The use of intravenous immunoglobulin (IVIG) has expanded in the last decades, increasing the cost of this product.1 IVIG is used in multiple hematologic disorders, although its indication is not always US Food and Drug Administration-approved. In this article, we review the most common indications for IVIG in pediatric hematologic diseases.
Illustrative Case 1
An otherwise healthy 19-month-old girl presented with a history of “red dots” and bruising on her legs and arms. The complete blood count results with differential had a normal white blood cell (WBC) count and hemoglobin, but had a platelet count of 9 × 103/mcL. There were no peripheral blasts, and electrolytes, lactate dehydrogenase (LDH), and uric acid were within normal limits. Her parents reported that she had upper respiratory symptoms and a few loose stools approximately 2 weeks prior, but no other concerning symptoms. She had been afebrile, active, and playful, and did not have any mucosal bleeding.
After reviewing the peripheral blood smear and confirming the presence of large platelets, as well as the absence of any dysmorphic cells or blasts, she was diagnosed with immune thrombocytopenia (ITP). A watchful waiting strategy was implemented given the lack of mucosal bleeding with a close follow-up check in 1 week. At that time, the platelet count was 6 × 103/mcL, and she had experienced intermittent epistaxis for 2 days, with worsening bruises and petechiae on the lower extremities. Due to the new onset of mucosal bleeding, the patient received one dose of 0.8 g/kg of IVIG. The platelet count 1 week later improved to 245 × 103/mcL.
Illustrative Case 2
A 9-year-old girl presented to the hematology clinic with newly diagnosed ITP. She had no significant past medical history but did have a family history of rheumatologic disorders. She originally presented with petechiae, bruising, and upper respiratory symptoms. Her platelet count at the time was 1 × 103/mcL. The total WBC, absolute neutrophil count, and hemoglobin were within normal limits as was the LDH, uric acid, coagulation studies, and comprehensive metabolic panel. There were no blasts or dysmorphic cells on review of the peripheral blood smear. She was admitted to another hospital where she received two doses of 0.8 g/kg of IVIG with a platelet count at discharge of 48 × 103/mcL.
When she was evaluated in the hematology clinic for a follow-up check, she complained of headaches, low-grade fevers, and a few episodes of vomiting, thought to be related to the IVIG infusion. At that time, she also had developed wet purpura on her buccal mucosa, and a repeat platelet count was 5 × 103/mcL. She was treated with 1 mg/kg of prednisone for 5 days with a transient response. Several weeks later she started complaining of intermittent arthralgias and myalgias. She was evaluated by rheumatology and eventually diagnosed with systemic lupus erythematous (SLE).
Hematologic Uses of IVIG
IVIG can be used as treatment in multiple hematologic disorders (Table 1), including as a single first-line agent for ITP and parvovirus-associated red blood cell aplasia in immunocompromised patients. It is often administered with steroids when used for other autoimmune cytopenias or immune-mediated diseases.
Summary of Recommended Doses of IVIG per Hematologic Disease
Adverse reactions to IVIG are usually self-limited, mild to moderate in nature, and generally occur during the first infusion. The most common side effects are headaches, tachycardia, flushing, myalgias, chills, wheezing, lower back pain, nausea, and hypotension. The risk of adverse reactions is usually related to the rate of infusion and the dose, and can be controlled by premedicating patients with antihistamines and/or steroids.
ITP is an acquired immune-mediated disorder. It typically presents in toddlers with a recent history of viral infection and new onset of petechiae and/or ecchymoses with or without mucosal bleeding, and with no other associated symptoms. The course is usually benign, lasting less than 1 year, but can recur and become chronic. This is more likely in patients who present in later childhood or during adolescence. ITP is a diagnosis of exclusion based on clinical history, isolated thrombocytopenia, and careful evaluation of the peripheral smear to rule out the presence of leukemic blasts or other dysmorphic cells. On review of the peripheral smear, the diagnosis of ITP is supported by the presence of large platelets (Figure 1). Patients with ITP generally do not have lymphadenopathy, hepatosplenomegaly, or malaise, and the presence of any of these is suggestive of other causes of thrombocytopenia.2
Peripheral blood smear (Wright-Giemsa, 1,000×) from a patient diagnosed with immune thrombocytopenia. A large, hyper-granular platelet, the size of a red blood cell, can be observed on the left upper quadrant. The number of platelets is also decreased. Figure courtesy of Dr. Sandeep Gurbuxani (The University of Chicago, Chicago, IL).
