Kawasaki disease and acute haemolytic anaemia after two IVIG infusions

ABSTRACT

Kawasaki disease (KD) is one of the most common vasculitis disorders of childhood, affecting predominantly medium-sized arteries, particularly the coronary arteries. For treatment, high-dose intravenous immunoglobulin (IVIG) is indicated. IVIG infusions are usually safe and well tolerated even though serious complications can be observed. We present a brief overview of KD and report a two-year-old girl with KD and two IVIG infusions (Gammagard®) because of persistent fever after the completion of the first IVIG. Haemolytic anaemia developed after IVIG retreatment. The direct antiglobulin test after haemolysis was positive. The etiology of the haemolysis was related to the presence of transient, passively acquired antibodies that cause a direct antibody-mediated attack. There are few reports of haemolytic anaemia after IVIG infusions. The haemolysis in KD is dose-dependent and occurs more frequently after the second IVIG dose. Non-0 blood group patients are at greater risk. Another factor increasing the risk of haemolysis is also the presence of anaemia due to inflammation in KD.

KEYWORDS:

• Kawasaki disease
• intravenous immunoglobulin
• haemolytic anaemia

Introduction

Kawasaki disease (KD) is one of the most common vasculitis disorders of childhood, affecting predominantly medium-sized arteries, particularly the coronary arteries. The disease causes coronary artery aneurysms (CAA) in 20%–25% of untreated patients. About 2%–3% of untreated cases die as a result of coronary vasculitis, myocardial infarction due to thrombosis or aneurysm rupture. KD is the main and the most important reason of myocardial infarction in childhood.[1] It is also potentially an important cause of long-term cardiac disease in adult life.[2] In the view of the frequency and severity of coronary artery complications, there have been great efforts put in treatment to reduce the risk of CAA. As stated by the American Heart Association (AHA), in 2004, administration of intravenous immunoglobulin (IVIG) (2 g/kg in a single infusion) combined with aspirin at a high dose (80–100 mg/kg/d in four divided doses) is effective in reducing the risk of CAA. This protocol has reduced the rate of coronary abnormalities to 3%–5%.[1,3]

Up to 20% of the patients may show IVIG resistance with consequent increased risk of developing CAA, unless they receive additional treatments.[3] These patients are indicated for a second IVIG infusion.[4] If it fails to elicit a response, an intravenous pulse of methylprednisolone is given at 30 mg/kg once daily for 1–3 days.[5]

History of KD in Bulgaria

The Children's Rheumatology Clinic, Medical University of Sofia, conducted a retrospective follow-up study and data analysis in all children with KD over a period of 21 years (1993–2014). One hundred and seven children with proven KD were enrolled (65 boys and 42 girls), aged 2 months to 13 years. The first infusion of IVIG for KD patients in Bulgaria started at the Pediatric Rheumatology Clinic in 1998. Since that time, 48 high-risk patients have been treated with IVIG. The number of patients was not large in the period from 1993 to 1998 because of inexperience in diagnosing KD. The condition was first reported by Tomisaku Kawasaki in 1967; however, the first description of the disease in the medical literature in English appeared in 1974.[6] The treatment of choice is IVIG plus high-dose aspirin. The preparations that have been used in our clinic during the follow-up period are Immunovenin® (Bulbio, Bulgaria), Gammagard® (Baxter), Kiovig® (Baxter) and Octagam® (Octapharma).

