 1 patient with kidney transplantation has been reported in the literature who suffered from COVID-19 infection in Wuhan, China, and improved 13 days after hospital admission.8Zhu L, Xu X, Ma K, et al. Successful recovery of COVID-19 pneumonia in a renal transplant recipient with long-term immunosuppression [e-pub ahead of print]. Am J Transplant. https://doi.org/10.1111/ajt.15869. Accessed March 27, 2020.Google Scholar The 63-year-old kidney transplant recipient presented with fever, chest pain, cough, low lymphocyte, high serum C-reactive protein (CRP), and abnormal chest computed tomography scan on February 2, 2020. Tacrolimus and mycophenolate administration was discontinued. He was treated with oxygen, methyl prednisolone, umifenovir, moxifloxacin, biapenem, i.v. Ig, inhaled interferon-α, and pantoprazole. He made a successful recovery and was discharged on day 13. We report here the first 7 cases of COVID-19 in kidney transplant recipients in south London hospitals. We have seen 7 cases of kidney transplant recipients with proven COVID-19 infection in south London in March 2020. These patients are described herein, and their main characteristics are summarized in Tables 1 and 2.Table 1Clinical characteristics and outcome of 7 kidney transplant patients with COVID-19 infectionPatientAge/sexTx dateComorbiditiesRespiratory and renal involvementBaseline creatinine (eGFR ml/min per 1.73 m2)Baseline immunosuppression and treatmentACEI or ARBOutcome148/M1989HTNo350 (15–18)Aza/PredNo changeNoStayed at home, full recovery267/F03/2019T2D/HTYes, ARDS + AKI (CVVH)150 (45)Tac/MMF/PredMMF stoppedYes ACEIDied354/F12/2019PTDM/CMVYes, ARDS + AKI (CVVH)132 (48)Tac/MMF/PredTac and MMF stoppedNoAlive, ventilated465/M08/2018Wheelchair/HTNNo ARDS180 (23)Tac/MMF/PredMMF stoppedNoAlive, in medical ward569/F02/2020DM/HTNo ARDSAKI165 (31)Tac/MMF/PredMMF stoppedNoBrief ITU stay, not intubated; stepped down to ward654/M05/2013Hemolytic anemia/HTNo ARDS187 (47)Tac/MMFMMF stoppedNoStayed at home, still has cough and some flu-like symptoms745/M09/2017 (2nd Tx)HTNo ARDSAKI (HD)450 (12–16)Tac/Aza/AzaAza stoppedTac dose reducedNoAdmitted, managed in the ward; severe AKIACEI, angiotensin-converting enzyme inhibitor; AKI, acute kidney injury; ARB, angiotensin receptor blocker; ARDS, acute respiratory distress syndrome; Aza, azathioprine; CMV, cytomegalovirus; COVID-19, coronavirus disease 2019; CVVH, continuous venovenous hemofiltration; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; F, female; ITU, intensive therapy unit; M, male; MMF, mycophenolate mofetil; Pred, prednisolone; PTDM, post-transplant diabetes mellitus; T2D, type 2 diabetes; Tac, tacrolimus; Tx, treatment(s). Open table in a new tab Table 2Blood parameters during COVID-19 infectionPatientWhite cell count (× 109/l) (3.5–10)Lymphocyte count (× 109/l) (1–3.5)Serum CRP (mg/l) (<5)Serum ferritin (μg/l) (25–200)Serum D dimer (μg/l) (0–500)Serum LDH (U/l) (100–240)Serum troponin I (ng/l) (<34)1———————26 (D1)0.8 (D1)83 (D1)2032 (D3), >6000 (D10)1226 (D10)78 (D1), 395 (D10)311.25 (D1)0.5 (D1)329 (D1)————4———————59.4 (D1)0.3 (D1)————30 (D4)aSerum troponin T (0–14 ng/l).610 (D1)4.0 (D1)—————75.5 (D1)0.3 (D1)198 (D1)6919 (D3)1907 (D3)502 (D3)35 (D7)COVID-19, coronavirus disease 2019; CRP, C-reactive protein; D, day after admission; D1, day of admission; LDH, lactate dehydrogenase.a Serum troponin T (0–14 ng/l). Open table in a new tab ACEI, angiotensin-converting enzyme inhibitor; AKI, acute kidney injury; ARB, angiotensin receptor blocker; ARDS, acute respiratory distress syndrome; Aza, azathioprine; CMV, cytomegalovirus; COVID-19, coronavirus disease 2019; CVVH, continuous venovenous hemofiltration; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; F, female; ITU, intensive therapy unit; M, male; MMF, mycophenolate mofetil; Pred, prednisolone; PTDM, post-transplant diabetes mellitus; T2D, type 2 diabetes; Tac, tacrolimus; Tx, treatment(s). COVID-19, coronavirus disease 2019; CRP, C-reactive protein; D, day after admission; D1, day of admission; LDH, lactate dehydrogenase. A 48-year-old man with deceased donor kidney transplant in 1989 with failing transplant kidney (estimated glomerular filtration rate [eGFR]: 15–18 ml/min per 1.73 m2) called the National Health Service (111) helpline in the first week of March 2020 with cough, fever, and mild shortness of breath. He tested positive for COVID-19 by nose and throat swabs taken on March 2. As he was clinically well, he was asked to stay at home and self-isolate. His immunosuppression was azathioprine 75 mg once daily (OD) and prednisolone 5 mg OD, which was not changed. He was not on angiotensin-converting enzyme inhibitor and/or angiotensin receptor blocker at the time of presentation. He has made a full recovery. The transplant kidney function remained stable. A 67-year-old woman with insulin-dependent type 2 diabetes and end-stage kidney disease on hemodialysis therapy for 4 years received a deceased donor kidney transplant in March 2019. Her eGFR was 45 to 55 ml/min per 1.73 m2. She was maintained on tacrolimus with levels between 5 and 8 ng/ml, mycophenolate mofetil (MMF) 250 mg twice a day (BD), and prednisolone 5 mg OD. Her other medications included ramipril, aspirin, alfacalcidol, and amiloride. She presented on March 5 with cough, fever, and shortness of breath. Chest X-ray revealed bilateral patchy consolidation (Figure 1a). SARS-CoV-2 RNA polymerase chain reaction tests from nose and throat viral swabs were positive. Bronchial washing for pneumocystis polymerase chain reaction was negative, as was blood polymerase chain reaction for cytomegalovirus DNA. There was no other positive microbiological diagnosis. She was hypoxic with peripheral oxygen saturation of 86% and a respiratory rate of 26 breaths/min, so she was transferred to intensive therapy unit (ITU) and commenced noninvasive ventilation (continuous positive airway pressure for type 1 respiratory failure) and subsequent intubation and ventilation as her clinical condition deteriorated. Serum CRP on admission was 83 mg/l, hemoglobin 110 g/l, with normal total white cell count, and mild lymphopenia (lymphocyte count 0.8 × 109/l). She was treated with broad spectrum antibiotics. No specific were MMF was tacrolimus was but 1 day day admission, she acute kidney injury with a serum creatinine to She remained on the with oxygen and in on chest X-ray (Figure but on March with high serum lactate and lactate levels and an acute of CRP to She severe to on continuous venovenous to an and/or She and died on March A woman with a of adult kidney disease, end-stage kidney disease in was on hemodialysis for 7 and received a deceased donor kidney transplant in December 2019. she an of cytomegalovirus infection and post-transplant diabetes Her medications included of tacrolimus mg and MMF mg and of prednisolone 5 5 75 2 and mg and mg and Three months after deceased donor kidney on March she presented with shortness of to the her oxygen were with rate of and blood pressure of She was on continuous positive airway pressure and her oxygen improved to of the chest revealed widespread and her chest X-ray bilateral She was to be positive for SARS-CoV-2 Her and other respiratory viral with pneumonia were There was no other positive microbiological diagnosis. She features of acute respiratory distress syndrome and AKI Her respiratory in the and she required intubation 8 and to be