Treatment of ITP varies with clinical presentation. The absolute number of platelets does not correlate with the risk of bleeding, as platelet function remains intact in ITP. If there are no signs of mucosal bleeding, a watchful waiting strategy can be used regardless of platelet count.3 This approach can be challenging, especially when treating active children, in which case first-line treatment such as IVIG, steroids, or anti-D immune globulin can be offered to the family.
IVIG has been used to treat ITP for decades; however, the mechanism of action is not completely understood. Blockage of the mononuclear phagocytic system to rescue antibody-sensitized platelets from phagocytosis, neutralization of autoantibodies, increased clearance of pathogenic autoantibodies, and cytokine and complement modulation are among the current postulated mechanisms of action for IVIG, although no one theory is completely accepted.2,4,5
If after careful consideration of the clinical scenario, including laboratory work, physical examination, and review of the peripheral smear, a patient is felt to have typical ITP, a bone marrow biopsy is not recommended. With that, inadvertent administration of steroids to a child with leukemia can lead to delays in diagnosis and potentially compromise the diagnostic testing. By using IVIG instead of steroids as a first-line treatment for ITP, one can avoid these consequences. Furthermore, IVIG has a more rapid response than steroids, which is important if bleeding symptoms are present.2,3 ITP is rarely associated with serious complications and patients generally achieve remission within 6 months. It is important to emphasize that no medical treatment will alter the natural course of the disease. For most patients, platelet counts and symptoms will wax and wane between 3 and 6 months and will ultimately resolve spontaneously. However, patients who will ultimately be diagnosed with chronic ITP will have recurrence of thrombocytopenia and symptoms despite initial interventions. Effective therapies (IVIG, steroids, or anti-D immune globulin) can be given as needed for patients with persistent or recurrent symptoms, especially during the first 12 months. If the disease becomes chronic, other therapeutic approaches, such as rituximab, thrombopoietin receptor agonists, or splenectomy can be implemented. However, those therapies are beyond the scope of this article.3
Autoimmune Hemolytic Anemia
Autoimmune hemolytic anemia (AIHA) is a heterogeneous group of disorders caused by autoantibodies against red blood cells.6 AIHA is a rare disease affecting about 1 to 3 people in 100,000 annually. It usually presents in adults with a peak in the fourth and fifth decades of life, and has the tendency to become chronic. However, in children, it is generally a self-limited disease precipitated by a viral infection. AIHA is traditionally classified into warm, cold, and mixed type based on the temperature in which autoantibodies react against red blood cells and produce hemolysis in the laboratory. Warm AIHA is immunoglobulin (Ig) G-mediated and accounts for 75% of all cases; it is usually idiopathic and most often affects children. Cold AIHA compromises 15% of all cases, generally presents in adults and elderly patients, and is IgM-mediated and complement-mediated. Mixed type AIHA is less common and is characterized by the presence of both warm and cold autoantibodies.7 AIHA can be further classified as primary (idiopathic) or secondary. Secondary causes include lymphoproliferative disorders, malignancies, immunodeficiency disorders, and certain drugs. It can also be a component of other autoimmune syndromes, such as Evan's syndrome or autoimmune lymphoproliferative syndrome (ALPS).8 Patients present with symptoms of anemia (dizziness, pallor, and/or palpitations) and signs of hemolysis (jaundice, hemoglobinuria, anemia, reticulocytosis, positive Coombs test, elevated LDH, and/or low haptoglobin).9 The onset of symptoms is typically insidious, but patients can also present with life-threatening anemia and signs of heart failure.7,10 Glucocorticoids are the mainstay of treatment of warm AIHA and are administered until the hemoglobin is higher than 10 g/dL and the hematocrit is higher than 30%.10 About 80% of patients respond well to a short course of steroids. IVIG can be used concomitantly with steroids or as a second-line agent, but its role is limited.1,11 IVIG is generally reserved for transfusion-dependent patients or those who do not respond to steroids.12 IVIG should not be given as a single agent, as only 39% of patients respond to this treatment.11
Evan's syndrome is a rare disease initially described by Evans et al.13 in 1951. To make the diagnosis, at least two autoimmune cytopenias (ITP ± AIHA ± autoimmune neutropenia) should occur either simultaneously or sequentially in the absence of any other systemic disorder.14 The diagnosis can be delayed for months until a second cytopenia occurs. The exact pathophysiology of Evan's syndrome is unknown, but seems to be related to a disorder of humoral and cellular immunity.14 The clinical presentation depends on the cell lines that are affected and include signs of hemolytic anemia, thrombocytopenia, and neutropenia. Most patients present with thrombocytopenia or anemia.15 Evan's syndrome is a diagnosis of exclusion and other diseases such as ALPS, common variable immune deficiency (CVID), HIV, SLE, and IgA deficiency should be excluded.16 Treatment is always challenging, and morbidity is significant even with treatment. Patients go through periods of remission and recurrences, and they do not always respond to therapy.
