Intern seminar- Refractory Kawasaki disease Supervisor: Dr. 謝旻玲 Date: 2015/07/01

Identifying information Name:何O妤 Chart Number: 169568OO Sex: F Age: 1-year and 4-month old Date of Admission: 2015/05/28(Referred from Chia-Yi Christian Hospital)

Chief complaint Fever with skin rash for 10 days

At Chia-Yi Christian Hospital Admission since 5/18

Course of the disease Diarrhea 4 times (no blood-tinged or mucoid stool) PE finding: mild injected throat, bilateral clear breathing sounds and soft abdomen Intermittent fever up to 39.1°C Mild cough 5/16 5/17 5/18(admission, day 1) Leukocytosis (WBC:23.5K) CRP: 36.89 mg/L U/A: pyuria (WBC > 100/HPF) Renal echo: suspect left APN Stool: rotavirus positive Cefazolin and Gentamycin

Neck LAP(-) Induration edema(?) Marked hyperemic conjunctiva Erythematous and fissured lips Strawberry tongue Skin rash and erythematous BCG scar Neck LAP(-) Induration edema(?) 5/20(day 3) 5/22 (day 5) 5/23(day 6) 5/25(day 8) WBC:14.6K CRP: 137.4 WBC: 26.5K CRP: 100.5 ESR: 106 Albumin:3.1 WBC: 20.3K CRP: 97.85 mg/L ESR: 63 Albumin: 3.7 AST: 39; ALT:176 Cardiac echo: LCA: 0.267cm RCA: 0.152cm U/C:negative Highly suspect Kawasaki disease First IVIG(2g/kg) and Aspirin Augmentin

Intermittent fever persisted(up to 39.1°C) Lip fissure improved Desquamation(+) on fingers Skin rash partially resolved 5/26(day 9) 5/27(day 10) 5/28(day 11) WBC:27.4K CRP: 111.9 mg/L ESR: 113 Albumin:2.7 Second IVIG Suspect refractory Kawasaki disease -> Transferred to NCKUH

On admission (NCKUH) Fever for 10 days Bilateral conjunctiva injection Injected throat Erythematous lip with some cracks Skin rash over bilateral legs and trunk Desquamation over finger tips Cough with sputum

a minority of children develop obstructive jaundice from hydrops of the gallbladder 1)Situs solitus, levocardia 2)No chamber enlargement 3)Good LV systolic function with LVEF: 72% 4)Coronary artery dilatation; proximal LCA size: 0.370cm, distal LCA size: 0.255cm, RCA size: 0.169cm 5)Mild tricuspid regurgitation, PG: 21mmHg 6)Mild mitral regurgitation 7)Left arch, no COA

Clinical course BW: 11.5 kg Aspirin 1.5# Q6H Aspirin 0.5# QD Dipyridamole 0.2# TID WBC: 26.5K CRP: 85.4 ESR: 145 WBC: 21.9K CRP: 72.1 ESR: 138 WBC: 26.4K CRP: 31.9 ESR: 108

MBD Cardiac echo: severe coronary artery dilatation proximal LCA size: 0.488cm, distal LCA size: 0.368cm, RCA size: 0.437cm WBC: 32.3K CRP: 58 ESR: 121 WBC: 16.7K CRP: 36.6

Coronary artery aneurysm Meeting at least one of the following criteria by the Japanese Ministry of Health criteria: ●Internal lumen diameter >3 mm in children less than five years of age, or >4 in children five years of age or greater ●Internal diameter of a segment at least 1.5 times the size of an adjacent segment ●The coronary lumen is clearly irregular

A classification system based upon z scores: z <2: no coronary involvement 2< z <2.5: mild coronary ectasia or dilation 2.5 <z <5: Small aneurysms medium aneurysms: z score between 5 and <10 and absolute dimension <8 mm large or giant aneurysms: z scores of ≥10 or absolute dimension of ≥8 mm. Mean and prediction limits for 2 and 3 SDs for size of (A) LAD, (B) proximal RCA, and (C) LMCA according to body surface area for children <18 years old. LMCA z scores should not be based on dimension at orifice and immediate vicinity; enlargement of LMCA secondary to Kawasaki disease usually is associated with ectasia of LAD, LCX, or both. The dimensions of coronary arteries in children are small (in the order of a few milimeters in internal diameter). In order to minimize measurement errors, the echocardiogram should be obtained using a transducer with the highest possible frequency. The image should be zoomed before measuring coronary artery segments. Multiple measurements should be done to ensure reproducibility.

Discussion

Initial treatment of Kawasaki disease High dose IVIG(2g/kg), single dose, infusion over 10–12 h, within 10 days of onset of fever Reduce incidence of coronary artery aneurysm(CAA) to 5% Shorten duration of fever Plus Aspirin(80-100mg/kg/day) divided in 4 doses a day No prospective study of reducing CAA Aspirin is continued until complete resolution of CAAs has been established, or indefinitely in those patients who developed persistent CAAs. Newburger JW, Takahashi M, Beiser AS et al. A single intravenous infusion of γ globulin as compared with four infusions in the treatment of acute Kawasaki syndrome. N. Engl. J. Med.324(23), 1633–1639(1991).