MMF was on March and tacrolimus on March spectrum and were She was treated for pneumocystis with high dose Serum CRP from on day of admission to 7 days She and continuous venovenous which Her chest X-ray some of the A with a of and end-stage renal disease in and received a deceased donor kidney transplant in months after kidney he presented to hospital with shortness of and chest and was to He was with COVID-19 infection on March MMF was and he with tacrolimus and He was discharged from the ITU and is to a medical still requiring 4 to oxygen to function remained stable. A woman with and end-stage kidney disease was on therapy 2012 and hemodialysis therapy she received a deceased donor kidney transplantation on February and was discharged on March Her included MMF, and Other medications included as as 4 mg and 1 mg as She presented with shortness of and on March 13. Her chest X-ray of on March 13 that on March and She tested positive for SARS-CoV-2 RNA on March 14, 2020. She was with oxygen saturation of and blood pressure saturation improved to with 4 oxygen by was g/l, serum of and serum Her count on day of admission to × and has remained Tacrolimus was and MMF was from March She was treated with and blood She was to ITU on March for respiratory but not more 5 oxygen and transferred to on March March 20, her serum creatinine was She an and is being managed in a A man with and of received a kidney transplant 7 years He presented on March with cough and and tested positive for SARS-CoV-2 RNA on March 13. He was and were stable. He received and medications the mg OD, MMF mg mg OD, mg at mg OD, mg OD, 8 mg 1 OD, and 250 mg OD. He AKI with a in creatinine from to was cell are in Table 2. He remained on March 21 with cough and mild fever. As the symptoms were not MMF was and he has managed to stay at A man with a kidney transplant from presented with fever, flu-like cough for 7 and shortness of for 1 He had with no other He was a recipient with at and was maintained on long-term azathioprine in from MMF due to and prednisolone mg OD. admission on March he was and hypoxic with oxygen saturation of on which was to on 4 oxygen and throat swabs were positive for SARS-CoV-2 He AKI with serum creatinine and eGFR 5 ml/min per 1.73 He was with count of × × 109/l) with normal hemoglobin and white cell function tests were normal on admission, but up to on day Chest X-ray revealed bilateral was on admission, tacrolimus and prednisolone to mg OD. he 1 hemodialysis He is from respiratory of and as of March 2020, the oxygen are on 2 He stable. In report we our first 7 cases of COVID-19 infection in kidney transplant recipients from south United age of transplant recipients was 54 years 4 7 patients, 2 were managed on an and at home, with the remaining 5 requiring hospital admission. the required ITU admission, and 1 is being managed in the renal 4 patients to ITU, 2 intubation and the other 2 were managed with oxygen and noninvasive ventilation There was 1 in of 7 patients rate of All patients with severe disease were and had Two patients presented within months of kidney transplantation within 2 while kidney transplant was months or more in the remaining 5 The patients were managed in and the total of transplant patients in was with patients from December 2019, to March 2020, during the patients are at higher risk due to immunosuppression, chronic kidney disease, and other in diabetes and which are as that outcomes in patients with COVID-19 F. Yu R. et and risk for of adult with COVID-19 in Wuhan, a cohort 2020; 395: Full Text Full Text PDF PubMed Scopus Google Scholar Three of our patients had chronic kidney disease 4 to with 1 at home and 1 requiring hospital admission but ITU admission. The remaining 4 patients had chronic kidney disease of which 2 had severe disease requiring intubation and ventilation and 1 of died. patients who had severe COVID-19 the one who died had diabetes immunosuppression in patients is and of COVID-19 infection, associated and time In transplant patients with mild to the is to or in the dose of but high in patients to hospital with COVID-19 we that are not on the of we suggest that and be at the time of admission to dose of prednisolone be or and tacrolimus dose be In severe infections intubation and an can be made for while therapy. The of and due to as a of severe respiratory disease and acute respiratory distress syndrome has been the of disease in December 2019, of and case for in patients. A can be made for but more is is risk of with in immunosuppression but the high rate of COVID-19 infection in patients, on their patients with a of of to it is likely that the in the United have requiring with or All patients in received therapy at time of et risk and of immunosuppression in renal transplant Nephrol. 2020; PubMed Scopus Google Scholar of the 7 patients presented here were Two patients with mild who not hospital admission and at home were on immunosuppression on azathioprine prednisolone and 1 on tacrolimus to therapy with angiotensin-converting enzyme receptor in with UK and of were not discontinued. One of our 7 patients which is a rate of it is to on likely in of patients. Two of our patients presented within months after transplantation and 1 presented within 2 UK National Health Service and and have guidelines on COVID-19 in deceased and the transplant are risk and recipients kidney transplantation. is a high-risk during pandemic due to the risk of COVID-19 infection from the donor to the recipient as as risk of recipient severe disease higher levels of immunosuppression in the first months We suggest that from transplantation is not during for recipients with in We have donor and are in to deceased donor In to about the of COVID-19 on patients, about to ITU in the and of to care to for of COVID-19 patients, it is likely that deceased donor be within of the UK AKI has been described with COVID-19 infections in up to patients, and of or has been In our the that 4 of 7 patients had AKI may be an that transplant patients are at higher risk of AKI with COVID-19 infection, with AKI in patients of in Wuhan, X, Yu Xu et al. and outcomes of patients with SARS-CoV-2 pneumonia in Wuhan, a [e-pub ahead of print]. Accessed March 27, 2020.Google Scholar enzyme 2 and which are in N. et enzyme 2 is a receptor for the SARS 2003; PubMed Scopus Google et 4 is a receptor for the human PubMed Scopus Google Scholar have been identified as for SARS-CoV and of SARS-CoV-2 virus the is a for to blood tests and serum levels of D dimer, ferritin and troponin are likely to be of 5 patients who required admission had the 2 who not admission had normal As patients on immunosuppression are likely to have a in count is likely to be of In our patient who both D dimer and troponin levels were on day admission with D during the of her In the of or with Very high ferritin and D dimer levels were in the case for patient 7 of our We suggest that D dimer, and troponin be in patients with severe COVID-19 infection on admission and in who are not clinical In 2 of our patients, the specific 7 to days admission. The patient who died is and was from the respiratory of She died of an and the clinical was or on we to that the in patients with COVID-19 infection be due to as or to specific a no of in patients with severe COVID-19, it that with as as be in patients with COVID-19 D, et al. A of in with severe [e-pub ahead of print]. J