IVIG treatment and adverse effects

IVIGs are sterile, purified IgG products manufactured from pooled human plasma and typically contain more than 95% unmodified IgG, which have intact fragment crystallizable (Fc)-dependent effector functions and only trace amounts of immunoglobulin A (IgA) or immunoglobulin M (IgM).[7] There are next-generation products, such as Kiovig® which is a 10% triple virally reduced immunoglobulin.[8] The marketing authorizations for another drug, Octagam®, in the EU were suspended by the European Commission, following a review by the Committee for Medicinal Products for Human Use (CHMP) in September 2010 due to unexpected presence of factor XIa and kallikrein in Octagam®, which were identified as the main cause of serious thromboembolic events (including stroke, myocardial infarction and pulmonary embolism).[9] Critical steps were identified in the manufacturing process that could explain the presence of substances that triggered these thromboembolic events. After a number of corrective and preventive measures had been implemented and the manufacturing process had been improved, a year later, in 2011, the suspension of Octagam® was lifted by the European Medicines Agency. In addition to the improvements in the medicine's manufacturing process, the safeguards also included tests carried out before the release of batches of Octagam® to the market in order to detect components (e.g. factor XIa and others) that can trigger thromboembolic events.[9]

The high single-dose IVIG indicated in KD patients poses risks, given the infancy of the patients. Adverse events following IVIG infusions may be classified as immediate (occurring during the infusion itself) or delayed (occurring after the infusion has ceased). These adverse events may be due to the relative ‘impurity’ of the commercial preparations, or the undesirable effects of its active component (IgG). The most common adverse effects occur soon after infusions and can include headache, flushing, chills, myalgia, wheezing, tachycardia, lower back pain, nausea and hypotension.[10,11] In our hospital, shaking, chills and fever were observed in five children treated with Immunovenin (not highly purified preparation) and one child on Kiovig®. An allergic reaction (rash, fever, chills and dyspnoea) was observed in one patient on Immunovenin, requiring cessation of therapy. Increase in serum viscosity observed after high-dose IVIG had no clinical manifestations and no thromboembolic complications were observed in our patients. Plasma hyperosmolality is obvious through significant increase in the rate of erythrocyte sedimentation after IVIG observed in all treated children (paradoxically to improvement of inflammation and decrease in C-reactive protein, CRP). Five children had low level haemolytic anaemia due to the presence of isohaemogglutinins in IVIG. In two of these cases (a two-year-old child and a seven-months-old infant), anaemia was treated with substitution haemotransfusion. Only 2 of our 48 patients treated with IVIG were IVIG-resistant. These two patients received a second IVIG infusion in the same dose, followed by corticosteroid course per os. In both children, the coronary abnormalities (including small aneurysms) normalized quickly.

Here, we report a two-year-old girl with KD and two doses of IVIG infusion because of persistent fever and high risk of CAA and further complications. Haemolytic anaemia developed after the second IVIG infusion due to specific blood group antibodies causing direct antibody-mediated attack. The direct antiglobulin test (DAT) was positive. Anaemia was borderline to haemotransfusion. The girl recovered without red blood cell (RBC) transfusion but received a short course of prednisolone. There were no cardiac complications after the high-dose aspirin treatment, two IVIG infusions and a short course of prednisolone. There are not many reports of haemolytic anaemia after IVIG infusions, but paediatricians have to be aware of this complication especially in KD patients where some factors increase the risk of haemolysis.[12,13]

Case report

Case presentation

A two-year-old Caucasian girl, previously a healthy child, was admitted to the Pediatric University Hospital, Rheumatology Clinic, SBALDB “Prof. Ivan Mitev” (Sofia, Bulgaria) quite sick, febrile, very irritable, with bilateral conjunctival infection and cracked red lips. Twelve days before hospitalization, her symptoms had started with high-grade fever and a sore throat. Two days later, she developed a diffuse, non-itchy, erythematous rash on her extremities and trunk, her hands and feet got oedematous, and her paediatrician observed perineal desquamation. Antibiotic treatment was started because of suspicion of scarlet fever. The fever persisted and the child started vomiting and complaining of abdominal pain. She was referred to our hospital with diagnosis of urinary tract infection.

