Low Dose Intravenous Immunoglobulin. Acute immune thrombocytopenic

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1 IASIAN PACIFIC JOURNAL OF ALLERGY AND IMMUNOLOGY (2001) 19: Lw Dse Intravenus Immunglbulin fr Acute Immune Thrmbcytpenic Purpura in Children Issarang Nuchprayn\ Panya Seksarnt, Preeda Vanichsetakul 1 and Rachanee O-charen 2 Acute immune thrmbcytpenic purpura (ITP), previusly knwn as idipathic thrmbcytpenic purpura, is a cmmn cause f thrmbcytpenia in children. Acute ITP is diagnsed when a child presents with abnrmal bleeding diathesis due t islated thrmbcytpenia, with increased megakarycytes in bne marrw aspirates, and absence f ther knwn disrders. 1 Acute ITP is caused by self-limited autimmunity t platelets, leading t platelet destructin in the spleen. 2 Althugh thrmbcytpenia spntaneusly reslves in mst cases within 6 mnths after diagnsis, platelet cunt is ften very lw with the assciated risk f spntaneus bleeding, thus necessitating treatment. Mst experts agree that treatment is indicated when children with acute ITP have spntaneus bleeding r have platelet cunt belw 20,000/1l1.1 Intravenus immunglbulin (IVIG) is ne f the mst effective treatments fr acute ITP in children. It is believed that large SUMMARY Acute Immune thrmbcytpenic purpura (ITP) Is a self llmlted autimmune disrder t platelets. The disease respnds well t Intravenus immunglbulin (IVIG) treatment. We studied the efficacy f lw dse (1 g/kg) IVIG t treat acute ITP In children. Of 17 children with ITP and platelet cunts < 20,0001,.1.1,13 (76%) had rapid platelet cunt recvery, reaching safe level (> SO,OOOlJ,1I) within 4 days after 1 g/kg IVIG. Fur children needed a secnd dse. In 5 f 15 patients, platelet cunts recvered t nrmal withut recurrence, while In 10 patients, platelet cunts declined again 2-3 weeks after the Initial treatment; 6 f whm (40%) needed re-treatment. All but ne patient had cmplete recvery f the platelet cunt by 6 mnths. Adverse effects f lw dse IVIG were minimal. We recmmend that fr childhd ITP, 1 g/kg IVIG shuld be tried Initially. If Inadequate respnse is seen (platelet cunt < 30,OOO/J,1I) by 48 hurs, a secnd dse Is needed. amunt f immunglbulin acts by saturating Fc receptrs n phagcytic cells, thus preventing them frm attacking aut-anti bdy-cated platelets. 2 IVIG at 2 g per kg bdy weight ver 5 days r 48 hurs has been shwn t be superir t treatment with high-dse prednislne and t n treatment in several trials. 3-6 Hwever, despite its efficacy, the cst f IVIG is ften t high t be used in medical practice in the develping wrld. T find an ecnmical way t use IVIG, we investigated the use f IVIG at lwer dses fr the treatment f acute ITP in children. PATIENTS AND METHODS Newly diagnsed and previusly untreated patients with acute ITP between 3 mnths and 15 years f age with severe thrmbcytpenia (platelet cunt <20,000/ Ill) and a bne marrw aspirate that Frm the ldepartment f Pediatrics. Fac ulty f Medicine. Chulalngkm University, Bangkk, Thailand and 2Natinal Bld Cen ter. Thai Red Crss Sciety. Bangkk. Thai land. Crrespndence: Issarang Nuchprayn

2 12 NUCHPRA YOON, ET AL. revealed nnnal cellularity with nnnal r increased megakarycytes, withut ther abnnnalities, were included in the study. Patients with diseases knwn t be assciated with thrmbcytpenia I frm peripheral destructin f platelets, including HIV infectin, and hemangima, were excluded. Patients wh had prir treatment with crticsterid and patients wh had a histry f allergy t IVIG r IgA deficiency were als excluded frm this study. The IVIG preparatin used in this study was LV. Glbulin. LV. Glbulin was purified frm vlunteer plasma frm Thai dnrs at the Natinal Bld Center, Thai Red Crss Sciety, using Khn fractinatin prvided by the Krea Green Crss Crpratin, Seul, Krea. The supplied batch (lt number , manufacturing date 18 February 1998, expiratin date 7 February, 2000) was tested t have the fllwing prperties: ph , IgG cntent 100%, anticmplement ~ 20 units, pyrgen test: temperature reactin < 1.3 C, absence f hepatitis B surface antigen (HBsAg), anti-hiv, anti HCV, and presence f measles antibdy titer f 22 units/i 50 mg. All patients whse parents cnsented t this treatment regimen were admitted t Chulalngkrn Hspital, Bangkk, Thailand, and infused with IVIG at 1 g/kg bdy weight cntinuusly ver 24 hurs. Each 2.5 g vial IVIG was recnstituted with 50 ml sterile water fr injectin and infused at the prescribed rate. Cmplete bld cunts (CBC) were detennined using a Technicn H*3 autmated CBC analyzer fllwed by manual cnfinnatin f platelet cunts under phase cntrast micrscpy. In each case, CBCs were detennined befre and daily after IVIG infusin until a platelet cunt f >50,000 /).11. If the platelet cunt did nt rise abve 50,000/).11 by 96 hurs after the start f the infusin, a secnd dse f IVIG was infused at 1 g/kg bdy weight as cntinuus infusin ver 24 hurs, and the platelet cunt was fllwed daily. When the platelet cunt reached> 50,000/).11, the patient was discharged and the CBC was checked nce weekly fr fur cnsecutive weeks. If the platelet cunt declined again belw 20,000/ ).11, the patient was re-treated at the physician's discretin, either with a repeat dse f IVIG, r with ral prednislne starting at 2 mglkg/ day. The fllwing symptms and signs were recrded during IVIG infusin: bdy temperature, pulse rate, bld pressure, presence r absence f rash, headache, r ther signs f anaphylactid reactins. If any sign f an anaphylactid reactin ccurred, the infusin was immediately stpped, and symptms were treated at the physician's discretin. If the symptms reslved spntaneusly, IVIG infusin was then resumed at a lwer rate. Data were recrded in Excel 5.0 spreadsheets. Survival curves were pltted using SPSS RESULTS Early respnse t IVIG treatment Between September 1998 and February 2000, 22 children met the inclusin criteria fr diagnsis f acute ITP and had platelet cunts belw 20,000/).11. Five patients were excluded frm the study because f treatment with crticsterids befre referral. Seventeen children, 8 males and 9 females, with a median age f 2 years and 6 mnths, were treated with IVIG and fllwed prspectively. The median platelet cunt prir t treatment was 6,000/ J.tl. After 24-hur IVIG infusins, platelet cunts rse abve 20,000//i1 by the end f infusins in the majrity f cases (12 f 17, Fig. la). The median time fr platelet cunts t rise abve 50,000/).11 was 2 days after starting IVIG. In mst cases (13 f 17, 76%), platelet cunts rse abve this level within 4 days after initiatin f IVIG infusin (Fig. 1A). Re-treatments with additinal IVIG at 1 g/kg were given in 4 cases whse platelet cunts did nt rise abve 50,000/).11 within 4 days (Fig. 2). All but ne case had prmpt reslutin f thrmbcytpenia within 1, 2, and 5 days after initiatin f the secnd dse. We fund that all f the patients wh respnded t IVIG 1 g/kg, but nne fthe 4 patients wh eventually needed IVIG 2 g/kg, had platelet cunts abve 30,000/).11 at 48 hurs after initiatin f IVIG infusin. Duratin f efficacy Duratin f efficacy f lw dse IVIG treatment was evaluated in 15 f 17 cases wh had been fllwed up fr at least 4 weeks. The median peak platelet cunt after IVIG at 1 g/kg was 144,000//i1 in the secnd week. Nine cases had cmplete reslutin f thrmbcytpenia (platelet cunts abve 150,000/).11) by the secnd week after treatment (Fig. la). In ne third (5 f 15) f the patients, platelet cunt cntinued t rise. Hwever, in mst cases (Fig. 2), platelet cunts declined again in the 2nd week (6 cases), r in the 3rd week (4 cases), after initial treatment. In

3 LOW DOSE IVIG FOR ITP ~ ~ ~ e 0.7 c:::.~ ~ 0.6 c. 0.1 "' "... I :... ~ :...., " "." r- r I Platelet cunt. > 20,000 /).1.1 > 50,000 f).l.l > 150,000 f).l.l ~~~ Days after IVIG c::: ''20.4 c E0.8.~ ~ 0.7 c. '+- :* : c:::.- & 'r I 0.5 r 0.4 r I 0.3 tr 0.2- I 0.1." r Platelet cunt > 20,000 /).1.1 > 50,000 /).1.1 > 150,000 /)J.I Days after IVIG Fig. 1 Prprtin f patients with platelet recvery t varius level. A. in the first tw weeks, B. up t 6 mnths after diagnsis. B A

4 14 NUCHPRAYOON. ET AL. Initial treatment with IVIG 1 glkg 16 Weekly fllw up platelet cunt 3 I Re.treatment with IVIG 1 glkg Lst t fllw up 5 Platelet cunt cntinued t increase 10 Platelets declined 6 Platelet cunt In 2nd.3rd week I----,tj < 20,000/j..tl 4 Spntaneus recvery Re.treatment with IVIG r sterids Cmplete recvery (platelet cunt >150,000/ j..tl by 6 mnths Fan Did nt recver by 6 mths (chric ITP) Fig. 2 Flwchart f childhd ITP treatment with IVIG. Number f patients in each categry is shwn. 6 cases (40%, Fig. 2), the platelet cunts fell belw 20,OOO/IlI, necessitating re-treatments with either IVIG (2 cases) r ral prednislne (4 cases). Three patients needed retreatment in the secnd week, while the ther three were re-treated at day 17,21, and 39 after the initial treatment. In all but ne cases treated with ral prednislne, satisfactry respnses were btained, althugh the patients needed a maintenance dse f prednislne fr 2-4 mnths. The tw patients wh were re-treated with IVIG, had prmpt but temprary respnses. They were switched t ral prednislne treatment at the subsequent recurrences. Lng-term fllw-up Thirteen patients were fl lwed fr at least 6 mnths t study the natural histry f the disease. The median time t reslutin (platelet cunt abve ISO,OOO/IlI) was 7.S days after the initial treat ment (Fig. la). Thrmbcytpenia cmpletely reslved within 6 mnths in all but ne patients (Figs. 1Band 2). This patient did nt respnd well t IVIG r ral crticsterid treatment. Safety f IVIG infusin During the 24-hur IVIG infusin, each patient was mni tred fr vital sign changes and bserved fr knwn adverse reactins. Only ne case had a transient erythematus macular rash, which reslved after a temprary discntinuatin f IVIG infusin. IVIG treatment was resumed at a slwer rate withut antihistamines r ther medicatins, and the rash did nt recur. N patient develped fever, abnrmal vital signs, r headache. DISCUSSION Childhd ITP is a selflimited disease. Treatment is indicated nly when platelet cunt is very lw «20,OOO/lll) and/r the patient has clinical evidence f

5 LOW DOSE IVIG FOR ITP 15 bleeding such as purpura, J t minimize the risk f intracranial hemrrhage- a cmplicatin that ccurs in apprximately 1 % f children with ITP.7,S Althugh ral prednislne is the drug f chice t raise the platelet cunt in ITP patients wh need treatment, it results in several adverse effects S including excessive weight gain (up t 6% f riginal bdy weight), epigastric discmfrt, behaviral change, transient glycsuria, hypertensin, and transient suppressin f the immune system. IVIG has been used fr treatment f childhd ITP since The use f IVIG in acute ITP is t temprary raise platelet cunt while allwing the abnrmal immune respnse t platelets subside spntaneusly. IVIG has been shwn t be superir t ral prednislne in several trials. 4 ' 6 When platelet cunt is abve 50,000/J..ll, the risk f bleeding is lw and the patient can be safely watched at hme. I I.V. GlbuIin is an IVIG preparatin that derived frm plasma dnatins frm Thai vlunteers, fllwed by a standard fractinatin prcedure by the Krean Green Crss. Safety and efficacy f ther IVIG prducts f the Krean Green Crss has been established. Because the surce f plasma is frm lcal vlunteer dnatin, the cst f this IVIG preparatin is cnsiderably less than many ther preparatins available internatinally. In mst pediatric studies, IVIG was given at 2 g/kg bdy weight ver 48 hurs s,6 r 5 days.3,4 Because f high cst f IVIG, we studied whether IVIG at 1 glkg bdy weight culd be used. Our results shwed that the lwer dse IVIG culd raise platelet cunts t a safe range in mst cases (Fig. 2). In this study, the median time t recver platelet cunts abve 50,000/J..lI is 2 days, which is cmparable t ther studies using 2 g/kg