1. Henoch Schonlein Purpura and Kawasaki Disease Peter Henning, DO MAJ, MC, USA 2 December 2008

2. Overview Summary Epidemiology Etiology and Pathogenesis Clinical Manifestations Diagnosis Treatment

3. Henoch Schonlein Purpura (HSP) Most common systemic vasculitis in children Etiology - Unknown Pathogenesis – End organ IgA immune complex (IC) deposition Diagnosis - Clinical – Palpable purpura- Abdominal pain – Renal disease- Arthritis Complication - Renal Treatment - Typically symptomatic – Disease usually self limited – Unclear role of corticosteroids in TX – No specific agent proven efficacious for persistent renal disease

4. Epidemiology Disease of early childhood – 20/100K in UK children < 17 years-old – 70/100K in UK children 4-6 years-old – No comparable data in adults, less common Male : Female 1.2-1.8 : 1 Less common in African American children More severe course in adults – More frequent and severe renal disease – Requirement for more aggressive treatment Seasonal variance; rare in summer Arthritis Rheum 1997 May;40(5):859-64

5. Etiology UNKNOWN Precipitating antigen may be infectious – Many cases follow URI Twins following simultaneous adenovirus: – HSP in one, IgA nephropathy in other J Pediatr 1985 Jan;106(1):27-32.

6. Pathogenesis Immune-complex mediated disease – IgA IC deposition within affected organs – Leukocytoclastic vasculitis of post capillary venules – IC of IgA1 ONLY subtype – Complexes activate complement (alternative) Hinge region O-linked glycans of IgA1 are deficient in galactose and/or sialic acid content – Renal mesangial cells bind galactose/sialic acid deficient hinge regions Berger’s disease (IgA nephropathy) also involves IgA1 exclusively

7. Clinical Features Classic Tetrad (cumulative incidence) – Rash (100%) – Arthralgias (82%) – Abdominal pain (63%) GI bleeding (33%) – Renal disease (40%) Presenting feature by % – Rash 74% – Arthralgias 15% – Abdominal pain 12% Medicine (Baltimore) 1999 Nov;78(6):395-409.

8. Classification Criteria ACR 1990 Palpable Purpura Age at onset < 20 years Actue abdominal pain BX – Granulocytes in walls of small arterioles / venules > or = 2 90% Sns / Spc EULAR / PRES 2005 Palpable purpura WITHOUT coagulopathy or PLTs AND Diffuse abd pain Arthritis or arthralgia BX with IgA deposition

9. Palpable Purpura Erythematous macules petechia / palpable purpura – NORMAL clotting studies and platelets Appears in crops Symmetric distribution – Gravity / pressure dependent areas Dependent & periorbital edema in children < 3 Palpable purpura DDX: – Mixed cryoglobulinemia – Hypersensitivity vasculitis

11. Arthralgias Transient, migratory oligo Knees and ankles > upper extremity joints Non-destructive Prominent periarticular swelling without synovitis Significant pain and limited use / ROM DDX – JIA, RF, SLE

12. Gastrointestinal Mild Nausea / vomiting Collicky abdominal pain Ileus Severe GI bleed Bowel ischemia / necrosis Intussusception Abd pain due to submucosal hemorrhage, edema ABNL endoscopy, small bowel series Onset within 8 days of rash Melana or hematochezia in 25% Occult bleeding in 50%

13. Gastrointestinal Intussusception – Most common serious GI complication (3.5%) Limited to small bowel in 60% of cases Initial diagnostic test – Ultrasound instead of contrast enema DDX – Appendicitis

15. Renal Disease Renal involvement in 20-54% of HSP pts – 2 days to 4 weeks after onset of systemic symptoms Retrospective review of 261 pts – Micro hematuria 11% (n=37) – Gross hematuria 5% (n=12) – Concominant proteinuria57% (n=28) Most patients suffer only mild disease Good prognosis –21 / 1133 pts (1.8%) with renal impairment at 6wks - 36yrs Chang WL. Ped Nephro 2005; 20(9):1269. Narchi H. Arch Dis Child 2005; 90(9):916.