On admission, the child's rectal temperature was 38.4 °C, the radial pulse was 110 beats/min with 2/6 protosystolic murmur and 100/60 mmHg blood pressure. She had bilateral bulbar conjunctival infection without discharge. Her pharynx and tonsils were infected; she had a strawberry tongue, erythema of her lips and left-sided cervical lymphadenitis. There was residual slight hyperpigmentation of previous rash and some perineal desquamation. Initial desquamation of the fingertips was observed. The respiratory examination revealed normal breathing. The abdomen was soft, with the liver palpable 1 cm below the right costal margin. The blood test results showed white blood cell count of 14,600/mm³ (reference range of 5,500–15,500/mm³), 68% polymorphonuclear leucocytes, haemoglobin 11.4 g/L (reference range of 11.5–12.5 g/L), haematocrit 33.2% (reference range of 35%–40%), platelet count 72,400,000/mm³ (reference range of 150,000–350,000/mm³), erythrocyte sedimentation rate of 62 mm/h (reference range of 4–20 mm/h) and CRP was 211 mg/L (reference range of 0–6 mg/L). Alanine aminotransferase, aspartate aminotransferase, gamma glutamyl transferase, total protein, albumin, urea and creatinine were in the normal range. Urine analysis showed sterile leukocyturia. The throat culture and anti-streptolysin O titres were normal. The blood culture, urine culture and viral serology test results were normal, as well. The patient's chest radiogram and electrocardiogram were normal. The two-dimensional (2D) echocardiography showed a 0.4 mm dilatation of the left coronary artery (LCA) without any aneurysm formation. The patient was diagnosed with KD: early subacute phase, still feverish and at risk of further coronary damage. The patient was started on high-dose aspirin (83 mg/kg/d) divided into four doses and on IVIG infusion (2 g/kg). Approximately 40 h after completion of the first IVIG infusion, there was recrudescence of fever (38.8 °C) and the 2D echocardiography revealed LCA with two aneurysm formations, 0.5 mm nearby r. circumflexus. The patient was given a second infusion of IVIG. After that, she was afebrile and all residual symptoms of the acute phase of the disease subsided. Two days later, the patient became very pale and her haemoglobin level dropped to 65 g/L with 62% reticulocytosis. The high levels of lactate dehydrogenase 570 U/L (reference range of 140–304 U/L), indirect bilirubin 18 µmol/L (reference range of 0–34 µmol/L) and urobilinogenuria confirmed haemolytic anaemia. Mild splenomegaly was also present.

The patient's blood group was A1B Rh (D) pos. The DAT after haemolysis was positive (fixed anti-RBC ab-IgG, type anti-A1). The girl recovered without RBC transfusion but received a short course of prednisolone treatment, starting on 1 mg/kg/d and tapered in four weeks.

On follow-up, there was good clinical recovery without cardiovascular complications because of complete regression of the coronary aneurysms.

Case discussion

IVIG preparations are fractionated from a plasma pool of several thousand donors. IVIGs contain immune antibodies and physiologic autoantibodies.[14] Since the early 1980s, highly purified IVIG preparations were developed by a number of manufacturers, whereas, the first products consisted of so-called modified products (modification of the Fc-part of IgG to allow intravenous administration). Modern non-modified preparations, the so-called native IVIGs, are now the standard of care for the replacement therapy of patients with primary immunodeficiency and they are part of the therapy regimen.[8] IVIG is used in high doses, most frequently at 2 g/kg, as an immunomodulatory agent.[15] Its mode of action is still not well understood, but several mechanisms have been proposed: supply of idiotypic antibodies and inhibition of pathologic autoantibodies,[16] inhibition of macrocyte-mediated phagocytosis and suppression of pathogenic cytokines,[17] neutralization of superantigens, enhanced clearance of IgG, modulation of B- and T-cell function and complement modulation.[15,18] In KD, the effects of IVIG may be related to the neutralizing antibody activity in IVIG against proinflammatory cytokines and bacterial enterotoxins.[10] It is also considered possible that infused antibodies block the recognition of infected cells by cytotoxic T-lymphocytes, preventing immune-mediated damage.[19] IVIG could modulate the cytokine-mediated endothelial cell activation by neutralizing the effects of cytokines, inhibiting endothelial cell responses to cytokines or inhibiting the production of cytokines and growth factors.[20,21] IVIG is considered a safe product that is generally well tolerated.[12,22] Minor and self-limiting side effects in IVIG therapy are fever, chills, headache, myalgia and chest discomfort. Rarely, skin reactions and aseptic meningitis with severe headache can be observed. Severe but rare adverse events in IVIG therapy are anaphylactic reactions and hypersensitivity. Special attention is given to IgA deficient patients (prevalence of 1/1000 in the population), who are at risk of developing anaphylactic shock because of the IgA content in the IVIG preparation.[23] About 30% of these individuals exhibit anti-IgA antibodies, which can lead to the formation of macromolecular complexes if encountering the infused IgA. Routine screening for IgA deficiency prior to IVIG infusion is recommended.[9] Thromboembolic complications, such as stroke, myocardial infarction and deep venous thrombosis, are reported in IVIG-treated patients due to increased viscosity and expanded blood volume combined with pre-existing cardiovascular or haematological conditions.[24,25] Renal complications like acute renal tubular necrosis have also been reported.[23]

