2016 EADV 欧洲指南_皮肤科大剂量静脉注射免疫球蛋白的应用[英语]

ORIGINAL ARTICLE

European Guidelines(S1)on the use of high-dose intravenous immunoglobulin in dermatology

A.H.Enk,1,*E.N.Hadaschik,1R.Eming,2G.Fierlbeck,3L.E.French,4G.Girolomoni,5M.Hertl,2S.Jolles,6 S.Karpati,7K.Steinbrink,8G.Stingl,9

B.Volc-Platzer,9D.Zillikens10

1Department of Dermatology,Ruprecht-Karls-University Heidelberg,Heidelberg,Germany

2Department of Dermatology,Philipps-University Marburg,Marburg,Germany

3Department of Dermatology,Eberhard-Karls-University T€u bingen,T€u bingen,Germany

4Department of Dermatology,University of Zurich,Zurich,Switzerland

5Department of Dermatology,University of Verona,Verona,Italy

6Immunode?ciency Centre for Wales,University Hospital of Wales,Cardiff,UK

7Department of Dermatology,Semmelweis University Budapest,Budapest,Hungary

8Department of Dermatology,Johannes Gutenberg-University Mainz,Mainz,Germany

9Department of Dermatology,Medical University of Vienna,Vienna,Austria

10Department of Dermatology,University of L€u beck,L€u beck,Germany

*Correspondence:A.H.Enk.E-mail:Alexander.Enk@med.uni-heidelberg.de

Abstract

Background The treatment of severe dermatological autoimmune diseases and toxic epidermal necrolysis(TEN)with high-dose intravenous immunoglobulin(IVIg)is a well-established procedure in dermatology.As treatment with IVIg is usually considered for rare clinical entities or severe clinical cases,the use of immunoglobulin is not generally based on data from randomized controlled trials that are usually required for the practice of evidence-based medicine.Owing to the rarity of the indications for the use of IVIg,it is also unlikely that such studies will be available in the foreseeable future.Because the high costs of IVIg treatment also limit its?rst-line use,the?rst clinical guidelines on its use in derma-tological conditions were established in2008and renewed in2011.

Materials and methods The European guidelines presented here were prepared by a panel of experts nominated by the EDF and the EADV.The guidelines were developed to update the indications for treatment currently considered as effective and to summarize the evidence base for the use of IVIg in dermatological autoimmune diseases and TEN. Results and conclusion The current guidelines represent consensual expert opinions and de?nitions on the use of IVIg re?ecting current published evidence and are intended to serve as a decision-making tool for the use of IVIg in der-matological diseases.

Received:22October2015;Accepted:9February2016

Con?icts of interest

Con?icts of interest statement presented in the appendix.

Funding sources

None declared.

Introduction

Immunoglobulin preparations are obtained from the pooled plasma of between3000and approximately10000individual donors.Pooling is performed to provide a species repertoire rep-resenting all antibodies and also natural autoantibodies.

Given the large number of donors,the potential risk of trans-mission of infectious agents such as viruses must be borne in mind.In order to ensure a high level of quality and maximum safety,all manufacturers of preparations derived from human plasma must adhere to European guidelines when obtaining and processing plasma.The Committee for Proprietary Medicinal Products of the European Medicines Agency and the Mono-graph in the European Pharmacopoeia govern writing and regu-lar updating of these guidelines.

The following issues are regulated:how plasma is obtained, the screening of donated plasma,viral safety issues,methods of biological and pharmacological characterization and the testing of end products for clinical ef?cacy.The national authorities are

DOI:10.1111/jdv.13725JEADV

responsible for authorizing the preparations,in that they carry out testing and de?ne from which countries blood and plasma may be obtained.The national authorities are also responsible for the regular inspection of the manufacturing process and for virological testing,as well as for the approval of any changes to the manufacturing process.

The manufacturing pathway for immunoglobulin prepara-tions starts with the identi?cation of suitable donors.These donors must be healthy and must not have any signs of infec-tions or chronic diseases.All plasma donations must be free of HBs antigen and anti-HCV antibodies as well as negative for HIV-1and HIV-2antibodies.All plasma donations are also sub-ject to a‘lookback’procedure with a holding period of at least 60days.Any seroconversion of a donor occurring during this time can thus be detected and all stored plasma from the donor will be destroyed.Nucleic acid ampli?cation technology(poly-merase chain reaction)is used to screen the plasma from indi-vidual donors as well as the resulting plasma pool for the presence of HCV RNA,HBV DNA,HIV RNA,HAV RNA and Parvovirus B19DNA.In the event of a reactive?nding,the rele-vant plasma donations will be rejected/the plasma pool destroyed.Besides immunoglobulin concentration steps,plasma processing includes several independent process steps for virus inactivation/removal.A range of both enveloped and non-envel-oped model viruses are used to spike the test preparations in order to quantify and validate the log reduction in virus of each individual step in the process.In addition to the antiviral prop-erties of the manufacturing processes,there are a number of dedicated steps for virus inactivation/removal which vary between manufacturers.For each batch of immunoglobulin manufactured,a certi?cate is produced which provides informa-tion on the main biological and pharmacological properties,the degree of purity and the antibody spectrum.

Besides viral safety,the clinical ef?cacy of the immunoglobu-lin preparations is also tested during this manufacturing process. Testing of functional integrity,determination of neutralizing antibodies and monitoring of immunomodulatory in?amma-tory properties is carried out on the basis of established test methods.Studies are also required in patients with primary anti-body de?ciencies.The successful treatment of patients with chronic idiopathic thrombocytopenic purpura(ITP)is consid-ered as evidence of the immunomodulatory activity of a prepa-ration.

All the IVIg preparations which are commercially available at the present time consist of intact IgG molecules with an IgG sub-class distribution which corresponds to the normal range.The half-life of IVIg in normal individuals is approximately3weeks. The F C region of the IgG permits interaction and signal trans-duction by F C gamma receptors on a range of immune cells.The mechanism(s)of action of immunoglobulins is complex and has not been elucidated completely in vivo.There has been signi?-cant progress in understanding the multiple potential mechanisms of action of immunoglobulin and it is likely that in any particular condition more than one mechanism may be operative.The roles played by F C receptors such as the inhibitory receptor Fc c RIIB,the effects of Fc sialylation,as well as changes in regulatory T cells(Tregs)and the TH17pathway have received recent attention.1–4Immunoglobulins have been used for more than50years in the treatment of diseases associated with primary and secondary immune de?ciency.Side-effects of the current generation of products are generally considered to be minimal,however,when using high-dose therapy,physicians should be aware of uncommon serious adverse events such as thromboembolic complications.In dermatology,IVIg is used mainly in the treatment of autoimmune diseases and toxic epi-dermal necrolysis(Tables1and2).5Although the list of diseases treated is long,it is generally based on small series or isolated case reports in uncontrolled studies.This is partly because the number of patients with these rare conditions is too small for large studies and it is usually dif?cult to compare the patients because of the very heterogeneous clinical courses and because of the concomitant medication used.As a result of the high costs of treatment,use of the preparations has to be highly selective, which makes it even more dif?cult to?nd large case series.

The aim of the current guidelines was to answer the following questions for each clinical condition(Fig.1):

1Diseases for which IVIg is indicated?

2Use of IVIg as?rst-or second-line

treatment?

Table1Indications for the use of IVIg

Severe forms of autoimmune blistering diseases

Severe systemic vasculitic syndromes

Severe forms of lupus erythematodes

Severe forms of collagen vascular diseases

Livedoid

vasculopathy

Table2Recommended dosage regimens

Treatment interval Initially every4weeks/after6months gradually

*3g/kg bodyweight in toxic epidermal necrolysis.

?Only one cycle in Kawasaki0s disease and toxic epidermal necrolysis.

2Enk et al.

3Initial duration of treatment?

4Interval between IVIg infusion cycles?

5Dosing of immunoglobulin therapy?

6Duration of treatment per IVIg cycle?

7Methods available for assessing therapeutic ef?cacy?

8Long-term treatment advisable?

Dermatomyositis

Dermatomyositis is the condition in which the highest level of evidence exists for treatment with IVIg besides pemphigus vul-garis.6There are numerous individual case reports and small case series7as well as a double-blind,placebo-controlled cross-over study,which demonstrate the ef?cacy of IVIg.8The follow-ing criteria were drawn up by the European Guidelines working group:

1Indications.All severe forms of dermatomyositis,inclusion body myositis and polymyositis represent indications for the use of IVIg.9This applies also to what is referred to as idio-pathic,paraneoplastic or juvenile forms10respectively.

2Timing of treatment.The data available for these diseases jus-ti?es the early use of IVIg in dermatomyositis.In patients

with a fulminant course,severe myolysis or paralysis,?rst-line treatment with immunoglobulins may be justi?ed.As a general rule,IVIg should be used as a second-line treatment if steroid monotherapy has failed to produce an improve-ment after1month,or if reducing the steroid dose below an acceptable level results in a?are-up of the disease,or if side-effects prevent further steroid medication.

The use of IVIg therapy is considered to be an adjuvant treat-ment with continuation of immunosuppressive therapy with corticosteroids and possibly also other immunosuppressive agents.11IVIg monotherapy has generally been less effective.

From the immunological perspective,suf?cient bone marrow function needs to be available given the concomitant immunosuppressive therapy.Therefore,treatment onset should not be delayed for too long.

3Initial duration of treatment.Initial treatment should be car-ried out over a period of6months in order to determine the ef?cacy of treatment with IVIg.If therapeutic ef?cacy has not been achieved after6treatment cycles,the IVIg treatment should be discontinued.After18treatment cycles,a washout period should be attempted.It is possible to increase the

High-dose IVIg in dermatology3

interval between infusions to a maximum of6weeks before-hand.In the event of recurrences,treatment can be resumed at any time.This recommendation needs to be adapted to the course of disease for each individual patient(some patients need longer treatment).

4Interval between infusions.Initially,adjuvant IVIg therapy should be administered every4weeks.If a good clinical response is achieved,the interval can be increased gradually to a maximum of6weeks.Longer intervals between infu-sions are not recommended because of the half-life of IVIg (approximately3weeks).

5IVIg dosing.The bulk of evidence with respect to the use of IVIg in dermatological autoimmune diseases has been obtained with a dose of2g/kg bodyweight per treatment cycle.Because there is no clear evidence of ef?cacy with lower doses,adherence to the aforementioned dose recommenda-tions is advised in these serious diseases.

Although there has been one report on the successful use of subcutaneously applied Ig in polymyositis and dermato-myositis in seven patients,this study awaits con?rmation in larger patient cohorts.12Therefore,s.c.Ig cannot generally be recommended in dermatomyositis.

6Period of IVIg administration.Administration of the immunoglobulin should be spread over2-5consecutive days.

Tolerability is generally better with greater dose fractionation.

In patients with cardiac or renal impairment,immunoglobu-lin preparations should be administered over a longer period of time.If the treatment is well tolerated at the beginning,it can generally also be carried out on an outpatient basis.

7Evaluation of therapeutic ef?cacy.The clinical picture is the most important parameter for evaluating the ef?cacy of treat-ment in dermatomyositis,with evaluation of muscle strength playing the most important role.Autoantibody titres,on the other hand,do not re?ect the response to treatment.In gen-eral,creatine kinase and muscle aldolase levels also return rapidly to normal under immunosuppressive therapy.This prohibits their use as indicators of ef?cacy.MRI or ultra-sonography of the proximal muscle groups is important for the initial diagnosis as is speci?c muscle biopsy,but are unsuitable for close monitoring.The criteria for evaluating the clinical response is therefore normalization of muscle strength with gradual tapering of the steroid dose,fading of erythema and gradual resolution of other parameters such as Gottron’s papules while on IVIg therapy.It is our experience that a response can be detected from the second treatment cycle on,mainly by the patient(especially on the basis of the improvement in muscle strength)but also by the treating physician.Nevertheless,tapering the concomitant medication too rapidly should be avoided.Between three and four treat-ment cycles are often required before a signi?cant improve-ment in symptoms is seen and in severely affected patients, extension of treatment intervals needs to be done with care.8Long-term IVIg therapy.In rare cases,long-term therapy may be necessary in patients with severe dermatomyositis and a prolonged course,although therapy-cessation periods should be attempted to allow the effects of the IVIg therapy on the course of the disease to be assessed.

Autoimmune blistering diseases

The autoimmune blistering diseases are autoantibody-mediated disorders,the autoantigens of which are largely known and have been molecularly characterized.Autoimmune blistering diseases are generally treated by dermatologists only and are therefore of great importance for our speciality.The following recommenda-tions were drawn up for the use of IVIg in these diseases:

1Indication.All severe forms of autoimmune blistering diseases, which are refractory to therapy or relapsing after therapy13 represent an indication for the use of IVIg.In fact,a random-ized controlled trial14as well as an extensive literature review15 have con?rmed these evidence levels.The experiences are par-ticularly good in pemphigus vulgaris,pemphigus foliaceus, mucous membrane pemphigoid16and epidermolysis bullosa acquisita.However,the use of IVIg may also be indicated in severe forms of bullous pemphigoid,linear IgA disease,IgA pemphigus or paraneoplastic pemphigus.

2Timing of treatment.On the basis of the scienti?c evidence available,the use of IVIg cannot be recommended as a ?rst-line treatment.However,contraindications to standard immunosuppressive therapy(e.g.aseptic bone necrosis, poorly controlled diabetes or advanced osteoporosis and cat-aracts)may justify the use of IVIg as a?rst-line treatment in isolated cases.Consequently,immunoglobulins should pri-marily be used as a second-line treatment following suf?cient combination therapy with steroids(e.g.prednisolone1–2mg/kg bodyweight per day)and another immunosuppres-sive agent,e.g.azathioprine or mycophenolate mofetil.17,18 Here again,IVIg is an adjuvant therapy,which must be administered while continuing the conventional immuno-suppressive therapy.IVIg may also be considered in patients treated with rituximab in whom suf?cient disease control was not attained.This also means that immunoglobulin use should not be delayed for too long because adjuvant treat-ment is useful only with concomitant immunosuppressive therapy and this requires adequate bone marrow function.

Monotherapy with immunoglobulin is generally not recom-mended.

3Initial duration of treatment.Treatment should be adminis-tered initially for a period of between3and6months in order to assess the ef?cacy of the IVIg in each individual case.

Some patients do not show a de?nitive sustained response until they have undergone up to six cycles of treatment.If a therapeutic response cannot be documented after six cycles of therapy,IVIg treatment should be discontinued.This rec-ommendation needs to be adapted to the course of disease

4Enk et al.

for each individual patient(some patients may need longer treatment).

4Interval between infusions.Adjuvant therapy with IVIg should be administered every4weeks initially.If the clinical response is good,the interval between infusions can be increased gradually to a maximum of6weeks.Longer inter-vals are not recommended because of the half-life of IVIg.

5Dosing.As already mentioned above,most studies have used

a total dose of2g/kg bodyweight by intravenous infusion.

Because only insuf?cient data are available at present for higher or lower doses,this dosage should be considered as the standard recommendation at present.

6Period of treatment.As already mentioned above,treatment should be administered over a period of2–5days,with frac-tionated administration of the IVIg therapy contributing to better tolerability.

7Evaluation of treatment ef?cacy.Both clinical and serological parameters are used for evaluating the ef?cacy of treatment in most blistering autoimmune diseases.The criteria for eval-uating the clinical picture are therefore cessation of blistering and healing of existing lesions under adjuvant IVIg therapy.

At the same time,a moderate reduction in concomitant immunosuppressive treatment should be possible without recurrence.Serological parameters such as IgG autoantibody titres measured by ELISA or indirect immuno?uorescence microscopy may provide an additional parameter to evaluate the therapeutic ef?cacy of IVIg.

8Long-term therapy.Long-term therapy with IVIg is recom-mended only in rare cases especially when mucous mem-branes are severely affected.An exception to this are patients in whom disease recurrence occurs after withdrawal of IVIg therapy and no other treatment options exist,and if this is the case,combination therapy with rituximab may be consid-ered.Regular washout periods should be attempted. Vasculitic syndromes

Vasculitic syndromes are systemic in?ammatory conditions which affect the blood vessels of one or more organ system.A distinction is made between primary and secondary systemic vasculitic syndromes.Because the skin is often involved as an indicator organ and the conditions often prove highly refractory to treatment,immunoglobulin is often considered as a therapeu-tic alternative.The following recommendations can be made on the basis of our current state of knowledge:

1Indication.Kawasaki’s disease is the only disease in this cate-gory for which IVIg is the?rst-line treatment.In all other cases,primary treatment generally consists of high-dose cor-ticosteroids together with additional immunosuppressive agents such as cyclophosphamide or others.The use of these aggressive immunosuppressive regimens is often associated with severe side-effects,and recurrences occur on withdrawal or dose reduction.In patients who do not respond to

standard therapy or those with a particularly fulminant pro-gressive disease,IVIg therapy may be considered as an early treatment option.All forms of severe vasculitis19can repre-sent potential indications for IVIg.20Particularly,positive results have been achieved in primary vasculitis,e.g.chronic polyangiitis(Wegener’s granulomatosis),polyarteritis nodosa,IgA-associated vasculitis,Churg–Strauss disease,21 microscopic polyangiitis and in secondary autoimmune vas-culitis.Good results have also been achieved in patients with anti-phospholipid antibody syndrome.22

2Timing of treatment.IVIg is only approved for Kawasaki0s syndrome as a?rst-line treatment.As already mentioned above,treatment in all other indications is considered as adjuvant therapy only after failure of immunosuppressive therapy or in the presence of contraindications.The early use of IVIg may,however,prevent massive tissue destruction and thus reduce the extent of damage in conditions such as haem-orrhagic necrotizing vasculitis of the skin or in Wegener’s granulomatosis.

3Initial duration of treatment.As with the aforementioned indications,a treatment period of3–6months is useful ini-tially in order to obtain a clear idea of the response to treat-ment.

4Interval between infusion.As described above,treatment should be administered at4-week intervals initially.If the clinical response is good,the intervals between infusions can be extended gradually to a maximum of6weeks.A clear ben-e?t of longer treatment intervals has not been documented. 5Dosing.The recommended dose for the treatment of Kawasaki syndrome in children is again1.6–2g/kg body-weight per treatment cycle(as bolus infusion or divided into single infusions given over2–5days)in addition to the recommended administration of acetylsalicylic acid with an initial dose of50mg/kg bodyweight per day.On the basis of this,all case series of patients with systemic vasculitic syndromes have so far been treated with a total dose of2g/kg bodyweight.

6Duration of treatment.Treatment should be administered over a period of2–5days,with a longer duration of treat-ment being associated with fewer side-effects.In the case of systemic vasculitis with renal involvement in particular,the infusion rate should be reduced or possibly a reduced dose should be used(e.g.a total of1g/kg bodyweight).

7Evaluation of treatment ef?cacy.The clinical response should be the main criterion used for evaluating therapeutic ef?cacy.

Because organ involvement is rather heterogeneous,only general recommendations can be expressed here.The pattern of c-reactive protein(CRP)and organ-speci?c laboratory tests,can be used as indicators of response.As an example,in Wegener’s granulomatosis,the c-ANCA titre and level of the proteinase3(PR3)ELISA can be used as additional indica-tors.

High-dose IVIg in dermatology5

8Long-term therapy.Long-term therapy with IVIg is recom-mended only in exceptional cases.

Lupus erythematosus,and other collagen vascular diseases

Almost all autoimmune connective tissue diseases have already been treated experimentally with IVIg in small series.The best data exist for systemic lupus erythematosus.The following rec-ommendations are proposed:

1Indication.All severe cases of lupus erythematosus can repre-sent an indication for attempted treatment with IVIg if no other treatment options are available.Its use in systemic lupus erythematosus,especially in lupus nephritis,23is considered effective.Less clear are the data in patients with scleroderma, in which no clear recommendation can be expressed.24Care should be taken in the setting of connective tissue disease as the infusion of IVIg in patients with high titre rheumatoid factor(RF)has been associated with renal damage.

2Timing of treatment.The use of IVIg is generally not a?rst-line treatment option.Previous combination treatment with steroids and another immunosuppressive associated with a poor response or severe complications is considered an indi-cation for the use of IVIg.Again,however,the use of IVIg should not be delayed for too long in conditions such as lupus nephritis to avoid tissue damage.Here too,treatment should be given in combination with adequate immunosup-pressive therapy.

3Initial duration of treatment.As with the aforementioned conditions,application of IVIg is initially recommended over

a period of6months.If there has been no response to treat-

ment after this time,treatment should be discontinued.

4Interval between infusions.The initial interval between infu-sions should again be4weeks.The interval between the indi-vidual bolus infusions can then be increased gradually to 6weeks.Any additional increase in the interval is not useful because of the half-life of immunoglobulin.

5Dosing.Again,the only experience available in the conditions listed above is with the standard dose of2g/kg bodyweight.

This should be adopted as the standard recommendation.

6Treatment period.Treatment should be administered over a period of2–5days.In the case of severe organ involvement such as kidney or heart involvement in particular,the treat-ment period should be increased to5days.

7Evaluation of treatment ef?cacy.The focus is again on the clinical evaluation of treatment ef?cacy.Because this is a very heterogeneous group of diseases,it is only possible to express the general recommendation that improvement in primary organ involvement(e.g.protein excretion in the urine) should be used as an indicator of response.In isolated cases, the pattern of disease-speci?c autoantibodies such as double-strand DNA antibodies can be used as an indicator of response in systemic lupus erythematosus.8Long-term therapy.Long-term therapy can be recommended only in exceptional cases.

Scleromyxedema

Scleromyxedema is a severe multi-organ condition characterized by?broblast proliferation and mucin deposition in skin and internal organs associated with monoclonal gammopathy in the majority of cases.Thickening and?brosis of skin often cause a debilitating situation and internal organ involvement can put the patient’s life at risk.25,26Scleromyxedema is refractory to most classical immunosuppressive therapies,but responds quickly to treatment with IVIg,as documented in many case reports and in small case series.27,28The body of evidence on ef?cient therapy of scleromyxedema with IVIg has substantially grown since the?rst report of ef?cacy in200026,29leading to the addition of this disease to the current guidelines.The following recommendations are proposed:

1Indication.All severe cases of scleromyxedema represent an indication for a treatment attempt with IVIg as treat-ment with other immunosuppressive agents is often not effective.Its use in scleromyxedema is considered effec-tive.26,30,31

2Timing of treatment.IVIg should be considered treatment of choice in refractory cases of scleromyxedema with either fast deterioration of skin symptoms,the dermato-neuro syn-drome or life-threatening involvement of internal organs.In milder cases,initial treatment with immunosuppressive regi-mens should be undertaken.Failure to respond to such treat-ment or contraindications to such treatments justify initiation of treatment with IVIg.In scleromyxedema no additional treatments are needed besides IVIg.

3Initial duration of treatment.As with the other conditions, the use of IVIg is initially recommended over a period of 6months.If there has been no response to treatment after this time,treatment should be discontinued.

4Interval between infusions.The initial interval between infu-sions should be4weeks.The interval between the individual bolus infusions can then be increased gradually to6weeks.

Any additional increase in the interval is not useful because of the half-life of immunoglobulin.

5Dosing.Most experience in scleromyxedema exists with the standard dose of2g/kg bodyweight.This should be adopted as the standard recommendation.

6Treatment period.Treatment should be administered over a period of2–5days.In the case of severe organ involvement such as kidney or heart involvement in particular,the treat-ment period should be increased to5days.

7Evaluation of treatment ef?cacy.The focus lies on the clinical evaluation of treatment ef?cacy.As skin involvement is pre-sent in nearly all cases and responds very well to treatment with IVIg,it should be used as an indicator of response.In isolated cases,clinical response to CNS or internal organ

6Enk et al.

involvement can be used as additional indicator of response in scleromyxedema.

8Long-term therapy.It has been documented in several cases that after discontinuation of IVIg there are relapses.26,32If a relapse is severe and life-threatening,long-term therapy can be recommended in exceptional cases.

Toxic epidermal necrolysis

Toxic epidermal necrolysis represents a life-threatening side-effect of drugs.33The condition is associated with Fas(CD95) and granulysin-mediated apoptosis,as well as annexin A1-mediated necroptosis of epidermal keratinocytes.34Therefore,it is assumed that antibodies interfering with these apoptotic path-ways(and contained in IVIg preparations)might be bene?cial in this disease.35Because of its life-threatening and fulminant pro-gressive course with detachment of large areas of the epidermis in severe cases,these patients are at acute risk of infection and must receive intensive care.The condition is nevertheless lethal in up to40%of cases.The following recommendations have been drawn up for the use of IVIg:

1Indication.In certain studies,the early administration of high doses of IVIg in toxic epidermal necrolysis was suggested to be potentially life-saving.A systematic review and meta-ana-lysis of observational controlled studies published before31 July2011indicated that high-dose IVIg(≥2g/kg)was associ-ated with signi?cantly lower mortality than low-dose IVIg (<2g/kg,P=0.022).36The pooled odds ratio for mortality in patients treated with IVIg(all doses confounded)vs.sup-portive care was,however,not signi?cantly reduced at0.63 (P=0.27).A subsequent meta-analysis of13published stud-ies between1996and2011in which severity of disease had been determined with SCORTEN,revealed again a non-sig-ni?cant reduction in standardized mortality rate of0.322 (P=0.155)in patients treated with IVIg(all doses con-founded),but a strong and signi?cant inverse correlation between IVIg dosage and standardized mortality rate (P=0.009),showing that IVIg at dosages of≥2g/kg signi?-cantly decreased mortality compared to that expected in patients with SJS or TEN.37Although the mechanism of action remains unclear,the early administration of high-dose immunoglobulin may be considered in con?rmed cases of toxic epidermal necrolysis in the absence of an alternative evidence-based therapeutic alternative given that the poten-tial bene?ts of high-dose IVIg outweigh the risks of the medi-cation and the disease’s natural course.

2Timing of treatment.Unlike in the aforementioned condi-tions,IVIg should be administered as soon as possible after con?rmation of the diagnosis.IVIg treatment can then be administered as monotherapy in addition to supportive mea-sures including intensive care.The concomitant administra-tion of corticosteroids or immunosuppressive agents is controversial.3Initial duration of treatment.Only one cycle of treatment is usually required in this condition,administered over a period of3–5days.

4Dosing.The dose recommendation in toxic epidermal necrol-ysis differs from that in autoimmune diseases.A total dose of at least3g/kg bodyweight is generally recommended.Frac-tionated administration(over3–5days)is required,particu-larly in the case of risk factors including renal impairment, pre-existing cardiovascular disease and diabetes in these patients.

5Evaluation of treatment ef?cacy.The cessation of ongoing epi-dermal detachment and the onset of re-epithelialization are good clinical parameters for evaluating treatment ef?cacy, but survival remains the most valid clinical outcome mea-sure.The contribution of IVIg to the healing process is dif?-cult to assess.

6Long-term therapy.Not applicable.

Other possible treatment indications

IVIg has been described as an effective treatment method in numerous clinical conditions in dermatology.Some of the more frequent entities will be mentioned here,although a conclusive assessment is not possible at present(Table1).

Atopic dermatitis According to the literature available and iso-lated case reports,the use of IVIg should de?nitely be considered in the most severe forms of atopic eczema.According to reports in the literature,healing can in some cases be signi?cantly accel-erated in cases which are refractory to conventional treat-ment.38,39

Autoimmune urticaria The use of immunoglobulin can also be considered as a last resort in severe cases of autoimmunologi-cally mediated urticaria.Only single case reports and smaller case series are available at present in this indication,and these describe the successful use of immunoglobulin at the aforemen-tioned standard dose.39A conclusive assessment of these reports is not possible at the present time and newer therapies including anti-IgE monoclonal antibodies may play a greater role in ther-apy-resistant urticaria in the future.

Pyoderma gangrenosum The use of IVIg can be considered as an option in severe refractory cases of pyoderma gangrenosum. As only small case series are available at present time,no general consensus statement is possible at present time.

Livedoid vasculopathy Numerous case studies have reported on the successful use of IVIg in therapy-resistant livedoid vasculopathy.40,41Although no general recommendation can be given at this point,the amount of evidence for a positive effect of IVIg is increasing,justifying their use in desperate cases.

High-dose IVIg in dermatology7

Summary

The treatment recommendations presented for the use of IVIg in dermatology highlight the importance of IVIg therapy in numer-ous de?ned dermatological autoimmune diseases and in toxic epidermal necrolysis.The value of IVIg therapy in diseases which are otherwise refractory to treatment is undisputed.Clear treat-ment recommendations can therefore be given for the diseases described above(Tables1and2).Because the exact mechanisms of action of IVIg in vivo are still unclear in these conditions,fur-ther efforts should be made to launch randomized controlled tri-als despite the rarity of some of the disorders described.The current guideline recommendations are intended to create a basis for future randomized controlled trials.The implementa-tion of this EU guideline in general practice means that the use of IVIg in dermatology will be optimized throughout Europe. Methodology/Additional information

The European guidelines presented here were prepared by a panel of experts nominated by the EDF and the EADV in order to present the indications for treatment currently considered as effective and to summarize the evidence base for the use of IVIg. These guidelines are intended to support informed therapeu-tic decision-making on the use of IVIg for dermatologists.

The current guidelines represent consensual expert opinions and de?nitions on the use of IVIg re?ecting current published evidence.The guidelines were prepared based on two rounds of evaluation of the previous guidelines(2011)with an individual update by each representative expert on the panel followed by a separate meeting of all panel members with discussion on the identi?ed topics.The email-based evaluation period and the fol-lowing expert panel meeting with discussion were coordinated and moderated by Professor Dr.med.A.Enk.An informal con-sensus was reached during the panel discussions,a structured formal consensus procedure was not applied.

The guidelines project did not receive?nancial support.The expert group did not receive?nancial incentives or reimburse-ment for the participation in the guidelines development.The summary of evidence was done independently from industrial interest.

A declaration of potential con?icts of interest(COI)adapted from the International Committee of Medical Journal Editors was required for the participation in the guidelines development. COIs were discussed.The expert group did not see any substan-tial con?icts of interest and there were no further comments or remarks.COI of each person involved in the guidelines develop-ment are presented in the appendix.

External reviewing was done according to EDF SOP for guide-lines development over a period of4weeks,including the mem-bers of the EDF guidelines commission,the EADV Board and the Union Europ e enne des M e decins Sp e cialistes.During the review period,the draft was piloted within the departments of the participating https://www.wendangku.net/doc/d44507596.html,ments and necessary changes coming from the external review were being discussed among the authors.European guidelines are subject to national or regional adaptation with consideration of local circumstances (regulatory approval and availability of treatments,health care provider and insurance systems).Thus,the national medical societies associated to the EDF will be responsible for the adap-tion and implementation of the guidelines on a national level. Due to the increasing amount of publications,guidelines need to be continually updated to re?ect the recent state of evidence. After31December312019,these guidelines will expire.Should important changes occur in the meantime,such as new available interventions,new important evidence or withdrawal of drug licensing,the information contained in the guidelines will be updated earlier.In these cases,an update issue of the guidelines is needed earlier.The EDF in cooperation with the current guidelines coordinator(Enk)will be responsible to initiate an update.

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High-dose IVIg in dermatology9

Appendix

2Consulting fee or honorarium

3Support for travel to meetings for the study or

other purposes

4Fees for participation in review activities,such as data monitoring boards,statistical analysis,

end point committees,and the like

5Payment for writing or reviewing the manuscript

6Provision of writing assistance,medicines,equipment, or administrative support

7Other

Relevant?nancial activities outside the submitted work

1Board membership

2Consultancy Biotest AG

MSD Oncology

Galderma Lab.

Janssen-Cilag

Abbvie Novartis Galderma

3Employment

4Expert testimony

5Grants/grants pending Fresenius Medical

Care

6Payment for lectures including service on speakers bureaus Biotest Bristol-Myers-Squibb

Roche Pharma

7Payment for manuscript preparation

8Patents(planned,pending or issued)

9Royalties

10Payment for development of educational presentations

11Stock/stock options

12Travel/accommodations/meeting expenses unrelated to

activities listed*

13Other(err on the side of full disclosure)

Other relationships

1Are there other relationships or activities that readers

could perceive to have in?uenced,or that give the

appearance of potentially in?uencing,what you wrote

in the submitted work?

*For example,if you report a consultancy above there is no need to report travel related to that consultancy on this line.

10Enk et al.

Fresenius Baxalta

2Consulting fee or honorarium GSK

UCB

Almirall CSL Behring Baxalta Biotest

3Support for travel to meetings for the study or other purposes Fresenius CSL Behring

Baxalta

4Fees for participation in review activities,

such as data monitoring boards,statistical

analysis,end point committees,and the like

GSK UCB Pharma

5Payment for writing or reviewing the manuscript

6Provision of writing assistance,medicines,

equipment,or administrative support

7Other

Relevant?nancial activities outside the submitted work

1Board membership

2Consultancy Biogen Idec

Biotest Shire SOBI BPL NISCHR

3Employment

4Expert testimony

5Grants/grants pending SOBI

Binding Site 6Payment for lectures including service on

speakers bureaus

Janssen-Cilag

7Payment for manuscript preparation

8Patents(planned,pending or issued)

9Royalties

10Payment for development of educational presentations Janssen-Cilag

11Stock/stock options

12Travel/accommodations/meeting expenses unrelated to activities listed*AbbVie Janssen-Cilag

13Other(err on the side of full disclosure)

Other relationships

1Are there other relationships or activities that readers

could perceive to have in?uenced,or that give the

appearance of potentially in?uencing,what you wrote

in the submitted work?

*For example,if you report a consultancy above there is no need to report travel related to that consultancy on this line.

High-dose IVIg in dermatology11

Almirall

Euroimmun Inc 2Consulting fee or honorarium Almirall

Miltenyi

UCB Inc.

Biogen

Dompe

Roche

Fresenius

arGEN X Belg.

3Support for travel to meetings for the

study or other purposes

4Fees for participation in review activities,

such as data monitoring boards,statistical

analysis,end point committees,and the like

5Payment for writing or reviewing the

manuscript

6Provision of writing assistance,medicines,

equipment,or administrative support

7Other

Relevant?nancial activities outside the submitted work

1Board membership

2Consultancy Af?ris

Bayer Healthcare

Delenex

Eli Lilly

Merck Sharp&Dohme

Novartis Novartis Euroimmun Inc.

Almirall

UCB

Fresenius

arGEN X,Belg.

3Employment

4Expert testimony

5Grants/grants pending CSL Behring Euroimmun Inc.

Miltenyi Inc.

Fresenius Inc.

Biotest Inc.

Dompe Inc.

Almirall

Biogen

Roche

6Payment for lectures including service on speakers bureaus AbbVie

Delenex

DiaSorin

Janssen-Cilag

Merck Sharp&Dohme

Novartis

Pelpharma

Bayer

Galderma

MEDA

Biotest

CSL Behring

Biotest

Fresenius Inc.

Miltenyi Inc.

Roche Pharma Inc.

7Payment for manuscript preparation

8Patents(planned,pending or issued)Euroimmun Inc.

9Royalties

10Payment for development of educational

presentations

11Stock/stock options

12Enk et al.

High-dose IVIg in dermatology13 Continued

Other relationships

1Are there other relationships or activities

that readers could perceive to have

in?uenced,or that give the appearance of

potentially in?uencing,what you wrote in

the submitted work?

*For example,if you report a consultancy above there is no need to report travel related to that consultancy on this line.

静脉用人免疫球蛋白治疗反复发作性过敏性紫癜的疗效观察(一)

静脉用人免疫球蛋白治疗反复发作性过敏性紫癜的疗效观察(一) 【摘要】目的探讨静脉用人免疫球蛋白（IVIG）治疗反复发作性过敏性紫癜的疗效。方法将52例反复发作性过敏性紫癜患儿随机分为两组，两组均采用综合治疗，治疗组给予IVIG静脉点滴，对治疗前后临床症状消失时间及随访复发率参数进行比较。结果治疗组在皮疹、消化道症状、关节肿痛、肾脏症状消失时间及复发率上均明显优于对照组（P0.01）。结论IVIG 可明显缩短病程，减少复发，疗效确切，是治疗反复发作性过敏性紫癜的有效药物。【关键词】过敏性紫癜；人免疫球蛋白 过敏性紫癜是一种主要侵犯毛细血管的变态反应性疾病，表现为特征性的皮肤紫癜，同时合并腹痛、关节肿痛、便血和血尿等，病程中易反复发作，临床上无特效治疗方法。我们应用IVIG辅助治疗反复发作性过敏性紫癜26例，疗效满意，复发率低。现报告如下。 1资料与方法 1.1一般资料我院儿科2000年7月～2004年6月符合过敏性紫癜诊断标准〔1〕，既往有1次以上反复发作史的患儿52例，皮肤紫癜52例，消化道症状37例，关节肿痛28例，肾脏损害16例。其中，男30例，女22例，年龄5～12岁，平均（8.5± 2.2）岁，病程1～25d，平均（8.6± 3.0）天。按入院先后顺序随机分成治疗组和对照组各26例，两组年龄、性别、临床特点、病程等方面比较差异无显著性（P>0.05）,具有可比性。 1.2方法两组急性期均卧床休息,尽可能寻找并避免过敏源,进行抗感染、抗凝、止血、脱敏等综合治疗，疗程2周左右。治疗组加用IVIG（广西北生药业股份有限公司郴州生物制品分公司），300～400mg/kg，静脉滴注，每日1次，连用3～5次。观察记录皮肤紫癜、消化道症状、关节症状、肾脏症状消失时间。随访观察2年。 1.3统计学处理应用SPSS统计软件，临床症状消失时间比较采用t检验，复发率比较采用χ2检验。 2结果 两组临床症状消失时间比较见表1，两组治疗后2年随访复发率比较见表2。治疗组临床症状消失时间均较对照组短，差异有显著性（P0.001）。治疗组治疗后2年随访复发率均较对照组低，差异有显著性（P0.01）。表1两组治疗后临床症状消失时间比较表2两组治疗后2年随访复发率比较（略）

大剂量免疫球蛋白静脉滴注疗法

【编号】B2.6.2.41 【名称】大剂量免疫球蛋白静脉滴注疗法 【别名】IVIG 【适应证】 免疫球蛋白是由免疫系统体液免疫分支中B淋巴细胞和浆细胞产生的抗体，是具有抗原特异性的免疫物质。其应用于临床已有近50年历史，20世纪80年代初开始用大剂量人血免疫球蛋白静脉注射(IVIG)治疗特发性血小板减少性紫癜，并获得良效。由此，该疗法引起广泛兴趣，并渐应用于治疗一些神经系统疾病，为一些难治的自身免疫性疾病提供了一种新的治疗途径。 1.重症肌无力 2.格林-巴利综合征 3.慢性感染性脱髓鞘性多发性神经病(CIDP) 4.多发性硬化(MS) 5.癫痫 6.多发性肌炎 7.病毒性脑炎 【禁忌证】 对IVIG过敏反应者。 【准备】 1.向病人解释治疗的过程及注意事项，以消除顾虑，争取配合。 2.诊断明确，严格掌握适应症。 3.建立静脉通道，便于用药。 【方法】 1.机理 研究证实在不同的IVIG治疗应用中可能有不同的机理，包括：①对原发性和继发性免疫缺陷的替代治疗；②特种被动免疫；③特种炎症和/或免疫失调的治疗。 具体环节可能有：①大剂量Ig与患者体内单核巨噬细胞上的Fc受体结合，使其丧失抗原递呈功能，中断免疫反应；②大剂量Ig可中和患者的致病性自身抗体；③大剂量Ig与患者自身抗体竞争性结合于靶组织部位，从而起到保护作

用；④通过负反馈机制抑制浆细胞产生自身抗体；⑤使T8升高，抑制NK细胞的功能；⑥充当活化补体成分的受体，防止补体介导性免疫损害；⑦Ig有直接修复髓鞘的功能。 2.临床应用 (1)重症肌无力：研究表明，IVIG可导致神经功能的改善和乙酰胆碱受体抗体的降低。对全身型和重症肌无力危象病人效果更好。大剂量丙种球蛋白静脉滴注为重症、难治的重症肌无力病人提供了一种安全、有效的辅助疗法。 常用量：200～400m g/k g/日，每日1次，共用5～7天。 (2)格林-巴利综合征：为一种免疫反应疾病。特别对重症病例，IVIG可迅速改善症状，明显缩短恢复时间，使病情得到缓解，尤其适用于激素无效或因副作用而不适合应用激素者。 常用量：150～500m g/k g/日，共3～5天。 (3)慢性感染性脱髓鞘性多发性神经病(CIDP)：IVIG可促进病情恢复，并可改善因长期应用激素所致的免疫功能低下状态。 用法：200～400m g/k g/日，连用5天，部分需间断IVIG以维持疗效。 (4)多发性硬化(MS)：IVIG可明显改善病情及症状体征，对严重病情恶化发展的病人，应用IVIG后神经系统症状体征可得到迅速好转，并可减少发作次数，减轻复发时程度。 用法200～400m g/k g/日，连用3～5天，以后每2月1次。 (5)癫痫：近年来的研究证实，某些癫痫患者存在免疫状态异常现象，IVIG 通过免疫调节机制而起到治疗作用。低温乙醇处理后的人血免疫球蛋白含有补体结合的Fc段，具有较好的抗惊厥作用。对于某些与免疫缺陷相关的癫痫，IVIG 可直接作用于病因。 常用量：20～40ms/k g/次，连用50～60日；亦可采用200～400m g/k g/次，第1周3次，以后每周1次，共6～7次；尚可采用400m g/k g/日，分别在第1、15、21天静脉滴注，多数病例在治疗2月内发作完全控制。 (6)多发性肌炎：对激素无效的病例可用。 剂量：200m g/k g/日，每月连续用2天，坚持半年，可促进症状恢复。 (7)病毒性脑炎：在常规治疗(脱水降颅压、降温止痉、激素、抗生素及对症

最新人血白蛋白静注人免疫球蛋白的区别

人血白蛋白、静注人免疫球蛋白的区别 冯媛

《离骚》理解性默写 1、屈原在《离骚》中，表明自己出身高贵的句子是帝高阳之苗裔兮，朕皇考曰伯庸；表明自己降生祥瑞的句子是摄提贞于孟陬兮，惟庚寅吾以降。包含

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静脉注射纯度级别人血浆丙种球蛋白(IgG)纯化流程

A chromatographic method for the production of a human immunoglobulin G solution for intravenous use K. Tanaka, E. Sawatani, Divis?o de Produ??o e Desenvolvimento Industrial, E.M. Shigueoka, Funda??o Pró-Sangue Hemocentro de S?o Paulo, S?o Paulo, SP, Brasil T.C.X.B. Campos, H.C. Nakao, G.A. Dias, R.K. Fujita and F. Arashiro Abstract Correspondence Immunoglobulin G (IgG) of excellent quality for intravenous use was Key words K. Tanaka obtained from the cryosupernatant of human plasma by a chromato-?Immunoglobulin G Divis?o de Produ??o e production graphic method based on a mixture of ion-exchange, DEAE-Sepharose Desenvolvimento Industrial ?Hemoderivate production FF and arginine Sepharose 4B affinity chromatography and a final Funda??o Pró-Sangue Hemocentro ?Intravenous gamma purification step by Sephacryl S-300 HR gel filtration. The yield of 10 de S?o Paulo globulin production experimental batches produced was 3.5 g IgG per liter of plasma. A Av. Enéas C. Aguiar, 155, 1o andar ?Industrial chromatography 05403-000 S?o Paulo, SP solvent/detergent combination of 1% Tri (n-butyl) phosphate and 1% ?Downstream process Triton X-100 was used to inactivate lipid-coated viruses. Analysis of the final product (5% liquid IgG) based on the mean for 10 batches Publication supported by FAPESP. showed 94% monomers, 5.5% dimers and 0.5% polymers and aggregates. Anticomplementary activity was 0.3 CH50/mg IgG and prekallikrein activator levels were less than 5 IU/ml. Stability at 37o C for 30 days in the liquid state was satisfactory. IgG was stored in flasks (2.5 Received April 28, 1998 Accepted August 18, 1998 g/flask) at 4 to 8o C. All the characteristics of the product were consistent with the requirements of the 1997 Pharmacopée Européenne. Introduction or purification by ion-exchange and gel filtration chromatography (4,5). The IgG iso- Commercially available liquid or lyo-lated from human plasma in the 1940’s and philized immunoglobulins G (IgG) are pro-1950’s by the method of fractionation with duced from pooled human plasma from a cold ethanol of Cohn and Oncley (2,6,7) was large number of donors, usually more than suitable for intramuscular use and could not one thousand, so that a wide variety of anti-be administered intravenously because of bodies will be present in the product (1).

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静脉注射免疫球蛋白的病毒安全性概况

静脉注射免疫球蛋白的病毒安全性概况 黄丽花 (广西百色市卫生防疫站,广西百色533000) 【关键词】　免疫球蛋白;非甲非乙型肝炎;丙型肝炎病毒;乙型肝炎病毒;病毒安全性 文章编号:1003-1383(2004)03-0284-03 中图分类号:R446.62 文献标识码:A 静脉注射免疫球蛋白(IV IG)作为治疗各种自身免疫病、原发性体液免疫缺陷症、防治获得性免疫缺陷者细菌和病毒感染的有效手段,已为国内外许多临床工作研究者证实,并将IV IG归纳为6个治疗领域。然而,随着Lane1对输注IV IG后发生非甲非乙肝炎传播的首次报道后,多个国家多个制造厂家的数批IV IG输注后引发上千例非甲非乙肝炎传播也相继报道,IV IG的病毒安全性问题引起了人们的关注。研究人员发现,IV IG传播病毒性疾病可能与IV IG的分离纯化工艺;原料血浆的病毒性抗原、抗体筛选;IV IG生产工艺中病毒灭活工艺的加入及灭活方法的选择等密切相关。 可经血与血液制品传播的病毒 1.丙型肝炎病毒　Y ap2报道10多年时间来发生IV IG 输注后传播HCV的几种IV IG制剂中包括试验产品和正式产品。首次由Lane1报道的是英国Herts血液制品实验室(BPL)的一批试验IV IG,它采用低温乙醇分离后加入Sephadex2G25凝胶过滤纯化,最终加入人血白蛋白作为稳定剂后冻干而成,该批试验IV IG具有较强的感染性,在临床使用中接受输注的12人均发生了非甲非乙肝炎的感染3;随后Baxter中试工厂生产的两批试验IV IG4和瑞典K abi公司生产上市的IV IG产品G ammonativ5,均采用低温乙醇分离加DEAE2Sephadex凝胶过滤纯化,也有输注者发生非甲非乙肝炎感染事件。上述产品尽管在回顾性调查中均未找到发生输注后非甲非乙肝炎传播的确切原因,但是很明确的一点是产品在生产中均未加入特定的病毒灭活步骤。其次是由苏格兰国家输血机构(SNB TS)采用低温乙醇分离加低p H和酶处理生产的一批IV IG,输注者中同样发生了非甲非乙肝炎感染的病例6,根据推测其原因可能与生产过程中执行GMP的失败有关。IV IG中发生HCV传播例数最多的产品是东德7和以色列输血协会(B TSB)8生产的抗2D IV IG,由于高效价的抗2D血浆来源短缺,两者均采用了收获率较高的分离方法(采用离子交换柱层析替代低温乙醇分离的方法)进行小规模的特异免疫血浆的分离。回顾性调查已证实,在为数较少的抗2D免疫血浆的供血者中有个别发生过急性HCV感染,其中东德的两名供血者因接受了HCV感染的Rh 阳性红细胞免疫而致HCV,在以色列的供血者中一例也发生过HCV感染。未经筛选的HCV感染血浆导致小规模混合血浆的HCV含量较高,而分离过程又不足以灭活和去除其中HCV,加上在生产工艺中未加入特定病毒灭活步骤,由此导致多批污染制品在上千例接受者中发生多例的HCV感染。十多年时间的跟踪调查证实两种抗2D IV IG均使接受输注者中大约60%的病人发生HCV感染9,事实表明分离工艺的选择对于原料血浆中病毒的去除和灭活具有非常重要的意义。IV IG输注后发生HCV传播引起了研究者的高度重视,各国血液制品生产厂家开始对原料血浆进行抗2HCV 筛选,采取这一措施的确对降低原料血浆中HCV负载起到了重要作用,但是抗2HCV筛选是否会去除血浆中HCV的特异性中和抗体,一直是受到关注和争论的问题,有研究发现, HCV外膜蛋白的抗体通过封闭HCV的吸附对其产生一定的中和作用,从而使HCV在IV IG分离过程中被去除,但是由于HCV RNA的高变异性,使这种中和抗体在临床上不能显示其对HCV感染的有效保护10。有报道认为原料血浆中抗2HCV的去除,可能改变在IV IG分离过程中HCV在各组分中分布特性11,对分离过程中HCV的去除产生一定影响。抗2HCV筛选毕竟不是HCV病原学检测,但随着HCV2 RNA检测工作的进展,相信不久的将来在供血者中采用更为灵敏、特异和快速的HCV2RNA检测将会变成现实。 2.人类细小病毒B19　人类细小病毒B19可污染血浆和血液制品而引起慢性病毒血症、再生障碍性贫血等疾病。由于该病毒为非脂包膜病毒,具有耐热、抗理化处理的特性,因此目前尚无稳定可靠的方法对其灭活,并有经凝血因子传播B19病毒感染的报道。采用PCR检测免疫球蛋白时发现,在经SD灭活处理的IV IG中的B19病毒DNA阳性率较高,而在经低p H处理、酶处理和巴氏消毒处理的IV IG中则未检出该病毒12。尽管如此,目前尚无资料表明PCR检测阳性的IV IG具有感染性。中和性抗2B19抗体可阻止病毒与细胞的结合,但是否具有对B19病毒感染的保护作用尚不清楚。有资料报道IV IG的分离过程对B19病毒具有去除作用,但不同工艺对该病毒的去除有较大差异13。尽管到目前为止经输注IV IG致病毒感染尚未见临床报道,但在IV IG制品中检出B19病毒DNA的情况已受到人们的关注。因此建立原料血浆中B19病毒的筛选方法以及采用适宜的病毒灭活工艺对于提高IV IG的安全性具有十分重要的意义。 3.甲型肝炎病毒(HAV)、乙型肝炎病毒(HBV)、人类免疫缺陷病毒(HIV)及巨细胞病毒(CMV)　①HAV属非脂包膜病毒,SD方法不能对其有效灭活,曾有报道经SD灭活的 作者简介:黄丽花(1966-),女,广西田阳县人,主管技师。 ? 4 8 2 ?Y oujiang Medical Journal2004,Vol.32No.3

大剂量丙种球蛋白在治疗川崎病中

毕业论文 论文题目：大剂量丙种球蛋白在治疗川崎病中的疗效观察与护理年级：大三 专业：护理 学生姓名：袁飞燕 指导老师 姓名：雷欢

大剂量丙种球蛋白在治疗川崎病中的疗效观察与护理 袁飞燕 摘要目的观察大剂量静脉注射丙种球蛋白(IVIG)治疗川崎病(KD)的临床效果。方法选取2015年2月-2016年2月我科收治的川崎病患儿56例，随机分为观察A组和B组。实验A组(28例)，在常规阿司匹林的治疗基础上加用静脉注射丙种球蛋白治疗；B组(28例)，采用单用阿司匹林的治疗方法。观察两组患儿住院时间、总热程、退热时间、黏膜充血、手足肿胀、淋巴结肿大消退时间及冠状动脉病变（CAL）发生情况并进行比较。结果A组的退热时间及热程明显短于B组；冠状动脉病变发生率明显低于B组；两组比较差异有统计学意义（p<0.05或p<0.01），56例川崎病患儿治疗情况进行回顾性分析。结论早期大剂量使用丙种球蛋白治疗川崎病能使体温迅速降低同时也明显的降低了冠状动脉病变的发生率。在使用丙种球蛋白的过程中，严格无菌操作、控制输液滴速是护理的关键，其次针对疾病特点实施科学护理，才能获得最佳治疗效果。 关键词：丙种球蛋白；川崎病；阿司匹林；冠状动脉病变 川崎病（kawasaki disease，KD）1967由日本川崎富首先报道，曾称为皮肤黏膜淋巴结综合症（MCLS），是一种以全身血管炎症为主要病理改变的急性发热出诊性疾病。其病因未明，临床发现为发热伴皮疹，颈部淋巴结肿大，球结膜及口腔黏膜充血，口唇皲裂，杨梅样舌以及恢复期指（趾）端特异性膜状脱皮，约15%～20%未经治疗的患儿发生冠状动脉损害，也是属于小儿后天性心脏病重要诱发原因。因此，儿科临床必须加强对小儿川崎病的治疗，传统治疗多采用阿司匹林，随着丙种球蛋白的研发，两者相联合可有效治疗小儿川崎病，则迅速在临床中应用。笔者我选取我科2015年2月至2016年2月收治的56例川崎病患儿，其中28例常规阿司匹林治疗基础上加用静注丙种球蛋白治疗取得了良好的临床效果，现将结果报告如下。 1 资料与方法 1.1 一般资料选取2015年2月～2016年2月本科川崎病患儿56例，其中男40例，女16例，年龄平均为 2.4岁。将56例川崎病患儿随机分为观察A组（28例）和B组（28例）。两组患儿性别、年龄、病情、病程及治疗时间比较无统计学意义（p<0.05或p<0.01）

第三代静脉注射人免疫球蛋白的作用机理和临床应用

第三代静脉注射人免疫球蛋白的作用机理和临床应用沈慕昌张岷 (成都生物制品研究所 610023) 20世纪40年代美国哈佛大学Cohn领导的研究组连续报道采用低温乙醇工艺从血浆蛋白中成功地分离出白蛋白、免疫球蛋白纯品的血液制品，以供临床应用。但后者不能作静脉输注，否则会产生严重副反应。一直到70年代初获得诺贝尔奖的Edelman , Orter报告抗体分子结构才搞清楚由于免疫球蛋白在提制过程中，有一部分产生聚合体，输入机体内有可 )。为解决ACA问题，而采用能激活补体，产生类过敏样的副反应，关键是抗补体活性(ACA 酶解法切除免疫球蛋白的恒区(Fc)或采用化学修饰的办法，所以，有静丙的第一代、第二代之称。以后经过工艺技术不断改进，可以从血浆中制备出天然分子结构的单体，不存在ACA问题。按照WHO血液制品专家委员会的规定特性，可以完全符合要求，故称为第三代静丙，其功效安全性等均有明显的提高。 大规模临床使用静丙，国际上要比我国早一点，国产的静丙在20世纪90年代初才投放市场。笔者从90年代中期连续3年征文活动中收到临床应用的论文、报告263篇。本文准备将应用的情况归纳一下，供临床专家和血液制品工作者参考。 一(药理学，免疫学作用机理: 第三代静脉注射用人免疫球蛋白治疗病种广泛，疗效显著，与制品内包含各种特异效应 7×10分子发挥药理学和免疫调节作用有关。每克分子静丙内含10效应分子。 替代治疗提高血清中抗体水平:

1(增强调理作用:中性粒细胞、单核细胞、巨噬细胞具有与IgG高亲和力的受体(FcRI)，尤其是IgG、IgG亚类起主要的调理作用。多形核白细胞发挥作用，也需要正常水平的抗体。 13 2(阻断传染的病毒，细菌与靶细胞结合;中和传染性抗原、病毒和超抗原。Rich、Takei等报告，IVIG含高滴度的抗链球菌性超抗原的抗体，能抑制T-细胞的反应。 3(竞争性结合网状内皮细胞Fc受体(FcR)，阻断自身抗体包被的红细胞、血小板被吞噬、廓清。这是IVIG治疗ITP和继发于SLE的血细胞减少症有效的机制。 4(抗体的Fc可以和活化的Cb、Cb补体成分结合;IgG的碎片Fd和补体C3、C4形成34 异种二聚体，可以象海绵一样吸附活化的补体，并能抵抗补体的降解。这两种情况均可以防止补体介导的免疫损伤。如Basta等报告，输注IVIG可以保护补体介导的Forssman休克的豚鼠模型免于死亡，这机理对逆转血小板减少、溶血性贫血、白细胞减少特别重要。 5(改变免疫复合物(IC)的结构和可溶性:Tomino等证实肾活检样品和IVIG孵育可 1 溶解沉积在肾小球内的IC。这种效果对SLE的临床是有利的。Lin C.V等用IVIG治疗9例对类固醇和细胞毒治疗无效的肾病患者，减轻了蛋白尿，改善了肌酐的廓清。IVIG治疗清 s而在组织中沉积。当治疗时循环血液中积存大量抗除抗原，使过剩抗原不致形成的细小IC 体，抗体过剩时形成巨大的复合物，易被吞噬廓清。

新冠病毒患者静脉注射免疫球蛋白是否可以预防新冠病毒感染,增强新冠病毒患者的免疫系统

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