Initial IVIG non-responders Persistent or recrudescent fever ≥36-48 h after the completion of the initial IVIG infusion Incidence:10-20% IVIG non-responders: significantly higher risk of CAAs (odds ratio: 10.38; 95% CI: 6.98–15.45) and of giant CAAs (odds ratio: 54.06; 95% CI: 12.84–227.65) Optimal therapy: controversial A large study of 15,940 Japanese patients reported in IVIG nonresponders a significantly higher risk of CAAs (odds ratio: 10.38; 95% CI: 6.98–15.45) and of giant CAAs (odds ratio: 54.06; 95% CI: 12.84–227.65) Uehara R, Belay ED, Maddox RA et al. Analysis of potential risk factors associated with nonresponse to initial intravenous immunoglobulin treatment among Kawasaki disease patients in Japan. Pediatr. Infect. Dis. J.27(2), 155–160(2008).

Prediction for IVIG non-responders laboratory data showed that neutrophil count, serum levels of CRP, TB, AST, ALT, and LDH were significantly higher (p=0.022, p=0.001, p<0.001, p<0.001, p<0.001, and p=0.008, respectively) in the IVIG-non-responsive group versus the IVIG-responsive group.

Prediction for IVIG non-responders

Prediction for IVIG non-responders

Management: IVIG retreatment Most experts recommend retreatment with IVIG, 2g/kg second dose effectiveness: up to 80% IVIG non-responders retreated with 1 g/kg infusion: a significantly greater likelihood of developing CAA (compared with 2 g/kg) Burns JC, et al. Intravenous γ-globulin treatment and retreatment in Kawasaki disease. US/Canadian Kawasaki Syndrome Study Group. Pediatr. Infect. Dis. J.17(12), 1144–1148(1998).

Other therapeutic options for failure of IVIG treatment Ultimate goal: To prevent or minimize dilatation of the coronary arteries aneurysms (defined as dilatation of coronary arteries to more than 4 mm internal diameter) 21

Steroids 3-day course of IV methylprednisolone (30mg/kg, once daily) v.s. 3rd IVIG(1g/kg) IVMP: faster resolution of fever Similar rate of CAAs Medical cost The recommendation of AHA: restrict steroid treatment to whom receive two or more IVIG infusions but ineffective Overall, these studies reported a faster resolution of fever, but a similar rate of CAAs in patients with IVIG failure treated with steroids compared with IVIG retreatment. Hashino K, et al. Re-treatment for immune globulin-resistant Kawasaki disease: a comparative study of additional immune globulin and steroid pulse therapy. Pediatr. Int.43(3), 211–217(2001).

TNF-α blockade The plasma level of TNF-α TNF-α polymorphism correlated with an increased risk of CAA TNF-α polymorphism may be associated with disease susceptibility A clinical trial in 24 children: infliximab (5 mg/kg) versus a second IVIG infusion (2 g/kg) in KD patients nonresponsive to the initial IVIG infusion: both safe and well tolerated a clinical trial in 24 children to assess the safety, tolerability and pharmacokinetics of infliximab (5 mg/kg) versus a second IVIG infusion (2 g/kg) in KD patients nonresponsive to the initial IVIG infusion. Both infliximab and IVIG retreatment were safe and well tolerated Burns JC, Best BM, Mejias A et al. Infliximab treatment of intravenous immunoglobulin-resistant Kawasaki disease. J. Pediatr.153(6), 833–838(2008). 23

Etanercept There are two types of TNF receptors: those found embedded in white blood cells that respond to TNF by releasing other cytokines, and soluble TNF receptors which are used to deactivate TNF and blunt the immune response. In addition, TNF receptors are found on the surface of virtually all nucleated cells (red blood cells, which are not nucleated, do not contain TNF receptors on their surface). Etanercept mimics the inhibitory effects of naturally occurring soluble TNF receptors, the difference being that etanercept, because it is a fusion protein rather than a simple TNF receptor, has a greatly extended half-life in the bloodstream, and therefore a more profound and long-lasting biologic effect than a naturally occurring soluble TNF receptor Tumor necrosis factor α activation of macrophages includes enhanced production and release of TNF-α receptor.Accordingly, patients with KD demonstrate marked elevation in serum soluble TNF-α receptor. Peripheral blood monocytes/macrophages obtained from patients with acute KD contain TNF-α–secreting granules. Tumor necrosis factor α stimulates migration of P-selectin and production of E-selectin, which promotes conformational changes in endothelium and offers a potential mechanism for development of vascular dilatation and coronary aneurysm noted in KD. Side effect: injection site reaction, headache, skin rash, GI upset, infection…

Multicenter, double-blind, randomized, and placebo-controlled trial Assess the efficacy of etanercept in reducing the intravenous immunoglobulin refractory rate during treatment of acute KD Each arm will enroll 110 patients who will receive 3 doses of study drug over 2 weeks in conjunction with standard therapy. Coronary artery dilation parameters will serve as secondary end points

Prospective open-label trial of etanercept in patients with KD (age range, 6 months- 5 years; n = 17) All received IVIG and high-dose aspirin Receiving etanercept immediately after IVIG infusion and then weekly two times No serious adverse events related to etanercept No patient demonstrated prolonged or recrudescent fever requiring re-treatment with IVIG No patient showed an increase in coronary artery diameter or new coronary artery dilation/cardiac dysfunction

Cyclosporin A Negative regulation of T-cell pathway Calcineurin/nuclear factor of activated T cells Suzuki et al: a pilot study of 28 Japanese patients with nonresponse to the initial and additional IVIG infusion Oral cyclosporin A treatment(4-8 mg/kg/d, oral administration) No serious adverse effects  CyA treatment was continued until the patients became afebrile and their CRP level decreased to a negative value  (median; 14) days. Suzuki H, Terai M, Hamada H et al. Cyclosporin A treatment for Kawasaki disease refractory to initial and additional intravenous immunoglobulin. Pediatr. Infect. Dis. J.30(10),871–876(2011).

Anti-IL-1 treatment Elevated levels of IL-1β in acute KD Patients Administration of IVIG Decrease in IL-1β secretion and increase of IL-1 RA production Anakinra First beneficial report on 2012: a case successfully treated with anakinra for 7 days after nonresponse to IVIG and IVMP nonresponsive to repeated IVIG treatment and intravenous methylprednisolone 28

Anti-CD20 treatment Marked increase of circulating B cells Cytotoxic immunoglobulins directed against endothelial cells A single case of Rituximab treatment: a boy not responded to three infusions of IVIG retreatment and steroid therapy Sauvaget E, Bonello B, David M, Chabrol B, Dubus JC, Bosdure E. Resistant Kawasaki disease treated with anti-CD20. J. Pediatr.160(5), 875–876(2012).

Methotrexate Lee TJ, Kim KH, Chun JK, Kim DS. Low-dose methotrexate therapy for intravenous immunoglobulin-resistant Kawasaki disease. Yonsei Med. J.49(5), 714–718(2008). Low-dose oral methotrexate therapy (10 mg/m2, once weekly until CRP levels normalized) administered in 17 IVIG-nonresponsive patients: Prompt resolution of fever and rapid improvement of inflammatory parameters Insufficient power to assess coronary artery outcomes and adverse effects .

Plasma exchange Reduce the incidence of CAAs Not generally recommended because of its medicals cost and possible risks hypotension, electrolyte abnormality, bleeding, allergy and infection

Therapy of early cardiovascular complications For patient without CAA or transient dilatation 6-8 wks: echocardiography follow up -> If normal: discontinue antiplatelet therapy Long-term treatment with aspirin recommended for patients with persistent coronary artery lesions Low-dose aspirin (3–5 mg/kg/day) for persistent small-to-medium-sized aneurysms(3–6 mm). Adjunctive anticoagulant for larger (>6 mm) or giant (>8 mm) aneurysms

A significantly lower incidence of myocardial infarction in patients with giant CAAs treated with a combination of low-dose aspirin and warfarin (n = 19; target INR: 1.5–2.5 IU) than in those treated with aspirin alone (n = 49). Sugahara Y, Ishii M, Muta H, Iemura M, Matsuishi T, Kato H. Warfarin therapy for giant aneurysm prevents myocardial infarction in Kawasaki disease. Pediatr. Cardiol.29(2),398–401(2008).

Cost Etanercept (Enbrel): 4600元(自費)/3834元; Cyclosporin:150元(自費)/100元 Child ≧ 2 yr: 0.4 mg/kg twice weekly or 0.8 mg/kg QW Cyclosporin:150元(自費)/100元 Oral: 1-3 mg/kg/day Rituximab: 40K元(自費)/30K元 375 mg/m2 once weekly for 4 doses No anakinra, infliximab

For our patient Discharge with Aspirin 0.5# QD Dipyridamole 0.2# TID 2nd and 3rd dose of Etanercept (Enbrel) at OPD

Take home message Diagnosis of Kawasaki disease Initial treatment of Kawasaki disease: high-dose IVIG (2g/kg) and aspirin Optimal therapy for refractory Kawasaki disease is still controversial, including IVIG retreatment and other therapeutic options (steroid, TNF-a blocker, cyclosporin A, anti IL-1, anti-CD20, methotrexate, plasma exchange)

Thank you for listening!!