First-line therapy involves steroids with or without IVIG. IVIG should not be used as a single first-line agent, and there are no studies evaluating whether coadministration of steroids with IVIG improves remission rates or not, although their concomitant use is common practice. Even after repeated courses of steroids and IVIG, most patients have another recurrence and require second-line treatment with immunosuppressive agents (rituximab, cyclophosphamide, mycophenolate mofetil, danazol).14
Autoimmune Lymphoproliferative Syndrome
ALPS is an inherited disorder of lymphocyte apoptosis. A dysregulation in the first apoptotic signal apoptotic pathway in lymphocytes causes an accumulation of lymphocytes that eventually manifests with chronic (>6 months) noninfectious, nonmalignant lymphadenopathy, hepatosplenomegaly, and recurring autoimmune cytopenias. The diagnosis of ALPS is based on clinical presentation, genetic mutations, and specific immunologic markers.17,18 The majority of patients diagnosed with ALPS have an autosomal-dominant somatic or germline mutation.17,18
Clinical presentation usually overlaps with other hematologic disorders (lymphoma, hemophagocytic lymphohistiocytosis, Evan's syndrome, and CVID, among others), making the diagnosis challenging. Increased double-negative T-cells (TCRab+, CD3+/CD4−/CD8− T cells) are pathognomonic of ALPS, but their role in the pathophysiology of the disease is unclear. IVIG plays a role as a therapeutic agent in patients with ALPS syndrome to treat autoimmune cytopenias. The same recommendations for sporadic autoimmune cytopenias also apply for patients with ALPS syndrome.1,3,17 IVIG should be coadministrated with high-dose oral steroids as part of the initial treatment. Patients with relapsed cytopenias will benefit from higher doses of IV steroids with or without IVIG, but they will eventually require steroid-sparing therapies and even splenectomy if splenomegaly is the primary cause of cytopenias.17,18
Acquired Red Blood Cell Aplasia
Pure red cell aplasia (PRCA) is characterized by severe normochromic, normocytic anemia, and low reticulocyte count. When a bone marrow biopsy is done, the absence of erythroblasts in an otherwise normal bone marrow is observed. PRCA can be a primary disorder (usually idiopathic) or secondary to underlying pathology (malignancy, autoimmune disease, drug related, infection, or ABO-incompatible stem cell transplant, which is when the donor and recipient have different ABO blood type).19,20
Treatment varies with severity of presentation and with the presence or absence of an underlying disease. If the presumed diagnosis is idiopathic self-limited PRCA, observation alone is recommended for at least 1 month as those patients usually recover without intervention.19 If PRCA is thought to be drug-induced, waiting for resolution of symptoms after discontinuation of the offensive medication is encouraged as well.19 A particular subtype of PRCA occurs in patients who are immunocompromised as a result of HIV, organ transplantation, or chemotherapy and develop chronic parvovirus B19 infection. In these groups of patients, IVIG should be considered first-line therapy.1,19
Secondary forms of PRCA that do not respond to management of the primary disease are treated with immunosuppressive therapy to maintain remission.20
IVIG for Hematologic Disorders in Neonates
Rh incompatibility anemia is a type of hemolytic disease of the newborn that occurs when mothers who are Rh-negative produce antibodies against fetal Rh-positive red blood cells. The disease presents in second or subsequent pregnancies of mothers who are Rh-negative and fathers who are Rh-positive after the mother has been sensitized to the D antigen. Incidence significantly decreases with the administration of Rho(D) immune globulin in women who are Rh-negative during their first pregnancy and soon after delivery. The mainstay of treatment for newborns with Rh hemolytic disease consists of intensive phototherapy and exchange transfusion. The American Academy of Pediatrics (AAP) recommends IVIG if the total bilirubin rises despite phototherapy and if it reaches the level for an exchange transfusion.21 However, a recent randomized, double-blind, placebo-controlled trial in neonates with Rh hemolytic disease cast doubt on this approach and concluded that the use of IVIG does not reduce the risk of adverse outcomes or the need for exchange transfusion.22 As of today, there are no new recommendations from the AAP based on this study. We encourage that decisions for these patients be made in conjunction with both a neonatologist and a pediatric hematologist.
Neonatal Alloimmune Thrombocytopenia
Neonatal alloimmune thrombocytopenia (NAIT) is caused by maternal alloantibodies against paternally inherited antigens on fetal platelets. The incidence is 1 in 1,000 live births and is defined as a platelet count at birth of <150 × 103/mcL.23 NAIT can occur in first pregnancies, in contrast to Rh-hemolytic disease, but is typically not diagnosed until delivery of a symptomatic infant.23,24 Treatment consists of antigen-negative compatible platelets from the mother or an unrelated donor. Treatment is indicated for symptomatic patients, full-term babies with a platelet count <30 × 103/mcL, preterm babies whose platelet count is <50 ×103/mcL, and patients with intracranial bleeding if the platelet count is <100 × 103/mcL.23,24 If such platelets are not available, or in patients who require multiple platelet transfusions, IVIG can be administered, although it does not have an immediate effect on the platelet count.25 In general, it takes 24 to 72 hours for the maximum effect on platelet counts after IVIG infusion, exposing neonates to long periods of thrombocytopenia.23
The chance of recurrences in future pregnancies is 100% if the father is homozygous for the responsible platelet antigen, and 50% if the father is heterozygous. Furthermore, the severity of the disease increases with each pregnancy. Testing is available to determine the risk for future pregnancies, and maternal counseling is extremely important to help prevent complications. IVIG is usually recommended as first-line therapy in pregnant women with a history of an infant born with NAIT.1,23 Other possible interventions are corticosteroids or intrauterine platelet transfusions, which must be managed by a trained, high-risk obstetrician.
IVIG has been broadly used in various medical fields including neurology, rheumatology, and hematology. Although IVIG is considered a safe product, side effects are not unusual, and it is a costly medication. In the field of pediatric hematology, IVIG is mostly used for the treatment of autoimmune cytopenias, and although there are postulated mechanisms, the precise mechanism of action remains unknown. Besides acute ITP and PRCA secondary to parvovirus B in immunocompromised patients, IVIG is not recommended as a single first-line agent given sparse evidence and a lack of randomized trials. In other hematologic disorders, it is generally given with systemic steroids, once malignancy is comfortably ruled out.
- Anderson D, Ali K, Blanchette V, et al. Guidelines on the use of intravenous immune globulin for hematologic conditions. Transfus Med Rev. 2007;21(2 Suppl 1):S9–56. doi:10.1016/j.tmrv.2007.01.001 [CrossRef]
- Provan D, Stasi R, Newland AC, et al. International consensus report on the investigation and management of primary immune thrombocytopenia. Blood. 2010;115(2):168–186. doi:10.1182/blood-2009-06-225565 [CrossRef]
- Neunert C, Lim W, Crowther M, Cohen A, Solberg L Jr, Crowther MA. The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia. Blood. 2011;117(16):4190–4207. doi:10.1182/blood-2010-08-302984 [CrossRef]
- Crow AR, Lazarus AH. The mechanisms of action of intravenous immunoglobulin and polyclonal anti-d immunoglobulin in the amelioration of immune thrombocytopenic purpura: what do we really know?Transfus Med Rev. 2008;22(2):103–116. doi:10.1016/j.tmrv.2007.12.001 [CrossRef]
- Schwab I, Nimmerjahn F. Intravenous immunoglobulin therapy: how does IgG modulate the immune system?Nat Rev Immunol. 2013;13(3):176–189. doi:10.1038/nri3401 [CrossRef]
- Sarper N, Caki Kilic S, Zengin E, Gelen SA. Management of autoimmune hemolytic anemia in children and adolescents: a single center experience. Turk J Haematol. 2011;28(3):198–205. doi:10.5152/tjh.2011.54 [CrossRef]
- Bass GF, Tuscano ET, Tuscano JM. Diagnosis and classification of autoimmune hemolytic anemia. Autoimmun Rev. 2014;13(4–5):560–564. doi:10.1016/j.autrev.2013.11.010 [CrossRef]
- Aladjidi N, Leverger G, Leblanc T, et al. New insights into childhood autoimmune hemolytic anemia: a French national observational study of 265 children. Haematologica. 2011;96(5):655–663. doi:10.3324/haematol.2010.036053 [CrossRef]
- Vagace JM, Bajo R, Gervasini G. Diagnostic and therapeutic challenges of primary autoimmune haemolytic anaemia in children. Arch Dis Child. 2014;99(7):668–673. doi:10.1136/archdischild-2013-305748 [CrossRef]
- Lechner K, Jager U. How I treat autoimmune hemolytic anemias in adults. Blood. 2010;116(11):1831–1838. doi:10.1182/blood-2010-03-259325 [CrossRef]
- Flores G, Cunningham-Rundles C, Newland AC, Bussel JB. Efficacy of intravenous immunoglobulin in the treatment of autoimmune hemolytic anemia: results in 73 patients. Am J Hematol. 1993;44(4):237–242. doi:10.1002/ajh.2830440404 [CrossRef]
- Michel M. Warm autoimmune hemolytic anemia: advances in pathophysiology and treatment. Presse Med. 2014;43(4 Pt 2):e97–e104. doi:10.1016/j.lpm.2014.02.009 [CrossRef]
- Evans RS, Takahashi K, Duane RT, Payne R, Liu C. Primary thrombocytopenic purpura and acquired hemolytic anemia; evidence for a common etiology. AMA Arch Intern Med. 1951;87(1):48–65. doi:10.1001/archinte.1951.03810010058005 [CrossRef]
- Norton A, Roberts I. Management of Evans syndrome. Br J Haematol. 2006;132(2):125–137. doi:10.1111/j.1365-2141.2005.05809.x [CrossRef]
- Mathew P, Chen G, Wang W. Evans syndrome: results of a national survey. J Pediatr Hematol Oncol. 1997;19(5):433–437. doi:10.1097/00043426-199709000-00005 [CrossRef]
- Schreiber AD, Chou ST. Nathan and Oski's Hematology and Oncology of Infancy and Childhood. 8th ed. Philadelphia, PA: Elsevier/Saunders; 2015.