Accessed March 27, 2020.Google Scholar The of inhibitor may have a to Thus, for A has been to have an on of and virus in while is not the case for A is to the of a of its impact on A and et A the of PubMed Scopus Google of coronavirus by PubMed Scopus Google Scholar we not to A from tacrolimus can be at for transplant patients with COVID-19 In in first of 7 renal transplant patients with 1 recipient died and AKI was high ferritin and D dimer and troponin levels are seen in severe disease and may be of These tests be of in kidney transplant patients requiring hospital admission for COVID-19 We suggest kidney transplantation during the COVID-19 pandemic for high-risk recipients with to and and/or transplant patients the and management of cases in the as we in 2 of our 7 patients The COVID-19 UK has been up by the UK transplant by and to cases of renal transplant patients with COVID-19 infection and of about management of patients in and All the declared no with A of the clinical characteristics and outcome of kidney transplant patients for outcome of infection in patients who have received a kidney and are being treated with immunosuppression is We kidney transplant recipients (median age years age of transplant 13 years eGFR with admission, had immunosuppression and were on but one was commenced on therapy and with for kidney PDF Open with COVID-19 in kidney of we 2 of patients who had kidney transplantation during the coronavirus disease 2019 (COVID-19) pandemic that have taken to transplant therapy and in the days of the pandemic in the United and The first of 7 cases of COVID-19 infection in patients who had kidney transplantation from and in south United and the of cases from University in PDF Open high of acute during the COVID-19 cause for coronavirus disease 2019 (COVID-19) pandemic has caused and We report a case of kidney and transplant recipients who presented in an time during the COVID-19 pandemic with transplant and time from the time of transplant to the presentation was 4 patients, had severe requiring of or therapy. 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OBJECTIVES: Eosinophilic esophagitis (EoE) represents a chronic, immune/antigen-mediated esophageal disease characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophil-predominant inflammation. With few exceptions, 15 eosinophils per high-power field (peak value) in ≥1 biopsy specimens are considered a minimum threshold for a diagnosis of EoE. The disease is restricted to the esophagus, and other causes of esophageal eosinophilia should be excluded, specifically proton pump inhibitor-responsive esophageal eosinophilia. This position paper aims at providing practical guidelines for the management of children and adolescents with EoE. METHODS: Relevant literature from searches of PubMed, CINAHL, and recent guidelines was reviewed. In the absence of an evidence base, recommendations reflect the expert opinion of the authors. Final consensus was obtained during 3 face-to-face meetings of the Gastroenterology Committee and 1 teleconference. RESULTS: The cornerstone of treatment is an elimination diet (targeted or empiric elimination diet, amino acid-based formula) and/or swallowed, topical corticosteroids. Systemic corticosteroids are reserved for severe symptoms requiring rapid relief or where other treatments have failed. Esophageal dilatation is an option in children with EoE who have esophageal stenosis unresponsive to drug therapy. Maintenance treatment may be required in case of frequent relapse, although an optimal regimen still needs to be determined. CONCLUSIONS: EoE is a chronic, relapsing inflammatory disease with largely unquantified long-term consequences. Investigations and treatment are tailored to the individual and must not create more morbidity for the patient and family than the disease itself. Better maintenance treatment as well as biomarkers for assessing treatment response and predicting long-term complications is urgently needed.

Neutralizing injurious stimuli, proinflammatory mediator catabolism, and polymorphonuclear leukocyte (PMN) clearance are determinants of inflammatory resolution. To this, we recently added innate-type lymphocyte repopulation as being central for restoring postinflammation tissue homeostasis with a role in controlling innate immune-mediated responses to secondary infection. However, although macrophages dominate resolution, their phenotype and role in restoring tissue physiology once inflammation abates are unknown. Therefore, we isolated macrophages from the resolving phase of acute inflammation and found that compared with classically activated proinflammatory M1 cells, resolution-phase macrophages (rMs) possess weaker bactericidal properties and express an alternatively activated phenotype but with elevated markers of M1 cells including inducible cyclooxygenase (COX 2) and nitric oxide synthase (iNOS). This phenotype is controlled by cAMP, which, when inhibited, transforms rM to M1 cells. Conversely, elevating cAMP in M1 cells transforms them to rMs, with implications for cAMP in the resolution of systemic inflammation. It transpires that although rMs are dispensable for clearing PMNs during self-limiting inflammation, they are essential for signaling postresolution lymphocyte repopulation via COX 2 lipids. Thus, rM macrophages are neither classically nor alternatively activated but a hybrid of both, with a role in mediating postresolution innate-lymphocyte repopulation and restoring tissue homeostasis.

Aspirin is a unique nonsteroidal anti-inflammatory drug; at high doses (aspirin(high), 1g), it is anti-inflammatory stemming from the inhibition of cyclooxygenase and proinflammatory signaling pathways including NF-kappaB, but is cardioprotective at lower doses (aspirin(low), 75 mg). The latter arises from the inhibition of thromboxane (Tx) B(2), a prothrombotic eicosanoid also implicated in polymorphonuclear leukocyte trafficking. As a result, aspirin(low) is widely used as a primary and secondary preventative against vascular disease. Despite this and its ability to synthesize proresolution 15-epi-lipoxin A(4) it is not known whether aspirin(low) is anti-inflammatory in humans. To address this, we generated skin blisters by topically applying cantharidin on the forearm of healthy male volunteers, causing an acute inflammatory response including dermal edema formation and leukocyte trafficking. Although not affecting blister fluid volume, aspirin(low) (75 mg, oral, once daily/10 days) reduced polymorphonuclear leukocyte and macrophage accumulation independent of NF-kappaB-regulated gene expression and inhibition of conventional prostanoids. However, aspirin(low) triggered 15-epi-lipoxin A(4) synthesis and up-regulated its receptor (FPRL1, ALX). From complimentary in vitro experiments, we propose that 15-epi-lipoxin A(4) exerts its protective effects by triggering antiadhesive NO, thereby dampening leukocyte/endothelial cell interaction and subsequent extravascular leukocyte migration. Since similar findings were obtained from murine zymosan-induced peritonitis, we suggest that aspirin(low) possesses the ability to inhibit mammalian innate immune-mediated responses. This highlights 15-epi-lipoxin A(4) as a novel anti-inflammatory working through a defined receptor and suggests that mimicking its mode of action represents a new approach to treating inflammation-driven diseases.

In 2006 guidelines for the diagnosis and management of multiple myeloma were published (Smith et al, 2006). These current guidelines represent a major revision. The guideline has been split into two documents, focussing on the 'Diagnosis and management of multiple myeloma' and 'Supportive care in multiple myeloma 2011' (Snowden et al 2011). They are designed to be used together and to complement each other. The contents of 'Diagnosis and management of multiple myeloma' are listed below: Methodology, epidemiology and clinical presentation Diagnosis, prognostic factors and disease monitoring Imaging techniques Management of common medical emergencies in myeloma patients Myeloma bone disease Renal impairment Induction therapy including management of major toxicities and stem cell harvesting Management of refractory disease High dose therapy and autologous stem cell transplantation Allogeneic stem cell transplantation Maintenance therapy Management of relapsed myeloma including drugs in development Patient Information and Support The key areas that are covered comprehensively in the document entitled 'Guidelines for Supportive Care in Multiple Myeloma 2011' (Snowden et al 2011) are listed below: Anaemia Haemostasis and thrombosis issues Pain management Peripheral neuropathy Other symptom control – gastrointestinal, sedation/fatigue, mucositis Bisphosphonate-induced osteonecrosis of the jaw Complementary therapies End of life care The production of these guidelines involved the following steps: Establishment of working groups in the topic areas detailed above followed by review of key literature to 30th June 2010 including Cochrane database, Medline, internet searches and major conference reports. Development of key recommendations based on randomized, controlled trial evidence. In the absence of randomized data, recommendations were developed on the basis of literature review and a consensus of expert opinion. Involvement of patient advocacy through Myeloma UK. Review by UK Myeloma Forum (UKMF) Executive and British Committee for Standards in Haematology (BCSH) Committees. Review by a British Society for Haematology (BSH) sounding board. Levels of evidence and grades of recommendation are those of the US Agency for Healthcare Research and Quality (see Appendix I, Tables 1 and 2). In preparing these guidelines the authors have considered overall cost-effectiveness of recommended interventions as well as clinical efficacy data but formal health economic assessments have not been carried out. The annual incidence of myeloma in the UK is approximately 60–70 per million (http://info.cancerresearchuk.org/cancerstats/types/multiplemyeloma/incidence/index.htm). The overall prevalence is likely to be increasing given the recently published data demonstrating improved survival rates over the last decade (Kumar et al, 2008a; Brenner et al, 2009). The median age at presentation is approximately 70 years. Only 15% of patients are aged <60 years. Myeloma has a higher incidence in Afro-Caribbean ethnic groups than in Caucasians but there are few other distinctive epidemiological features. The majority of cases present de novo but it is now recognized that myeloma is preceded by an asymptomatic monoclonal gammopathy of undetermined significance (MGUS) phase in virtually all patients (Landgren et al, 2009). Presenting clinical features include symptoms of: Bone disease Impaired renal function Anaemia Hypercalcaemia Recurrent or persistent bacterial infection Hyperviscosity Other patients are diagnosed following the incidental detection of a raised erythrocyte sedimentation rate (ESR), plasma viscosity, serum protein or globulin. Patients with suspected myeloma require urgent specialist referral. Spinal cord compression, hypercalcaemia and renal failure are medical emergencies requiring immediate investigation and treatment. Investigation of a patient with suspected myeloma should include the screening tests indicated in Table I, followed by further tests to confirm the diagnosis. Electrophoresis of serum and concentrated urine should be performed, followed by immunofixation to confirm and type any M-protein present. Immunofixation and serum-free light chain (SFLC) assessment are indicated in patients where there is a strong suspicion of myeloma but in whom routine serum protein electrophoresis is negative (Pratt, 2008). Quantification of serum M-protein should be performed by densitometry of the monoclonal peak on electrophoresis; immunochemical measurement of total immunoglobulin (Ig) isotype level can also be used and is particularly useful for IgA and IgD M-proteins. Quantification of urinary total protein and light chain excretion can be performed directly on a 24 hour (h) urine collection or calculated on a random urine sample in relation to the urine creatinine. Quantification of SFLC levels and κ/λ ratio is an additional tool for the assessment of light chain production. The serum tests are particularly useful for diagnosis and monitoring of light chain only myeloma (Bradwell et al, 2003) and patients with oligosecretory/non-secretory disease (Drayson et al, 2001) and in requests for which urine has not been sent to the laboratory. In renal impairment the half-life, and thus serum concentration of SFLC, can increase ten-fold and there is often an increased κ/λ ratio (Hutchison et al, 2008). A diagnosis of myeloma should be confirmed by bone marrow (BM) assessment. It is recommended that an adequate trephine biopsy of at least 20 mm in length be obtained in all patients as it provides a better assessment of the extent of marrow infiltration than aspirate smears (Ng et al, 2006; Al-Quran et al, 2007). It is recommended that a diagnosis of myeloma be confirmed by the demonstration of an aberrant plasma cell phenotype and/or monoclonality. Plasma cell phenotyping may be performed by flow cytometry and/or immunohistochemistry on trephine sections. The European Myeloma Network have provided practical guidance on the optimal methods for flow cytometry (Rawstron et al, 2008) and rapid and cost effective single-tube assays have been developed (Rawstron et al, 2008). CD138 immunostaining of trephine sections can be useful to determine the extent of infiltration in selected cases (Ng et al, 2006; Al-Quran et al, 2007). All diagnoses should be made or reviewed by an appropriately constituted Multidisciplinary Team (MDT) (National Institute for Health and Clinical Excellence (NICE), 2003). Cytogenetic and radiological investigations are discussed in Sections 2.4 and 3, respectively. A diagnosis of myeloma should be made using the criteria proposed in 2003 by the International Myeloma Working Group (IMWG), which are detailed in Table II. These criteria distinguish between myeloma and MGUS principally on the basis of M-protein concentration, percentage of BM plasma cells and presence or absence of myeloma-related organ and tissue impairment (ROTI) (Table III). Other differential diagnoses in patients with M-proteins include solitary plasmacytoma and other B-cell lymphoproliferative disorders. Detailed guidance on the diagnosis and management of MGUS and solitary plasmacytoma are provided in recently published UKMF/BCSH guidelines (Bird et al, 2009; Hughes et al, 2009). IMWG diagnostic criteria should be used Investigation should be based on the tests shown in Table I including an assessment of possible myeloma-related organ and tissue impairment All diagnoses should be made or reviewed by an appropriately constituted MDT Plasma cell phenotyping by flow cytometry and/or immunohistochemistry on trephine biopsy sections is recommended in all cases Chemotherapy is indicated for the management of symptomatic myeloma defined by the presence of ROTI. Early intervention in patients with asymptomatic myeloma is not required (Hjorth et al, 1993; Riccardi et al, 2000) although chemotherapy may be considered in patients with a rising M-protein concentration in the absence of ROTI. Patients with asymptomatic myeloma require close monitoring under the supervision of a Consultant Haematologist. The overall risk of progression is 10% per year for the first 5 years but, interestingly, declines in subsequent years (Kyle et al, 2007). The SFLC ratio (≤0·125 or ≥8) appears to be predictive of outcome and a risk score incorporating BM plasma cell percentage, M-protein concentration and SFLC ratio has been proposed (Dispenzieri et al, 2008). Flow cytometry is also predictive of outcome as the risk of progression is significantly greater when aberrant phenotype plasma cells determined by flow cytometry comprise ≥95% of total BM plasma cells (Perez-Persona et al, 2007). Chemotherapy is only indicated in patients with symptomatic myeloma based on the presence of ROTI (Grade A recommendation; level of evidence Ib) Patients with asymptomatic myeloma should be monitored under the supervision of a Consultant Haematologist. These patients should be offered entry into clinical trials if available. (Grade C recommendation; level of evidence IV) Monitoring of patients with asymptomatic myeloma should include regular (typically 3-monthly) clinical assessment for the emergence of ROTI and measurement of serum and urinary M-protein (and SFLC when indicated). Repeat BM examination and skeletal imaging should be considered prior to the start of treatment (Grade C recommendation; level of evidence IV) The natural history of myeloma is heterogeneous with survival times ranging from a few weeks to >20 years. Analysis of prognostic factors is essential to compare outcomes within and between clinical trials. The Durie/Salmon staging system was published in 1975 (Durie & Salmon, 1975) but has been superseded by the International Staging System (ISS) reproduced in Table IV (Greipp et al, 2005). This defines three risk categories determined by the serum concentration of β2-microglobulin and albumin. The use of staging systems to determine choice of therapy for individual patients remains unproven. Certain cytogenetic and molecular genetic abnormalities have been shown to predict outcome in myeloma. It is generally accepted that the t(4;14), t(14;16) and deletion 17p, demonstrated by fluorescence in situ hybridization (FISH), confer an adverse outcome in myeloma. It has therefore been proposed that these abnormalities define 'high-risk' myeloma and should be specifically sought at diagnosis in all patients (Fonseca et al, 2009; Munshi et al, 2011). The prognostic significance of chromosome 13 deletions has been difficult to clarify as some studies have suggested that it is only of prognostic significance when demonstrated by conventional karyotyping, which significantly underestimates the overall incidence of the abnormality. Emerging data however suggests that the adverse effect of chromosome 13 deletion relates to its close association with high-risk abnormalities, particularly the t(4;14) and there is now consensus that conventional karyotyping has little or no added value in the routine setting (Fonseca et al, 2009). Although there are preliminary data to suggest that the adverse effect of these factors may be abrogated by newer agents (San Miguel et al, 2008a), the current international consensus is that further prospective evaluation is required before clinical decisions can be guided by genetic factors (Munshi et al, 2011). A number of groups have used gene expression profiling to define risk in both newly diagnosed and relapsed patients (Mulligan et al, 2007; Shaughnessy et al, 2007) but its role in determining treatment decisions is yet to be defined. Baseline SFLC concentration may also provide useful prognostic information (Dispenzieri et al, 2008). It is essential that new prognostic indicators continue to be evaluated in prospective clinical trials. The International Staging System based on serum albumin and β2-microglobulin should be used FISH studies are encouraged for all patients at diagnosis as they provide important prognostic information but their role in directing therapy needs further evaluation in prospective clinical trials The European Group for Blood and Bone Marrow Transplant/International Bone Marrow Transplant Registry/American Bone Marrow Transplant Registry (EBMT/IBMTR/ABMTR) criteria (Blade et al, 1998) were updated by the IMWG in 2006 (Durie et al, 2006) and further modifications were subsequently proposed (Rajkumar et al, 2011). The uniform response criteria are detailed in Table V. There are two new response categories, stringent complete response (sCR) and very good partial response (VGPR). The criteria now incorporate changes in the SFLC assay to support the uniform reporting of clinical trials. In routine clinical practice there is a clear rationale for utilising the SFLC assay to assess response in light chain only disease, irrespective of the extent of light chain excretion in the urine (Pratt, 2008). The response category 'sCR' (for use in the reporting of clinical trials) has been refined recently to incorporate the use of flow cytometry to detect minimal residual disease on the basis of the presence of an aberrant immunophenotype (Rajkumar et al, 2011). Low levels of residual disease may also be demonstrated using allele-specific polymerase chain reaction (PCR) and a further new category of molecular CR is proposed, which is defined as the absence of disease by sequence specific PCR methods with a sensitivity of 10−5. Delayed achievement of complete remission (CR) is seen in a significant proportion of patients following high-dose therapy (Davies et al, 2001). The majority of such patients will have IgG M-proteins which have a half-life of approximately 23 d, significantly longer than that of IgA (6 d) and free light chains (4 h) (Mead et al, 2004). Repeat BM aspirate assessment is required to confirm CR (repeat trephine biopsy is not required under the response criteria but may be needed for accurate assessment; Durie et al, 2006) and should be performed in all patients at Day 100 following high-dose therapy in accordance with EBMT standards. Flow cytometric assessment of minimal residual disease at this time point also provides prognostic information (Paiva et al, 2008) and may in the future be used to guide maintenance/consolidation therapies. The definitions of progressive disease and relapse have also been revised by the IMWG (Table VI) and include a new category of clinical relapse, which reflects the fact that progressive disease (PD) as defined does not necessarily indicate a need for further therapy. Response to therapy should be defined using the IMWG uniform response criteria The response category sCR is recommended only for use in the clinical trial setting The SFLC assay should be used to assess response in all patients with light chain only, non secretory and oligo-secretory disease The rare myelomas comprise up to 7% of all myelomas and consist of plasma cell leukaemia, IgD, IgE, IgM and non-secretory myeloma. Plasma cell leukaemia. Plasma cell leukaemia (PCL) may be primary or secondary to multiple myeloma and is characterized by the presence of ≥20% circulating plasma cells and/or an absolute level of >2·0 × 109/l (Kyle et al, 1974). IgD, E and M Myelomas. IgD myeloma may comprise up to 1·8% of all myelomas (Blade & Kyle, 1994; Wechalekar et al, 2005). Diagnosis may be difficult because some patients may present with a very small or no visible monoclonal spike on serum electrophoresis. Care must be exercised to avoid a false diagnosis of non-secretory or light chain only myeloma (Sinclair, 2002). The clinical features are similar to that of other myelomas but Bence-Jones proteinuria, extramedullary involvement, lytic lesions and amyloidosis seem to be more frequent (Jancelewicz et al, 1975). Relatively few cases of IgE myeloma have been reported in the literature (Endo et al, 1981; Kairemo et al, 1999Morris et al, 2010). There may be clinical similarities with IgD myeloma and in both conditions the prognosis appears to be poor (Morris et al, 2010). With the increased use of BM trephine biopsies and improved immunohistomorphology (Konduri et al, 2005; Feyler et al, 2008), IgM myelomas are being recognized more frequently and may comprise up to 0·3% of all myelomas (Morris et al, 2010). It is important that such cases are distinguished from other IgM secreting disorders, particularly Waldenstrom macroglobulinaemia (Avet-Loiseau et al, 2003a). There is a high incidence of the t(11;14) and prognosis appears to be poor (Avet-Loiseau et al, 2003b; Feyler et al, 2008; Morris et al, 2010). Non-secretory myeloma. Non-secretory myeloma poses particular diagnostic difficulties as there is no serum M-protein and no urinary Bence-Jones protein excretion. The SFLC assay is informative in approximately two thirds of patients (Drayson et al, 2001). While the clinical presentation is essentially similar to standard myeloma, anaemia and lytic lesions may be seen more frequently while renal failure is uncommon (Morris et al, 2010). Significant advances in available imaging technologies have paralleled developments in therapy for myeloma and may play a more prominent role in determining prognosis in the future (Durie, 2006). A detailed guideline for the use of imaging in myeloma has been published (D'Sa et al, 2007). Key recommendations are summarized below. The skeletal survey remains the screening technique of choice at diagnosis The skeletal survey should include a postero-anterior (PA) view of the chest, antero-posterior (AP) and lateral views of the cervical spine, thoracic spine, lumbar spine, humeri and femora, AP and lateral view of the skull and AP view of the pelvis; other symptomatic areas should be specifically visualized with appropriate views Computerized tomography (CT) scanning or magnetic resonance imaging (MRI) should be used to clarify the significance of ambiguous plain radiographic findings, such as equivocal lytic lesions, especially in parts of the skeleton that are difficult to visualize on plain radiographs, such as ribs, sternum and scapulae Urgent MRI is the diagnostic procedure of choice to assess suspected cord compression in myeloma patients with or without vertebral collapse (Grade B recommendation; level IIB evidence). Urgent CT scanning is an alternative, when MRI is unavailable, intolerable or contraindicated (Grade B recommendation; level III evidence) CT or MRI is indicated to delineate the nature and extent of soft tissue masses and where appropriate, tissue biopsy may be guided by CT scanning (Grade B recommendation; level IIB evidence) There is insufficient evidence to recommend the routine use of positron-emission tomography (PET) or 99mTechnetium sestamibi (MIBI) imaging. Either technique may be useful in selected cases for clarification of previous imaging findings preferably within the context of a clinical trial Bone scintigraphy has no place in the routine staging of myeloma Routine assessment of bone mineral density cannot be recommended, owing to the methodological difficulties of the technique and the universal use of bisphosphonates in symptomatic myeloma patients Hyperviscosity syndrome may develop in patients with high serum paraprotein levels, particularly those of IgA and IgG3 type. Symptoms include blurred vision, headaches, mucosal bleeding and dyspnoea due to heart failure. All patients with high protein levels should undergo fundoscopy, which may demonstrate retinal vein distension, haemorrhages and papilloedema. Patients usually have raised plasma viscosity and symptoms commonly appear when it exceeds 4 or 5 mPa. This usually corresponds to a serum IgM level of at least 30 g/l, an IgA level of 40 g/l and an IgG level of 60 g/l (Mehta & Singhal, 2003). Plasma viscosity results should not be used to determine the need for plasma exchange as this may result in delay but testing should be carried out both before and after the procedure. Symptomatic patients should be with plasma may be useful if plasma exchange are not available. is exchange should be The need for further over the few should be determined by symptoms and for of protein levels is and treatment should be Symptomatic should be with plasma exchange with is not available but symptoms are with as a treatment of the disease should be as as possible to of myeloma patients present with hypercalcaemia in the context of hypercalcaemia can present with system and of the on and renal of hypercalcaemia should be considered of the disease should be as as possible with treatment of hypercalcaemia to renal The of treatment are and hypercalcaemia may be with and/or to hypercalcaemia with urine should be and use of such as should be considered to avoid and heart failure and urinary excretion. All patients with to hypercalcaemia should a A randomized controlled trial in patients with hypercalcaemia of has shown that is to et al, 2001). the remains high after a further dose of may be modifications are required in renal impairment and dose may be more appropriate in patients with renal impairment (see Appendix Patients with refractory hypercalcaemia may require and In hypercalcaemia with and/or In to hypercalcaemia with and if required is the of choice in the treatment of hypercalcaemia A level I of the cord from extramedullary of disease in of patients with myeloma the of their disease (Kyle et al, 2003). Clinical features on the nature of the cord compression to or to soft tissue the extent of disease and the rate of development of cord compression, but commonly include and This is a medical requiring rapid diagnosis and treatment. clinical suspicion of cord compression, 40 for 4 should be and MRI obtained as as MRI is or due to patient or an urgent CT should be The between soft tissue and cord compression is essential and should be discussed with on if there is any the need for is usually for in the setting of compression and/or to the and is usually by soft tissue disease is the treatment of choice and should be preferably within 24 of the diagnosis of cord There are no randomized controlled trials to guidance on optimal dose and but a of myeloma patients has been published and demonstrated a better overall outcome in of in function for patients with at least 30 et al, 2006). Urgent MRI should be performed and or obtained is the treatment of choice for lesions and should be as as is preferably within 24 of diagnosis. A dose of 30 in is recommended (Grade B recommendation; level evidence) is recommended for in the setting of compression and/or to the cord compression is a it is important to a rapid diagnosis and to therapy as as possible Myeloma is with an increased incidence of This is to in both and and poor which are all with both the disease and its treatment. It has been reported that up to 10% of patients of within 60 of diagnosis et al, 2005). is not usually a in infection et al, 2005). There is increasing evidence that high dose in the or in patients with poor may be with increased and a higher rate in the and should be given to the use of in this et al, et al, 2009; et al, 2010). Patient as well as to specialist and treatment is in and infection in myeloma. and management of infection in myeloma patients is discussed in more in the care guideline (Snowden et al 2011). There must be to specialist for the patient and/or primary care myeloma patient should be with are required for infection or should be if possible There is insufficient evidence to recommend the routine use of Bone disease in of myeloma The development of bone disease, or can result in cord compression and hypercalcaemia & & and of life & et al, et al, 2007) and increase overall treatment bone require and subsequent is useful to control and may also of the a lytic may skeletal an should be sought and considered in selected clinical interventions for with including and are discussed in the care guideline (Snowden et al, 2011). is for a dose of is recommended bone require and subsequent a dose of is recommended A Cochrane Review of the use of bisphosphonates in myeloma et al, data from trials of or and from a preliminary of a trial of on a of trial data at that the was that bisphosphonates to the treatment of myeloma vertebral and but does not The evidence also suggested a in both patients with and without bone disease at trials with and in myeloma patients have now been published in et al, 2009). has been shown to be in myeloma and may et al, There are as yet no published randomized studies of or while to any effect on rates or survival et al, 2002). The trials of et al, et al, 2001) demonstrated for up to years in patients chemotherapy for the first including patients with no lytic using the bisphosphonates have been in patients with more and have demonstrated their in the of skeletal in this setting et al, et al, 2003). and appear with to although there has been no randomized and no of treatment is however with greater in skeletal and of of type 1 in some studies et al, 2001). The Research Myeloma trial has recently reported with a median up of years and demonstrated significant of

OBJECTIVE: Previous in vitro and animal studies have suggested that vitamin D, in particular, its metabolite 25-hydroxyvitamin D (25[OH]D), may have immunomodulatory effects. To study further the potential immunomodulatory effects of vitamin D in humans, we explored the hypothesis that serum vitamin D metabolites may be inversely associated with current disease activity, severity, and functional disability in patients with early inflammatory polyarthritis (IP). METHODS: We studied 206 consecutive patients with IP who were enrolled in the Norfolk Arthritis Register between January 2000 and November 2003 inclusive. Patients were studied within 6 months of symptom onset. None of the patients was taking steroids, and all had received <6 weeks of disease-modifying therapy. Associations between serum levels of 25(OH)D and 1,25-dihydroxyvitamin D (1,25[OH](2)D) at baseline and the swollen and tender joint counts, Health Assessment Questionnaire (HAQ) scores, C-reactive protein (CRP) levels, and the Disease Activity Score 28-joint assessment (DAS28) scores at baseline and 1 year were assessed. RESULTS: The median age at symptom onset was 59 years (range 20-88 years), with a median disease duration of 4 months. At baseline, there was an inverse relationship between 25(OH)D levels and the tender joint count, DAS28 score, and HAQ score. The only inverse relationship with 1,25(OH)(2)D was with the HAQ score. Each 10-ng/ml increase in the level of 25(OH)D was associated with a decrease in the DAS28 score of 0.3 and in the CRP level of approximately 25%. At 1 year, the only significant result was an inverse association between baseline vitamin D metabolite levels and the HAQ score; that is, those with higher metabolite levels had lower HAQ scores. CONCLUSION: These data provide further support that vitamin D plays an immunomodulatory role in inflammatory arthritis. This association needs to be examined in other cohorts of patients with early IP, as well as in longitudinal studies. If confirmed, the clinical response to vitamin D supplementation should be examined in early IP.

Hematopoietic prostaglandin D(2) synthase (hPGD(2)S) metabolizes cyclooxygenase (COX)-derived PGH(2) to PGD(2) and 15-deoxyDelta(12-14) PGJ(2) (15d-PGJ(2)). Unlike COX, the role of hPGD(2)S in host defense is ambiguous. PGD(2) can be either pro- or antiinflammatory depending on disease etiology, whereas the existence of 15d-PGJ(2) and its relevance to pathophysiology remain controversial. Herein, studies on hPGD(2)S KO mice reveal that 15d-PGJ(2) is synthesized in a self-resolving peritonitis, detected by using liquid chromatography-tandem MS. Together with PGD(2) working on its DP1 receptor, 15d-PGJ(2) controls the balance of pro- vs. antiinflammatory cytokines that regulate leukocyte influx and monocyte-derived macrophage efflux from the inflamed peritoneal cavity to draining lymph nodes leading to resolution. Specifically, inflammation in hPGD(2)S KOs is more severe during the onset phase arising from a substantial cytokine imbalance resulting in enhanced polymorphonuclear leukocyte and monocyte trafficking. Moreover, resolution is impaired, characterized by macrophage and surprisingly lymphocyte accumulation. Data from this work place hPGD(2)S at the center of controlling the onset and the resolution of acute inflammation where it acts as a crucial checkpoint controller of cytokine/chemokine synthesis as well as leukocyte influx and efflux. Here, we provide definitive proof that 15d-PGJ(2) is synthesized during mammalian inflammatory responses, and we highlight DP1 receptor activation as a potential antiinflammatory strategy.

T he overall aim of the NHS R&D Health Technology Assessment (HTA) programme is to ensure that high-quality research information on the costs, effectiveness and broader impact of health technologies is produced in the most efficient way for those who use, manage and work in the NHS. Research is undertaken in those areas where the evidence will lead to the greatest benefits to patients, either through improved patient outcomes or the most efficient use of NHS resources.

BACKGROUND: Health-related quality of life (QOL) is an important outcome for older people who are often on dialysis for life. Little is, however, known about differences in QOL on haemodialysis (HD) and peritoneal dialysis (PD) in older age groups. Randomising patients to either modality to assess outcomes is not feasible. METHODS: In this cross-sectional, multi-centred study we conducted QOL assessments (Short Form-12 Mental and Physical Component Summary scales, Hospital Anxiety and Depression Scale and Illness Intrusiveness Ratings Scale) in 140 people (aged 65 years or older) on PD and HD. RESULTS: The groups were similar in age, gender, time on dialysis, ethnicity, Index of Deprivation (based on postcode), dialysis adequacy, cognitive function (Mini-Mental State Exam and Trail-Making Test B), nutritional status (Subjective Global Assessment) and social networks. There was a higher comorbidity score in the HD group. Regression analyses were undertaken to ascertain which variables significantly influence each QOL assessment. All were influenced by symptom count highlighting that the patient's perception of their symptoms is a critical determinant of their mental and physical well being. Modality was found to be an independent predictor of illness intrusion with greater intrusion felt in those on HD. CONCLUSIONS: Overall, in two closely matched demographic groups of older dialysis patients, QOL was similar, if not better, in those on PD. This study strongly supports offering PD to all suitable older people.

Clinical biochemists have long known the analytical and clinical limitations of creatinine and creatinine clearance measurement in the assessment of glomerular filtration rate (GFR). This background is reviewed in the article before assessing the utility of cystatin C, the most promising replacement biochemical marker yet identified. Cystatin C has been used in clinical research studies for more than 20 years and yet has been introduced into clinical practice in very few centres, firstly in Lund in Sweden and now Carshalton in the UK. Why is this? The review compares our ability to measure creatinine and cystatin C and their relative sensitivity and specificity for changes in GFR. Comparison is made of cystatin C with creatinine as screening tests for early renal dysfunction and for monitoring its progression where issues of reference ranges and within-individual variation are important. The superiority of cystatin C as a screening test is probably accepted but there are still concerns about non-renal influences upon its circulating concentration, particularly steroid therapy, insufficient data on the influence of malignancy and a general lack of prospective clinical studies confirming the prognostic significance of cystatin C.

BACKGROUND: Pulmonary sarcoidosis is a common condition with an unpredictable course. Oral (OCS) or inhaled steroids (ICS) are widely used in its treatment, but there is no consensus about when and in whom therapy should be initiated, what dose should be given and for how long. Corticosteroids given for several months have deleterious side-effects so it is important to know whether they have any maintained benefit in pulmonary sarcoidosis. OBJECTIVES: To determine the randomised controlled trial (RCT) evidence for the benefit of corticosteroids (oral or inhaled) in the treatment of pulmonary sarcoidosis. SEARCH STRATEGY: MEDLINE, EMBASE and CENTRAL were searched using predefined terms. Bibliographies of retrieved RCTs and reviews were searched for additional RCTs. Pharmaceutical companies and authors of identified RCTs were contacted for other published and unpublished studies. Searches are current as of May 2004. SELECTION CRITERIA: Two reviewers independently assessed full text articles for inclusion based upon the following criteria: the study had to be a RCT or controlled clinical trial in adults with histological evidence of pulmonary sarcoidosis, treated with OCS (oral steroids) or ICS (oral steroids), compared with a control. DATA COLLECTION AND ANALYSIS: Study quality was assessed and data extracted independently by two reviewers. The primary outcome was CXR (chest x-ray). Outcomes were analysed as continuous and dichotomous outcomes, using standard statistical techniques. Heterogeneity was explored where it was identified. MAIN RESULTS: Twelve RCTs of variable quality involving 1051 participants met the inclusion criteria of the review. The oral steroid dose was equivalent to prednisolone 4-40 mg/day. OCS: there was an improvement in CXR over 3-24 months (Relative Risk (RR): 1.46 [1.01 to 2.09], 3 studies), but this finding requires cautious interpretation. No other significant differences were identified on secondary outcomes. ICS: Data were inadequate to perform meaningful analysis of data on CXR. Two studies showed no improvement in lung function, In one study there was an improvement in diffusing capacity in the treated group. There were no data on side-effects. In one study symptoms improved at the end of six months of treatment. AUTHORS' CONCLUSIONS: Oral steroids improved the chest X-ray and a global score of CXR, symptoms and spirometry over 3-24 months. However, there is little evidence of an improvement in lung function. There are limited data beyond two years to indicate whether oral steroids have any modifying effect on long-term disease progression. Oral steroids may be of benefit for patients with Stage 2 and 3 disease with moderate to severe or progressive symptoms or CXR changes.

OBJECTIVES: To determine whether microalbuminuria is an independent prognostic factor for the development of diabetic complications and whether improved glycaemic or blood pressure control has a greater influence on the development of diabetic complications in those with microalbuminuria than in those with normoalbuminuria. DATA SOURCES: Electronic databases up until January 2002. REVIEW METHODS: A protocol for peer review by an external expert panel was prepared that included selection criteria for data extraction and required two independent reviewers to undertake article selection and review. Completeness was assessed using hand-searching of major journals. Random effects meta-analysis was used to obtain combined estimates of relative risk (RR). Funnel plots, trim and fill methods and meta-regression were used to assess publication bias and sources of heterogeneity. RESULTS: In patients with type 1 or type 2 DM and microalbuminuria there is a RR of all-cause mortality of 1.8 [95% confidence interval (CI) 1.5 to 2.1] and 1.9 (95% CI 1.7 to 2.1) respectively. Similar RRs were found for other mortality end-points, with age of cohort being inversely related to the RR in type 2 DM. In patients with type 1 DM, there is evidence that microalbuminuria or raised albumin excretion rate has only weak, if any, independent prognostic significance for the incidence of retinopathy and no evidence that it predicts progression of retinopathy, although strong evidence exists for the independent prognostic significance of microalbuminuria or raised albumin excretion rate for the development of proliferative retinopathy (crude RR of 4.1, 95% CI 1.8 to 9.4). For type 2 DM, there is no evidence of any independent prognostic significance for the incidence of retinopathy and little, if any, prognostic relationship between microalbuminuria and the progression of retinopathy or development of proliferative retinopathy. In patients with type 1 DM and microalbuminuria there is an RR of developing end-stage renal disease (ESRD) of 4.8 (95% CI 3.0 to 7.5) and a higher RR (7.5, 95% CI 5.4 to 10.5) of developing clinical proteinuria, with a significantly greater fall in glomerular filtration rate (GFR) in patients with microalbuminuria. In patients with type 2 DM, similar RRs were observed: 3.6 (95% CI 1.6 to 8.4) for developing ESRD and 7.5 (95% CI 5.2 to 10.9) for developing clinical proteinuria, with a significantly greater decline in GFR in the microalbuminuria group of 1.7 (95% CI 0.1 to 3.2) ml per minute per year compared with those who were normoalbuminuric. In adults with type 1 or type 2 DM and microalbuminuria at baseline, the numbers progressing to clinical proteinuria (19% and 24%, respectively) and those regressing to normoalbuminuria (26% and 18%, respectively) did not differ significantly. In children with type 1 DM, regression (44%) was significantly more frequent than progression (15%). In patients with type 1 or type 2 DM and microalbuminuria, there is scarce evidence as to whether improved glycaemic control has any effect on the incidence of cardiovascular disease (CVD), the incidence or progression of retinopathy, or the development of renal complications. However, among patients not stratified by albuminuria, improved glycaemic control benefits retinal and renal complications and may benefit CVD. In the effects of angiotensin-converting enzyme (ACE) inhibitors on GFR in normotensive microalbuminuric patients with type 1 DM, there was no evidence of a consistent treatment effect. There is strong evidence from 11 trials in normotensive type 1 patients with microalbuminuria of a beneficial effect of ACE inhibitor treatment on the risk of developing clinical proteinuria and on the risk of regression to normoalbuminuria. Patients with type 2 DM and microalbuminuria, whether hypertensive or not, may obtain additional cardiovascular benefit from an ACE inhibitor and there may be a beneficial effect on the development of retinopathy in normotensive patients irrespective of albuminuria. There is limited evidence that treatment of hypertensive microalbuminuric type 2 diabetic patients with blockers of the renin--angiotensin system is associated with preserved GFR, but also evidence of no differences in GFR in comparisons with other antihypertensive agents. The data on GFR in normotensive cohorts are inconclusive. In normotensive type 2 patients with microalbuminuria there is evidence from three trials (all enalapril) of a reduction in risk of developing clinical proteinuria; in hypertensive patients there is evidence from one placebo-controlled trial (irbesartan) of a reduction in this risk. Intensive compared with moderate blood pressure control did not affect the rate of progression of microalbuminuria to clinical proteinuria in the one available study. There is inconclusive evidence from four trials of any difference in the proportions of hypertensive patients progressing from microalbuminuria to clinical proteinuria when ACE inhibitors are compared with other antihypertensive agents, and in one trial regression was two-fold higher with lisinopril than with nifedipine. CONCLUSIONS: The most pronounced benefits of glycaemic control identified in this review are on retinal and renal complications in both normoalbuminuric and microalbuminuric patients considered together, with little or no evidence of any greater benefit in those with microalbuminuria. Hence, microalbuminuric status may be a false boundary when considering the benefits of glycaemic control. Classification of a person as normoalbuminuric must not serve to suggest that they will derive less benefit from optimal glycaemic control than a person who is microalbuminuric. All hypertensive patients benefit from blood pressure lowering and there is little evidence of additional benefit in those with microalbuminuria. Antihypertensive therapy with an ACE inhibitor in normotensive patients with microalbuminuria is beneficial. Monitoring microalbuminuria does not have a proven role in modulating antihypertensive therapy while the patient remains hypertensive. Recommendations for microalbuminuria research include: determining rate and predictors of development and factors involved in regression; carrying out economic evaluations of different screening strategies; investigating the effects of screening on patients; standardising screening tests to enable use of common reference ranges; evaluating the effects of lipid-lowering therapy; and using to modulate antihypertensive therapy.

GOALS: To determine the efficacy of triple therapy supplemented with a specially designed fermented milk product containing specific probiotic Lactobacillus casei (L. casei) DN-114 001 strain on Helicobacter pylori eradication in children. BACKGROUND: Lactobacillus species possess in vitro activity against H. pylori. There are no consistent data on the impact of eradication therapy supplemented with probiotics on H. pylori cure rates in childhood in vivo. STUDY: Multicenter, prospective, randomized, double-blind controlled study. Eighty-six symptomatic H. pylori-positive children were randomized either to receive the control treatment of omeprazole, amoxicillin, and clarithromycin (OAC) for 7 days or the test treatment of omeprazole, amoxicillin, and clarithromycin for 7 days supplemented with fermented milk (Actimel) containing L. casei DN-114 001 (OAC-LC), for 14 days. H. pylori status was assessed at 4 weeks following therapy using two noninvasive tests. RESULTS: Intention-to-treat (ITT) based eradication rates for the OAC-LC group were 84.6% (95% CI, 71.2%-95.5%), and 91.6% (95% CI, 76.9%-98.2%) by per-protocol (PP) analysis. Eradication in the OAC group was 57.5% (95% CI, 42.2%-72.3%) in the ITT set and 61.3% (95% CI, 44.4%-75.0%) in the PP group. Eradication success was higher in the OAC-LC group compared with the OAC group in both ITT (P=0.0045) and PP analysis (P=0.0019). Primary resistance for clarithromycin could be determined in 21.2%. Side effects were infrequent. Drug compliance was good throughout the study. CONCLUSION: Supplementation with fermented milk, containing live special probiotic L. casei DN-114 001, confers an enhanced therapeutic benefit on H. pylori eradication in children with gastritis on triple therapy.

The flow cytometric test measures the fluorescence intensity of intact red cells labelled with the dye eosin-5-maleimide, which reacts covalently with Lys-430 on the first extracellular loop of band 3 protein. In this study, red cells from patients with hereditary spherocytosis (HS), congenital dyserythropoietic anaemia type II, South-east Asian ovalocytosis and cryohydrocytosis have produced a greater degree of reduction of mean channel fluorescence readings than those for other patient groups and normal controls. The predictive value of this test for membrane abnormality was compared with the results obtained from the sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) method, which is currently the reference laboratory test for the identification of membrane protein deficiencies in hereditary spherocytosis and for the detection of spectrin variants in hereditary elliptocytosis. The dye method is a reliable, speedy diagnostic test (2 h from sample collection to result) for HS with a sensitivity of 92.7% and a specificity of 99.1%. Thus, it will serve well as a first-line screening test for the diagnosis of hereditary spherocytosis in routine haematology.