Haemolysis is another reported adverse effect of IVIG. IVIG is prepared from a pool of several thousands of healthy blood donors and it contains measurable levels of anti-A and anti-B (IgG subclass) as well as non-ABO erythrocyte antibodies (e.g. anti-D).[26] Clinically significant haemolysis is observed in patients who receive high-dose IVIG.[12] Daw et al. [27] reported significant haemolysis in 1.6% of high-dose IVIG-treated patients. Characteristics of these patients include a large dose of IVIG, female sex, non-O blood group and underlying inflammatory state. The authors propose a two-step mechanism of haemolysis: sensitization by ABO isohaemagglutinins followed by phagocytosis by activated macrophages.[27] Individual reports of acute haemolysis in children with KD treated with IVIG have been reported.[13,28] Our patient was treated with Gammagard® infusion and there are reports that this product has higher isohaemagglutinin titres than lyophilized ones.[29] Haemolysis after Gammagard® infusion is considered to be usually mild, but many patients require RBC transfusion, according to the overview of the literature covering not only KD patients.[30]

The etiology of haemolysis in KD patients who received IVIG is multifactorial. The most common one is the presence of transient, passively acquired antibodies (confirmed by positive DAT that causes direct antibody-mediated attack).[12] In our patient, there were specific blood group antibodies anti-A1-(blood group A1B) type. It is presumed that the haemolysis is dose-dependent, commonly seen after a second dose of IVIG for persistent fever (a total dose of 4 g/kg) as in the reported case. Patients with non-O blood groups are at a greater risk for haemolysis, due to their inability to neutralize the anti-A and/or anti-B isohaemagglutinins present in the plasma after IVIG infusion.[12,31] Other risk factors for haemolytic anaemia are the presence of anaemia due to inflammation in KD and the immune dysregulation in the disease.[30] Another possible mechanism is erythrophagocytosis due to the presence of high-molecular-weight IgG complexes in IVIG binding to complement receptors on RBCs.[32] In the light of available evidence, haemolytic anaemia should be considered in KD patients receiving IVIG, especially in those who need a second infusion.

Conclusions

KD is an acute febrile illness of early childhood that is associated with the development of CAA in 20%–25% of the cases. The occurrence of coronary artery abnormalities is effectively prevented using high-dose IVIG, which suppresses the pronounced immune activation associated with KD. IVIG therapy of KD seems to be effective and safe. In the majority of our KD patients, no or mild adverse side effects occurred. Haemolytic anaemia is a serious complication, although most patients do not have clinically significant haemolysis. Clinicians should be aware of the risk of haemolysis and should take appropriate preventive action when needed.

Disclosure statement

No potential conflict of interest was reported by the authors.