- Rao VK, Oliveira JB. How I treat autoimmune lymphoproliferative syndrome. Blood. 2011;118(22):5741–5751. doi:10.1182/blood-2011-07-325217 [CrossRef]
- George LA, Teachey DT. Optimal management of autoimmune lymphoproliferative syndrome in children. Paediatr Drugs. 2016;18(4):261–272. doi:10.1007/s40272-016-0175-3 [CrossRef]
- Sawada K, Fujishima N, Hirokawa M. Acquired pure red cell aplasia: updated review of treatment. Br J Haematol. 2008;142(4):505–514. doi:10.1111/j.1365-2141.2008.07216.x [CrossRef]
- Sawada K, Hirokawa M, Fujishima N. Diagnosis and management of acquired pure red cell aplasia. Hematol Oncol Clin North Am. 2009;23(2):249–259. doi:10.1016/j.hoc.2009.01.009 [CrossRef]
- American Academy of Pediatrics Subcommittee on Hyperbilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics. 2004;114(1):297–316. doi:10.1542/peds.114.1.297 [CrossRef]
- Smits-Wintjens VE, Walther FJ, Rath ME, et al. Intravenous immunoglobulin in neonates with rhesus hemolytic disease: a randomized controlled trial. Pediatrics. 2011;127(4):680–686. doi:10.1542/peds.2010-3242 [CrossRef]
- Risson DC, Davies MW, Williams BA. Review of neonatal alloimmune thrombocytopenia. J Paediatr Child Health. 2012;48(9):816–822. doi:10.1111/j.1440-1754.2012.02528.x [CrossRef]
- McQuilten ZK, Wood EM, Savoia H, Cole S. A review of pathophysiology and current treatment for neonatal alloimmune thrombocytopenia (NAIT) and introducing the Australian NAIT registry. Aust N Z J Obstet Gynaecol. 2011;51(3):191–198. doi:10.1111/j.1479-828X.2010.01270.x [CrossRef]
- Sillers L, Van Slambrouck C, Lapping-Carr G. Neonatal thrombocytopenia: etiology and diagnosis. Pediatr Ann. 2015;44(7):e175–180. doi:10.3928/00904481-20150710-11 [CrossRef]
Summary of Recommended Doses of IVIG per Hematologic Disease
||0.8 to 1 g/kg per dose3
||IVIG or corticosteroids or anti-D in Rh+patients
||2 g/kg/day over 2 days12
||Corticosteroids are the first-line therapy; IVIG can be used as a second-line therapy but it has limited efficacy
||2 g/kg in divided doses14
||Corticosteroids ±IVIG are used as first-line therapy
||1 to 2 g/kg18
||Pulse of corticosteroids followed by taper ±IVIG
||0.5 g/kg weekly for 4 weeks1
||IVIG is the first-line therapy for parvovirus B19-related PRCA in immunocompromised patients
||0.5 to 1 g/kg (use if the TSB is rising despite intensive phototherapy or the TSB level is within 2 to 3 mg/dL of the exchange level; repeat in 12 hours if necessary21)
||IVIG is recommended as an alternativetherapy to exchange transfusion for rhesus hemolytic disease. However, recent data question this approach18
||1 g/kg for 1 to 3 days25
||IVIG is used as an adjunctive therapy for neonates that require multiple transfusions