Updated Commissioning Guidance For The Use Of Therapeutic .
Updated Commissioning Guidance for the use of therapeutic immunoglobulin (Ig) in immunology,haematology, neurology and infectious diseases in England December 2018This updated commissioning guidance on the use of therapeutic immunoglobulin (Ig) in immunology, haematology, neurology and infectiousdiseases has been based on a previous review of the literature updated with a further evidence review, expert opinion and multi-organisationalinput. The guidelines have been developed by the Ig policy working group following wide consultation with specialty experts, relevant scientificsocieties and the respective Clinical Reference Groups for haematology, immunology, neurology and infectious diseases. Recommendationson Ig dose and outcomes are based on a combination of available evidence and expert opinion. This guidance applies to the use of Ig in bothadults and children.As compared with the previous iteration of the Department of Health guidelines (2nd edition update; July 2011), it provides greater detail aroundthe role, dose and place of Ig in the treatment pathway for individual indications alongside possible alternative treatment options. The colourcoding scheme, which was previously devised for demand management but often utilised as a commissioning tool, has been replaced bycategorisation of Ig use in to routinely commissioned or not commissioned categories based on the strength of evidence. Note: The Departmentof Health guidelines colour coding scheme will still apply if the demand management scheme is officially implemented in times of short supply.This commissioning guidance has focused on those indications previously categorised as Red (conditions for which Ig treatment is consideredthe highest priority because of a risk to life without treatment) and Blue (conditions for which there is a reasonable evidence base for the use ofIg but other treatment options are available). As a significant proportion of Ig use is in haematology, immunology and neurology, the first phaseof the guidance review focused on those indications within these specialties. There have been a number of supply issues of pathogen specificimmunoglobulin over the past year, so use of Ig in specific infectious diseases was also included in phase one of the overall Ig review.Within this updated commissioning guidance, an additional column clarifying whether prior panel approval is required for use of Ig in individualindications is included. Where local expertise is not available, panels will also be able to advise on dose optimisation and trials of treatmentwithdrawal.The second phase of the update will review the use of Ig in those indications classified as ‘red’ or ‘blue’ under “other” within the current ClinicalGuidelines for Immunoglobulin use. This will include: Autoimmune congenital heart block/paediatric myocarditisImmunoglobulin Commissioning Guidelines V1.0 Dec 2018
Autoimmune uveitisKawasaki diseaseNecrotising (PVL associated) staphylococcal sepsisSevere or recurrent Clostridium difficile colitisStaphylococcal or streptococcal toxic shock syndromeToxic epidermal necrolysis, including Steven Johnson SyndromeTransplantation (solid organ)The third phase will be based on a detailed evidence review of the use of Ig in disorders previously categorised as Grey indications (immunemediated disorders with limited or little/no evidence), where the high quality evidence base was weak or absent, or the disease was rare. Aswith Red and Blue indications, only those Grey indications which are supported by adequate evidence of Ig efficacy will be commissioned.Whilst the 2nd and 3rd phases of the guidance review are underway NHS England will continue to commission Ig in “other” indications and inGrey indications in line with the Current Clinical Guidelines for Immunoglobulin use (2nd edition update; July 2011).In keeping with the advice included in previous iterations of these guidelines and to ensure cost-effective use and minimise dose-dependentadverse effects, Ig prescribing will be based on ideal body weight- adjusted dosing (Chow et al Transfusion and Apheresis Science2012;46:349-52;Stump et al. Pharmacotherapy 2017; 37:1530-1536). In a small minority of patients where this approach may be sub-optimal,higher doses of Ig may be required.Immunoglobulin Commissioning Guidelines V1.0 Dec 2018
Use of Immunoglobulin in immunology:Immunoglobulin is routinely commissioned in the following indications, under the circumstances described:IndicationsSelection criteriaPrimaryimmunodeficienciesassociated withsignificant antibodydefects (excludingspecific antibodydeficiency) – longterm useA specific PID diagnosis must be establishedby a clinical immunologistThymoma withimmunodeficiency –long term useProfound B cell depletion and/or significantantibody deficiencyHSCT in primaryimmunodeficiencies– long term usePID patients undergoing HSCTImmunoglobulin Commissioning Guidelines V1.0 Dec 2018Exclusioncriteria:NoNoNoPosition ofimmunoglobulin, takinginto account alternativetherapies:Ig is the only definitivetreatment for antibodydeficiencyRecommendeddoseClinical outcomesInitiate at 0.4–0.6g/kg/month;dose requirementsmay increase andshould be based onclinical outcomeTrough IgGIg is the only definitivetreatment for antibodydeficiencyInitiate at 0.4–0.6g/kg/month;dose requirementsmay increase andshould be based onclinical outcomeTrough IgGIg is the only definitivetreatment for antibodydeficiencyInitiate at 0.4–0.6g/kg/month;dosing requirementsmay increase andshould be based onclinical outcome.Because of thepossibility of B-cellreconstitution,evaluation ofimmune function (offIg) is required at 2years.Trough IgGPrior panelapproval requiredNoReduction in number ofinfections, treatment coursesof antibiotics, days inhospital.NoReduction in number ofinfections, treatment coursesof antibiotics, days inhospital.No
Specific antibodydeficiency – longterm use Secondary antibodydeficiency – longterm use Diagnosis by a clinical immunologistSevere, persistent, opportunistic orrecurrent bacterial infections despitecontinuous oral antibiotic therapy for 6monthsDocumented failure of serum antibodyresponse to unconjugatedpneumococcal or other polysaccharidevaccine challengeNo, but seecomments incolumn ofposition ofimmunoglobulinMany patients with specificantibody deficiency willachieve protection frombacterial infections withprolonged antibioticprophylaxis. Ig is reservedfor those patients in whomantibiotic prophylaxis provesto be ineffective.Underlying cause ofhypogammaglobinaemia cannot bereversed or reversal is contraindicated;No, but seecomments incolumn ofposition ofimmunoglobulinMany patients withsecondary antibodydeficiency will achieveprotection from bacterialinfections with prolongedantibiotic prophylaxis. Ig isreserved for those patientsin whom antibioticprophylaxis proves to beineffective.OR: Hypogammaglobinaemia associatedwith drugs, therapeutic monoclonalstargeted at B cells and plasma cells(rituximab and other anti-CD20,CD19agents, daratumumab etc) post-HSCT,NHL, CLL, MM or other relevant B-cellmalignancy confirmed by haematologist;AND Recurrent or severe bacterial infectiondespite continuous oral antibiotictherapy for 6 monthsIgG 4 g/L (excluding paraprotein)Documented failure of serum antibodyresponse to unconjugatedpneumococcal or other polysaccharidevaccine challengeIt is recognised that vaccine challengemay be of limited value in patients withvery low serum IgG ( 3g/L). In thesecircumstances vaccine challenge maybe omitted if it is consideredinappropriate clinically.It is acknowledged that not all of theImmunoglobulin Commissioning Guidelines V1.0 Dec 2018Since infection susceptibilityin patients withhaematologicalmalignancies is frequentlymultifactorial, the reductionin overall burden ofinfections with long term Igreplacement may bevariable. For this reasonannual reviews of treatmentare recommended. Inpatients with seasonalpreponderance of infections,it may be appropriate toconsider temporarycessation of Ig in thesummer.Initiate trial at 0.4–0.6 g/kg/month for aperiod of 6 to 12months;Long-termmaintenancetreatment should bebased on clearevidence of benefitfrom this trial andrequire panelapproval.Dose requirementsmay increase andshould be based onclinical outcome. 0.4 – 0.6g/kg/monthmodified toachieve an IgGtrough level ofat least thelower limit ofthe age-specificserum IgGreference rangeReduction in number ofinfections, treatment coursesof antibiotics, days inhospital. Databaseparameters will include entryof number of infections anddays in hospital pretreatment and 6 monthlythereafterYesReduction in number ofinfections and days inhospital (Databaseparameters will include entryof number of infections anddays in hospital pretreatment and 6 monthlythereafter)Yes
above criteria will need to be fulfilled foran individual patient. In patients developinghypogammaglobinaemia associatedwith B-cell aplasia as a consequence ofChimeric Antigen Receptor – T celltherapy (CAR-T cells) targeted againstB cell antigens, the prophylactic use ofIg in the absence of a burden of severeinfections and vaccine challenge maybe appropriate.**There is controversy regarding Ig replacement in adult patients with hypogammaglobinaemia post-HSCT for haematological malignancy. The American Society for Blood and Marrowtransplantation and the Canadian Blood and Marrow Transplant group have recently stated as follows: Don’t routinely give Ig replacement to adult HSCT recipients in the absence of recurrent infections regardless of the IgG level (Bhella et al. Choosing Wisely BMT. Biol Blood MarrowTransplant 2018;24:909-13)It is possible that patients with recurrent sino-pulmonary infections on a background of chronic pulmonary GVHD and hypogammaglobinaemia may benefit if they fulfil the criteria for secondaryantibody deficiency.Immunoglobulin Commissioning Guidelines V1.0 Dec 2018
Use of Immunoglobulin in Haematology:Immunoglobulin is routinely commissioned in the following indications, under the circumstances described:IndicationEligibility nia(foetalmaternal/neonatal)(FMAIT NAIT):/Prevention or treatment of foetalthrombocytopenia or haemorrhage:Clinical suspicion of FMAIT in theantenatal setting based on clinical andlaboratory features:NoPosition ofimmunoglobulin, takinginto account alternativetherapies:Immunoglobulin is theprimary treatment andsometimes combined withsteroidsUnexplained previous foetal death,haemorrhage, hydrocephalus orthrombocytopenia or known affectedsibling,ANDthe presence of maternal platelet-specificalloantibodies directed against currentpaternal antigens (most commonly HPA1a or HPA-5b).Prevention or treatment of neonatalthrombocytopenia or haemorrhage:Clinical suspicion of NAIT in the neonatalsetting based on clinical featuressuggestive of bleeding e.g. purpuraand/or bruising and/or more seriousbleeding and a low platelet count.Haemolytic diseaseof the newborn –short term use:Adjunct to continuous multiplephototherapy in cases of Rhesushaemolytic disease, or ABO haemolyticdisease:Immunoglobulin Commissioning Guidelines V1.0 Dec 2018NoFirst line treatment is withHPA-1a/5b – negativeplatelets which covers95% of HPAincompatibilitiesresponsible for NAIT.Platelet transfusion iseffective immediately.In contrast,immunoglobulin is asecond line treatment andworks in approximately75% of cases. It has adelayed effect over 24 –48 hours. Immunoglobulinmay be of value if there isprolongedthrombocytopenia with theaim of minimising theneed for platelettransfusions.Immunoglobulin is anadjunct to phototherapyRecommended dose:Outcome measures to berecorded on the nationaldatabase:Prior panelapproval requiredMaternal: 0.5 -1g/kg weeklythroughout pregnancy.Dose and stage ofgestation at which to starttreatment to be tailored toindividual risk profileprimarily based on thehistory of NAIT in earlierpregnancies.Patients with alow-risk obstetric historyshould be commenced on0.5.g/kg (Winkelhorst D etal. Fetal and neonatalalloimmunethrombocytopenia:evidencebased antenatal andpostnatal managementstrategies. Exp RevHematol 2017;10:729-737)Successful outcome ofpregnancy i.e. no severehaemorrhage such asintracranial haemorrhageNo – for NAITYes – for FMAITPlatelet count above50x109 /L at time ofdeliveryIncrement in neonatalplatelet countNeonatal: 1g/kg; a 2nd dosemay be required ifthrombocytopenia persists0.5kg/kg over 4 hoursBilirubin levelNeed for exchangetransfusionNo
Long term morbidityRising bilirubin despite intensivephototherapy ImmuneThrombocytopenicPurpura (ITP) shortterm use:Prevention of foetal haemolyticdisease in women with a previoushistory of this and confirmed red cellantibodies to current paternal orfoetal antigens, to delay the need forintrauterine transfusionsImmunoglobulin generally used in only 3situations in ITP:1) Life-threatening bleeding2) Where an immediate increase inplatelet count is required e.g. beforeemergency surgery or otherprocedure (see table for targetplatelet counts)3) Where the patient is refractory to allother treatment to maintain theplatelet count at a level to preventhaemorrhage. It may need to begiven every 2-3 weeks during aperiod where other second linetreatments are being tried.Target platelet counts for surgery*ProcedurePlatelet countDentistry 20Simple dental 30extractionComplex dental 50extractionRegional dental 30blockMinor surgery 50Major surgery 80Major neurosurgery 100ITP in pregnancy:Maintenance treatment with Ig may berequired antenatally to maintain plateletsabove 20x109/l and/or to increaseplatelets to over 50 x109/l for delivery inwomen with symptomatic persistent orchronic ITP where other treatments havefailed.Immunoglobulin Commissioning Guidelines V1.0 Dec 2018NoThrombopoietin mimeticsmay be useful substitutesin some patientsAdults: 1g/kg as a singleinfusion.A 2nd dose may be requiredafter 24 – 48 hours, ifsevere or life-threateningbleeding:e.g. Intracranial bleed orpulmonary haemorrhageOtherwise, if ahaemostatically adequateplatelet count is notachieved a 2nd dose (1g/kg)may be considered at day5 to 7Children: 0.8 – 1g/kg as asingle infusion.A 2nd dose may be requiredafter 24 – 48 hours, ifsevere or life-threateningbleeding, such as anintracranial bleed orpulmonary haemorrhage.Otherwise, if ahaemostatically adequateplatelet count is notachieved a 2nd dose (1g/kg)may be considered at day5 to 7Increase in platelet countResolution of bleedingNumber of bleedingcomplicationsNo for acute ITP;the use of a 2nddose should bediscussed with thedesignated panellead.Yes – formaintenancetreatment
*There is controversy regarding thetarget platelet count for epiduralanaesthesia (Provan et al. Blood2010;115:168-186). There are no data tosupport a minimum platelet count andeach case must be carefully considered.In the absence of bruising, bleedinghistory, and anticoagulation and if theINR, APTT and fibrinogen levels arenormal, a small consensus of obstetricanaesthetists agree no changes tonormal practice are needed until theplatelet count drops below 50.Acquired red cellaplasia associatedwith chronicparvovirus B19infection– shortterm useParvovirus B19 infection: Parvovirus B19 infection confirmedby PCR, AND Evidence of high viral load, usuallyabove 109 IU/mlIn cases of foetal hydrops: Likely to be associated withparvovirus B19Autoimmunehaemolytic anaemia(AHA, includingEvans syndrome) –short term useAHA, including Evans syndrome: Symptomatic or severe anaemia,except in patients with comorbidities),AND Refractory to conventional treatmentwith corticosteroids,OR Corticosteroids contra-indicated,OR As a temporising measure prior tosplenectomyAHA in pregnancy: Pregnant women with warm AHArefractory to corticosteroids OR withImmunoglobulin Commissioning Guidelines V1.0 Dec 2018 NoInfectionotherthanparvovirus B19Immunoglobulin is anadjunct to transfusion.Chronic parvovirusinfection generally occurson a background ofimmunosuppressivetherapy, primary or HIVrelated immunodeficiencyand may resolve with areduction inimmunosuppression.Acute parvovirus infectionassociated with transientaplastic crisis requiresurgent transfusion ratherthan Immunoglobulin.1 – 1.2g/kg in divideddoses. This may berepeated on relapse andfor a 2nd relapseRise in haemoglobinYesTransfusion independenceReticulocyte count1-2g/kg in two to fivedivided doses. This may berepeated on relapse andfor a 2nd relapseRise in haemoglobinTransfusion independenceReduction in haemolysismarkers (bilirubin, lactatedehydrogenase)No – for treatmentof acute episodesYes – for repeatcourses
Post-transfusionhyperhaemolysis –short term use Prevention ofhaemolysis inpatients with ahistory oftransfusionassociatedhyperhaemolysisPrevention ofdelayed haemolytictransfusion reactionevidence of fetal anaemia.Neonates of mothers with AHA whohave evidence of haemolysis andrising bilirubin despite intensivephototherapyTreatment of acute post-transfusionhyperhaemolysis:Symptomatic or severe anaemia (Hb 6g/dL, with evidence of on-goingintravascular haemolysis due to adelayed haemolytictransfusion/hyperhaemolysis). It isrecognised that some patients withan Hb 6 g/dl may requiretreatment.No2g/kg (usually over twodays) given with IVmethylprednisoloneRise in haemoglobinNoTransfusion IndependenceReduction in haemolysismarkers (bilirubin, lactatedehydrogenase)Patients who have had previous delayedhaemolytic transfusion reactions/posttransfusion hyperhaemolysis or whohave single or multiple allo-antibodiesAND who may require a bloodtransfusion1-2g/kg over two or fivedays given with steroidsNo haemolysis1 – 2 g/kg over 2 to 5days, given with IVmethylprednisoloneMaintenance of posttransfusion Hb at 1 – 3weeksAvoidance of need forrepeated transfusionCoagulation factorinhibitors*(alloantibodies andautoantibodies) –short term use:Acquired von Willebrand disease (VWD): Life- or limb-threateninghaemorrhage, AND Failure to respond to othertreatments, AND/OR Prior to invasive procedure Treatment directed by thehaemophilia centre at which thepatient is registeredAcquired VWDassociatedwith IgMmonoclonalgammopathyHaemophagocyticsyndrome – shortterm use: No Diagnosis by consultanthaematologist based on bonemarrow biopsy, AND ORPancytopenia, ANDNon-response to conventionalImmunoglobulin Commissioning Guidelines V1.0 Dec 2018Immunoglobulin is atherapeutic option inacquired VWD,particularly in casesassociated with a IgGmonoclonal gammopathyalongside other therapies– plasmapheresis,desmopressin, VWFcontaining concentratesand recombinant FactorVII.Either 0.4g/kg for five daysor 1g/Kg for two daysRise of factor levelYesResolution of bleedingNumber of bleedingepisodes2g/kg in two to five divideddoses. This may berepeated on relapse andfor a 2nd relapseImprovement of cytopeniasSurvivalImprovement of HLHmarkers – Ferritin/solubleYes
Post-transfusionpurpura – short termuse: treatment (e.g. corticosteroids,immunosuppressive agents,chemotherapy), ORConventional treatment is contraindicated or inappropriateSudden severe thrombocytopenia 5to 10 days post-transfusion of bloodproducts, ANDActive bleeding (typically occurs inCaucasian HPA-1a antigen negativefemales previously exposed to HPA1a antigen in pregnancy ortransfusion)Immunoglobulin Commissioning Guidelines V1.0 Dec 2018CD25NoThere are now very fewcases in UK following theimplementation ofuniversal leucocytereduction of bloodcomponents in 1999.1 - 2g/kg in divided dosesover two to five daysIncrease in platelet countResolution of bleedingNumber of bleedingcomplicationsNo
Use of Immunoglobulin in Neurology:Immunoglobulin is routinely commissioned in the following indications, under the circumstances described:IndicationEligibility criteria:Exclusioncriteria:CIDP (including IgGor IgA athy)Probable or definite diagnosis of CIDP by aneurologist according to theEFNS/International Peripheral Nerve SocietyGuidelines;No specificexclusioncriteria butsee ge
prolonged antibiotic prophylaxis. Ig is reserved for those patients in whom antibiotic prophylaxis proves to be ineffective. Initiate trial at 0.4– 0.6 g/kg/month for a period of 6 to 12 months; Long-term maintenance treatment should be based on clear evidence of benefit from this trial and require panel approval. Dose requirements may .
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