16. Renal Disease General correlation between disease severity and biopsy findings Asymptomatic hematuria: focal mesangial proliferation Proteinuria: cellular proliferation Nephrotic range proteinuria: crescents Percentage of glomeruli with crescents has prognostic significance >50% – 37% progressed to ESRD – 18% with CRI DDX – Berger’s Disease J Am Soc Nephrol 1999 Dec;10(12):2637-44

17. Clinical Findings in Adults with HSP Less common Similar to children Exceptions – Intussusception rare – Increased risk of renal involvement

18. Diagnosis CLINICAL CLASSIFICATION CRITERIA Gold Standard: BIOPSY – Unusual presentation or significant renal disease – Adults due to decreased incidence – Typically skin or kidney – IgA deposition by immunofluorescence (IF)

19. Skin Biopsy Superficial dermis sufficient BX < 24 hour-old lesion – Older lesions with less specific changes Leukocytoclastic vasculitis in post capillary venules IgA deposition

20. Renal Biopsy Reserved for patients with severe renal involvement IgA deposition in mesangium – IgG, fibrin, C3 Mesangial proliferation to crescentic GN – BX generally parallels clinical disease severity

21. Additional Diagnostics Labs – NL coagulation studies, platelets Due to DDX considerations – Labs non specific – UA at DX and F/U Imaging – Plain films – Abdominal ultrasound

22. Treatment Complete recovery 94% children, 89% of adults Supportive TX in vast majority – Rest – Hydration – NSAIDS Hospitalization – Complications: GI, renal – Severe SXs: GI, dehydration, arthritis

23. Treatment: Corticosteroids (CS) Reported benefits – duration abd pain, risk of recurrence, intussusception and renal involvement Literature review, 2007 – CS may duration of abd pain and risk of persistent renal disease – Significant limitations 2 RCT’s – 40 outpatients TX oral prednisone 2mg/kg x 1 week NO difference at one year in renal involvement – 171 hospitalized pts TX oral prednisone x 1 month NO difference in rate of renal involvement HOWEVER greater resolution at 6 mos in those with renal involvement abd and joint pain Further study needed Weiss PF. Pediatrics 2007; 120(5):1079.

24. Treatment: Specific TX GI – CS not proven to decrease risk of intussusception Renal disease – No prospective studies Methylprednisolone pulse followed by oral (1mg/kg) x 3 months CS and azathioprine CS, cyclophosphamide, anticoagulation Efficacies of plasmapheresis and IVIG are uncertain – TXP: clinically evident recurrence in 35% of patients at 10 years Medicine (Baltimore) 1999 Nov;78(6):395-409.

25. Recurrence Reported in 1/3 of affected children – Usually within 4 months of presentation – Recurrences shorter, more mild – More common in pts with renal involvement

26. Kawasaki Disease (KD)

27. Mucocutaneous lymph node syndrome 2nd most common childhood vasculitis < 5 year old, Asian Acute, self-limited medium-vessel vasculitis – Fever- Conjuctivitis – Rash- Mucositis – Extremity changes - LAD Complicated by coronary artery aneurysm (CA) IVIG dramatic improves morbity / mortality – 4X prevalence of CA in pts TX with IVIG within 10 days Furusho, K. Lancet 1984, 2(8411): 1055.

28. Epidemiology 85% of cases in children < 5 years Peak age 9-12 months 3% in children < 6 months Isolated case reports in adults 1.5:1 male to female ratio Genetic – 10x risk if affected sibling – 2x risk if affected parent

29. Epidemiology Annual incidence varies – Japan ~100/100,000 children < 5 years Increasing? – South America – 3/100,000 – US – 17/100,000 > 5 years 9/100,000 among Caucasians 17/100,000 among African-Americans 33/100,000 among Asians

30. Etiology UNKNOWN Genetic Factors – High incidence among Asians and Asian-Americans – Relative risk of siblings of index case is 10 (Japanese data) Inositol 1,4,5-triphosphate 3-kinase (ITPKC) – Negative regulator of T-cell activation – Polymorphism of ITPKC assd with increased risk of KD Multiple HLA allele associations – B5, B44, Bw51, DR3 and DRB3*0301 in Caucasians – B54, Bw15 and Bw35 in Japanese – Bw51 in Israelis

31. Etiology – Infectious Agent? Circumstatital supporting data – Similar clinical features to other infectious diseases – Seasonal peak in winter and spring – Geographically focal epidemics – Houoshold contacts (Japan) at increased risk – Peak incidence in toddler age group and rare cases in infants < 3 months Protective effect of transplacental antibodies? HOWEVER – NO substantiated specific infectious association

32. Pathogenesis Aberrant immune response – Activated macrophages Subendothelial inflammation Transmural inflammation Destruction of the media and aneurysm formation

33. Clinical Manifestations Fever Bilateral conjunctivitis Mucositis Polymorphous rash Extremity changes Cervical LAD Arthritis Lipid abnormalities Renal/urinary findings Vasculitis – Coronary artery aneurysm – Cardiac complications

34. Fever 100% of patients – Consider KD in children with unexplained fever > 5 days 38 o to > 40 o C Persistent ; > 5 consecutive days – Untreated, usually lasts 1-2 weeks – Fever > 4 weeks, suspect other etiology Unresponsive to antibiotics, antipyretics

35. Conjuctivitis Bilateral Seen in > 85% of patients Onset within 2-4 days of fever onset Non exudative Blubar – spares the limbus May present with acute, anterior uveitis, photophobia Usually subsides within one week Courtesy of Robert Sundel, MD.

36. Mucositis 90% of pts 2-5 days after fever onset Discrete lesions NOT typical Fissuring/cracking of lips “Strawberry” tongue Courtesy of Robert Sundel, MD.

37. Name two other diseases in which you can see a “strawberry” tongue? Scarlet fever and toxic shock syndrome

38. Rash POLYMORPHOUS 80% of pts Within 1-5 days of fever onset Trunk and extremities Frequently pruritic Disappears when fever subsides

39. Extremity Changes 70% of pts – Last SXs to develop Painful erythema hands / feet Indurated edema Desquamation Disappear with resolution of fever Arthritis – 7.5-25% of cases – Oligo and poly of large joints – No prognostic difference b/t pts with and without arthritis

40. Eponym for transverse nail depressions (below) seen after KD?

41. Eponym for these transverse nail depressions? Beau’s lines Develop in response to many diseases (uncontrolled DM, syphilis) including acute illnesses accompanied by high fevers. such as scarlet fever, KS, measles, mumps and pneumonia.

42. Lymphadenopathy Least consistent feature – Absent in 50-75% Frequently unilateral Usually anterior cervical – NOT generalized LAD > One lymph node>1.5cm

43. Lab Findings Markers of inflammation – ESR, CRP, leukocytosis, thrombocytosis Lipid ABNL – TG, LDL – HDL – NL with TX NC, NC anemia LFTs – Hepatic congestion CSF – Mononuclear pleocytosis UA with WBCs

44. Differential Diagnosis Most common DDX = exanthems of childhood DX clues – Absence of fever – Presence of …. (SXs NOT consistent with KD) EXUDATIVE conjunctivitis or pharyngitis Bullous or vesicular rash Generalized LAD

45. Differential Diagnosis Viral – Measles, EBV, echo and adenovirus Toxin Mediated – Toxic shock syndrome, scarlet fever RMSF, leptospirosis Drug Reaction – Steven’s Johnson Systemic JIA

46. Cardiovascular Complications Major cause of morbidity and mortality – Coronary artery aneurysm (CA) – Coronary arteritis – Decreased intropy – Myocarditis and pericarditis – Mitral valve regurgitation (mild) Near universal coronary artery involvement Infants < 1 year-old at increased risk Treatment directed at preventing aneurysm formation

47. Coronary Artery Aneurysm 20-25% untreated vs. 4-13% treated Findings associated with CA – Age 6- Male – Fever > 14 days - Na+ < 135 mEq/L – HCT 12K / mm 3 Prognosis dependant on size, shape – Best small (<8mm), fusiform (vs. saccular) Complications – Rupture- Thrombosis – MI- Stenosis after regression

48. Coronary Artery Aneurysm

50. Other Complications Renal – rare aside from sterile pyuria – ARF due to multiple mechanisms GI – rare – Case series 10 patients, 5 gallbladder hydrops Macrophage activation syndrome – Case reports

51. Diagnosis: Diagnostic Criteria Fever for > 5 days plus – Four of five following: – Bilateral conjunctivitis – Mucositis – Polymorphous rash – Extremity changes – Cervical adenopathy No other identifiable cause

52. Diagnosis: Incomplete KD Definition – Presentation c/w KD but < 4 DX criteria Why is incomplete KD important? – CA risk – Delayed treatment – Poor prognosis for patients with incomplete KD Infants < 6 months at particular risk – Tend to have less complete presentation Chang, FY. