Predictive factors of first dosage intravenous immunoglobulin-related adverse effects in children

Autoři: Jun Kubota aff001;  Shin-ichiro Hamano aff001;  Atsuro Daida aff001;  Erika Hiwatari aff001;  Satoru Ikemoto aff003;  Yuko Hirata aff001;  Ryuki Matsuura aff001;  Daishi Hirano aff002
Působiště autorů: Division of Neurology, Saitama Children's Medical Center, Saitama, Japan aff001;  Department of Pediatrics, The Jikei University School of Medicine, Tokyo, Japan aff002;  Department for Child Health and Human Development, Saitama Children's Medical Center, Saitama, Japan aff003
Vyšlo v časopise: PLoS ONE 15(1)
Kategorie: Research Article



Intravenous immunoglobulin (IVIG) therapy is used in the treatment of various diseases, and IVIG-related adverse effects (IVIG-AEs) vary from mild to severe. However, the mechanisms underlying IVIG-AEs and the potential predictive factors are not clear. This study investigated whether certain IVIG-AEs can be predicted before IVIG administration.

Study design and methods

This retrospective cohort study at the Division of Neurology, Saitama Children’s Medical Center included patients enrolled from 2008 to 2018 who were < 18 years old and received IVIG for the first time. IVIG-AEs were classified according to the Common Terminology Criteria for Adverse Events version 5.0.


A total of 104 patients fulfilled the inclusion criteria. The rate of IVIG-AEs was 37.5% (39/104). The most frequent IVIG-AEs were fever (41.0% [16/39]) and headache (38.5% [15/39]). AEs were below grade 2 in all except one patient and there were no grade 4 AEs. High serum total protein (TP) level was significantly related to the occurrence of IVIG-AEs (odds ratio, 14.8; 95% confidence interval, 2.4–90.5; P < 0.01). The optimal cutoff TP level was 6.7 g/dL. Although low WBC count and immunoglobulin G level may be predictive risk factors of IVIG-AEs, it was not confirmed in this study.


IVIG-AEs occurred in 37.5% of cases, and most were mild. TP was the best predictive risk factor of IVIG-AEs before IVIG administration. These results may aid in elucidating the mechanism underlying IVIG-AEs.

Klíčová slova:

Abdominal pain – Adverse events – Antibodies – Blood – Epilepsy – Headaches – Medical risk factors – Pediatrics


1. Guo Y, Tian X, Wang X, Xiao Z. Adverse Effects of Immunoglobulin Therapy. Front Immunol. 2018;9: 1299. doi: 10.3389/fimmu.2018.01299 PubMed Central PMCID: PMC6008653. 29951056

2. Geng J, Dong J, Li Y, Ni H, Jiang K, Shi LL, et al. Intravenous immunoglobulins for epilepsy. Cochrane Database Syst Rev. 2017;7: CD008557. doi: 10.1002/14651858.CD008557.pub3 28675262.

3. Singh-Grewal D, Kemp A, Wong M. A prospective study of the immediate and delayed adverse events following intravenous immunoglobulin infusions. Arch Dis Child. 2006;91(8):651–654. doi: 10.1136/adc.2005.078733 16638785; PubMed Central PMCID: PMC2083046.

4. Bharath V, Eckert K, Kang M, Chin-Yee IH, Hsia CC. Incidence and natural history of intravenous immunoglobulin-induced aseptic meningitis: a retrospective review at a single tertiary care center. Transfusion. 2015;55(11): 2597–2605. doi: 10.1111/trf.13200 26095012.

5. Katz U, Achiron A, Sherer Y, Shoenfeld Y. Safety of intravenous immunoglobulin (IVIG) therapy. Autoimmun Rev. 2007;6(4): 257–259. doi: 10.1016/j.autrev.2006.08.011 17317619.

6. Bichuetti-Silva DC, Furlan FP, Nobre FA, Pereira CT, Goncalves TR, Gouveia-Pereira M, et al. Immediate infusion-related adverse reactions to intravenous immunoglobulin in a prospective cohort of 1765 infusions. Int Immunopharmacol. 2014;23(2): 442–446. doi: 10.1016/j.intimp.2014.09.015 25257732.

7. Palabrica FR, Kwong SL, Padua FR. Adverse events of intravenous immunoglobulin infusions: a ten-year retrospective study. Asia Pac Allergy. 2013;3(4): 249–256. doi: 10.5415/apallergy.2013.3.4.249 24260730; PubMed Central PMCID: PMC3826603.

8. Thornby KA, Henneman A, Brown DA. Evidence-based strategies to reduce intravenous immunoglobulin-induced headaches. Ann Pharmacother. 2015;49(6): 715–726. doi: 10.1177/1060028015576362 25757469.

9. Souayah N, Hasan A, Khan HM, Yacoub HA, Jafri M. The safety profile of home infusion of intravenous immunoglobulin in patients with neuroimmunologic disorders. J Clin Neuromuscul Dis. 2011;12(Suppl 4): S1–10. doi: 10.1097/CND.0b013e3182212589 22361589.

10. Shah S. Pharmacy considerations for the use of IGIV therapy. Am J Health Syst Pharm. 2005;62(16 Suppl 3): S5–11. doi: 10.2146/ajhp050282 16100386.

11. Stangel M, Kiefer R, Pette M, Smolka MN, Marx P, Gold R. Side effects of intravenous immunoglobulins in neurological autoimmune disorders—a prospective study. J Neurol. 2003;250(7): 818–821. doi: 10.1007/s00415-003-1085-1 12883923.

12. Nosadini M, Mohammad SS, Suppiej A, Sartori S, Dale RC, Group IiNS. Intravenous immunoglobulin in paediatric neurology: safety, adherence to guidelines, and long-term outcome. Dev Med Child Neurol. 2016;58(11): 1180–1192. doi: 10.1111/dmcn.13159 27242065.

13. Orbach H, Katz U, Sherer Y, Shoenfeld Y. Intravenous immunoglobulin: adverse effects and safe administration. Clin Rev Allergy Immunol. 2005;29(3): 173–184. doi: 10.1385/CRIAI:29:3:173 16391392.

14. Cherin P, Marie I, Michallet M, Pelus E, Dantal J, Crave JC, et al. Management of adverse events in the treatment of patients with immunoglobulin therapy: A review of evidence. Autoimmun Rev. 2016;15(1): 71–81. doi: 10.1016/j.autrev.2015.09.002 26384525.

15. Yelehe-Okouma M, Czmil-Garon J, Pape E, Petitpain N, Gillet P. Drug-induced aseptic meningitis: a mini-review. Fundam Clin Pharmacol. 2018;32(3): 252–260. doi: 10.1111/fcp.12349 29364542.

16. Sekul EA, Cupler EJ, Dalakas MC. Aseptic meningitis associated with high-dose intravenous immunoglobulin therapy: frequency and risk factors. Ann Intern Med. 1994;121(4): 259–262. doi: 10.7326/0003-4819-121-4-199408150-00004 8037406.

17. Graf J, Ingwersen J, Lepka K, Albrecht P, Hartung HP, Ringelstein M, et al. Factors associated with headache in intravenous immunoglobulin treatment for neurological diseases. Acta Neurol Scand. 2019;140(4):290–295. doi: 10.1111/ane.13144 31269227.

18. Markvardsen LH, Christiansen I, Andersen H, Jakobsen J. Headache and Nausea after Treatment with High-Dose Subcutaneous versus Intravenous Immunoglobulin. Basic Clin Pharmacol Toxicol. 2015;117(6):409–412. doi: 10.1111/bcpt.12428 26096187.

19. Steinberger BA, Ford SM, Coleman TA. Intravenous immunoglobulin therapy results in post-infusional hyperproteinemia, increased serum viscosity, and pseudohyponatremia. Am J Hematol. 2003;73(2): 97–100. doi: 10.1002/ajh.10325 12749010.

20. US Department of Health and Human Services: National Institutes of Health NCI. Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. Available from: https://ctepcancergov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_5x7pdf. 2017.

21. Merkel SI, Voepel-Lewis T, Shayevitz JR, Malviya S. The FLACC: a behavioral scale for scoring postoperative pain in young children. Pediatr Nurs. 1997;23(3):293–297. 9220806.

22. Crellin DJ, Harrison D, Santamaria N, Babl FE. Systematic review of the Face, Legs, Activity, Cry and Consolability scale for assessing pain in infants and children: is it reliable, valid, and feasible for use? Pain. 2015;156(11):2132–2151. doi: 10.1097/j.pain.0000000000000305 26207651.

23. Matsuishi Y, Hoshino H, Shimojo N, Enomoto Y, Kido T, Hoshino T, et al. Verifying the validity and reliability of the Japanese version of the Face, Legs, Activity, Cry, Consolability (FLACC) Behavioral Scale. PLoS One. 2018;13(3):e0194094. doi: 10.1371/journal.pone.0194094 29534083; PubMed Central PMCID: PMC5849287.

24. Malviya S, Voepel-Lewis T, Burke C, Merkel S, Tait AR. The revised FLACC observational pain tool: improved reliability and validity for pain assessment in children with cognitive impairment. Paediatr Anaesth. 2006;16(3):258–265. doi: 10.1111/j.1460-9592.2005.01773.x 16490089.

25. Pedersen LK, Rahbek O, Nikolajsen L, Moller-Madsen B. The revised FLACC score: Reliability and validation for pain assessment in children with cerebral palsy. Scand J Pain. 2015;9(1):57–61. doi: 10.1016/j.sjpain.2015.06.007 29911640.

26. Perkins NJ, Schisterman EF. The inconsistency of "optimal" cutpoints obtained using two criteria based on the receiver operating characteristic curve. Am J Epidemiol. 2006;163(7): 670–675. doi: 10.1093/aje/kwj063 16410346; PubMed Central PMCID: PMC1444894.

27. Sherer Y, Levy Y, Langevitz P, Rauova L, Fabrizzi F, Shoenfeld Y. Adverse effects of intravenous immunoglobulin therapy in 56 patients with autoimmune diseases. Pharmacology. 2001;62(3): 133–137. doi: 10.1159/000056085 11287813.

28. Kwaan HC. Hyperviscosity in plasma cell dyscrasias. Clin Hemorheol Microcirc. 2013;55(1): 75–83. doi: 10.3233/CH-131691 23455837.

29. Stone MJ, Bogen SA. Evidence-based focused review of management of hyperviscosity syndrome. Blood. 2012;119(10): 2205–2208. doi: 10.1182/blood-2011-04-347690 22147890.

30. Bentley P, Rosso M, Sadnicka A, Israeli-Korn S, Laffan M, Sharma P. Intravenous immunoglobulin increases plasma viscosity without parallel rise in blood pressure. J Clin Pharm Ther. 2012;37(3):286–290. doi: 10.1111/j.1365-2710.2011.01287.x 21767284.

31. Lemm G. Composition and properties of IVIg preparations that affect tolerability and therapeutic efficacy. Neurology. 2002;59(12 Suppl 6): S28–32. doi: 10.1212/wnl.59.12_suppl_6.s28 12499468.

32. Saeedian M, Randhawa I. Immunoglobulin replacement therapy: a twenty-year review and current update. Int Arch Allergy Immunol. 2014;164(2): 151–166. doi: 10.1159/000363445 25011425.

33. Hurelbrink CB, Spies JM, Yiannikas C. Significant dermatological side effects of intravenous immunoglobulin. J Clin Neurosci. 2013;20(8): 1114–1116. doi: 10.1016/j.jocn.2012.10.026 23659929.

Článek vyšel v časopise


2020 Číslo 1
Nejčtenější tento týden