IVIG s r a lwer dse (0.8 g/kg) IVIG. 6 By 96 hurs, 76% f patients had platelet cunts abve 50,000/J..lI, which was als cmparable t the lw dse arm f the Blanchette study (83%, n = 35).6 We fund that nly a quarter f ur patients needed treatment with 2 glkg IVIG t successfully raise the platelet cunt. Our result was similar t a study by Busse! and clleagues 9 wh reprted that 3/12 cases f their previusly untreated patients failed t respnd t 1 glkg IVIG. We fund that in patients wh needed high dse IVIG, platelet cunts did nt reach 30,000/J..lI by 48 hurs after the start f the infusin. Therefre, the decisin t give the secnd dse culd be made as early as 48 hurs after starting the first dse using this platelet cunt criteria. In mst trials, platelet cunts remained high abve the f ther symptms. This may be safe range fr 3-4 weeks as the explained by the relatively yung immunglbulin level declined. In higher dse IVIG studies, the platelet age f children in ur study. Serial CBCs, which included hemglbin cunt als declined belw the level, did nt shw a significant safe level «20,000IJlI) within 28 anemia after IVIG infusin in any days after diagnsis.s. 6 Re-treat c~s~. Other trials with 1 g /kg MG ment was necessary in 12-22% f stmtlarll reprted few adverse the effective level with the lw dse IVIG, resulting in shrter duratin fsafe platelet cunts. In ur chrt, there was nly ne patient whse thrmbcytpenia did nt reslve by 6 mnths after initial diagnsis, thus meeting the diagnstic criteria fr chrnic ITP.l This prprtin seems lwer than the 10-30% reprted frm larger chrts in Western cun S tries. 3. Adverse effects f IVIG are cmmn (15-75%), particularly with high-dse infusin in 48 hrs,s but are generally mild. These include headache, backache, nausea, and fever. Aseptic meningitis may ccur.io Allimmune hemlysis is reprted rarely. 11 There were very few adverse effects in ur study; nly ne case f transient rash that seemed t be assciated with the rapid infusin rate. There was n febrile reactin, and n cmplaints cases. In ur study, 40% f patients required re-treatments, a rate cmparable t the lwer dse arm (32%) f the Blanchette study,s and the 5112 (42%) patients in the Bussel study.9 In 3 f ur cases, retreatment was needed in the secnd week, earlier than expected in highdse IVIG regimen. This phenmenn might be due t lwer dses f IVIG raising serum immunglbulin just abve the effective level t blck platelet destructin, re~ulting in a temprary rise f the platelet cunt. Subsequently, serum immunglbulin sn fall belw effects. IVIG preparatins are expensive. At the time f preparatin f this reprt, the relative cst rati f mst IVIG preparatins in Thailand (ttal 2 glkg) t ral prednislne therapy (2 mglkglday fr 28 days) was calculated t be 240 t 1. The use f lcal plasma dnrderived IVIG preparatins (I.V. Glbulin ) infused at 1 g/kg wuld bring this rati dwn t 60 t 1. The cst f therapy must be balanced against reductin in anxiety amng parents and physicians, and

6 16 NUCHPRAYOON, ET AL the shrtened hspital stay. The clinical practice guideline develped by the American Sciety f Hematlgy nw recmmends a lw dse IVIG ver the standard 2 glkg fr the treatment f acute ITP.I Hwever, fr mst patients in Sutheast Asian cuntries, where cst f treatment is an imprtant factr, IVIG may nt be the mst cst-effective way t manage ITP, even at a lwer dse. Because f lw cst and acceptable efficacy, ral crticsterid therapy has been recmmended by the Thai Sciety f Hematlgy l2 as the treatment f chice fr childhd ITP that needed treatment. A bne marrw aspiratin is als required t establish the diagnsis f ITP befre sterid treatment. Pre-treatment bne marrw aspiratin is ptinal, hwever, fr children selected t be treated with IVIG, but shuld als be dne fr IVIG nn-respnders fr whm crticsterid treatment is planned. IVIG is als useful fr treatment f chrnic ITP t delay r avol 'd sp I enectmy B ecause 0 f gd but transient respnses, multiple dsing is required as 'maintenance dse'. This can be achieved with 0.5 t 1 glkg IVIG every 2-3 weeks. 16 In additin, IVIG is particularly useful fr predicting respnse t splenectmy.17 Children with chrnic ITP wh respnd well t IVIG treatment will usually have cmplete reslutin f thrmbcytpenia after splenectmy.17 In cnclusin, ur results suggested that when IVIG is cnsidered fr initial treatment fr childhd acute ITP, an initial dse f 1 glkg IVIG may be used. If' inadequate respnse is bserved (platelet cunt nt reaching 30,000/ /-ll) by 48 hurs, anther dse f 1 glkg may be repeated. Platelet cunt shuld be fllwed at least weekly fr 4 weeks as re-treatment may be necessary in sme cases. ACKNOWLEDGEMENTS We wish t thank the medical staff f the pediatric hematlgy unit, and resident physicians f the Department f Pediatrics, Faculty f Medicine, Chulalngkrn University, fr their help in the clinical service f these children. We thank Dr. Surang Nuchprayn, and Ms. Narak Triteeraprapab fr assistance in preparatin f this manuscript. REFERENCES I. Gerge IN, Wlf SH, Raskb GE et at. Idipathic thrmbcytpenic purpura: A practice guideline develped by explicit methds fr the American Sciety f Hematlgy. Bld 1996; 88: Keltn JG, Singer J, Rdger C, Gauldie 2. 1, Hrsewd P, Dent P. The cncentratin f IgG in the serum is a majr determinant f Fc-dependent reticulendthelial functin. Bld 1985; 66: Imbach P, d'apu720 V, Hirt A et at. High-dse intravenus gamma-glbulin fr idipathic thrmbcytpenic purpura in childhd. Lancet 1981; I: Imbach P, Wagner HP, Berchtld W. Intravenus immunglbulin versus ral crticsterids in acute immune thrmbcytpenic purpura in childhd. Lancet 1985; 2: Blanchette VS, Luke B, Andrew M et al. A prspective, randmized trial f high-dse intravenus immune glbulin G therapy, ral prednisne therapy, and n therapy in childhd acute immune thrmbcytpenic purpura. 1 Pediatr 1993; 123: Blanchette V, Imbach P, Andrew M et al. Randmised trial f intravenus immunglbulin G, intravenus anti-d, and ral prednisne in childhd acute immune thrmbcytpenic purpura. Lancet 1994; 344: McClure PD. Idipathic thrmbcytpenic purpura in children: Diagnsis and management. Pediatrics 1975; 55: Lammi AT, Lvric VA. Idipathic thrmbcytpenic purpura: an epidemilgic study. J Pediatr 1973; 83: Bussel IB, Gldman A, Imbach P, Schulman I, Hilgartner MW. Treatment f acute idipathic thrmbcytpenia f childhd with intravenus infusins f gamma-glbulin. 1 Pediatr. 1985; 106: Sekul EA, Cupler El Dalakas Me. Aseptic meningitis assciated with high dse intravenus immunglbulin therapy- frequency and risk factrs. Ann Intern Med 1994; 121: II. Thmas Ml, Misbah SA, Chapel HM, lnes M, Elringtn G, Newsm-Davis 1. Hemlysis after high-dse intravenus immunglbulins. Bld 1993; 82: Krutveche T, Suvatte V, Mahasandana C et al. ITP in children. In: Intrakumtmchai T, ed. Evidence-Based Practice Guideline fr Treating Hematlgic Diseases in Thailand Bangkk, Beynd Enterprise [in Thai]. 13. Lasmbat V, Wiriyasatienkul A, Wngchanchailert M. Intravenus gamma glbulin fr treatment f chrnic idipathic thrmbcytpenic purpura in children. 1 Med Assc Thailand 2000; 83: Bussel lb, Schulman I, Hilgartner MW, Barandun S. Intravenus use f gamma-glbulin in the treatment f chrnic immune thrmbcytpenic purpura as a means t defer splenectmy. 1 Pediatr 1983; 103: Imhlz B, Imbach P, Baumgartner C et al. Intravenus immunglbulin (Lv. IgG) fr previusly treated acute r fr chrnic idipathic thrmbcytpenic purpura (ITP) in childhd: A prspective multicenter study. B1ut 1988; 56: Bussel IB, Fitzgerald-Pedersn 1, Feldman e. Alteratin f tw dses f intravenus gamma-glbulin in the maintenance treatment f patients with immune thrmbcytpenic purpura: Mre is nt always better. Am J Hematl1990; 33: Law C, Marcacci M, Tam P, Heddle N, Keltn J. High-dse intravenus immune glbulin and the respnse t splenectmy in patients with idipathic thrmbcytpenic purpura. N Engl J Med 1997; 336: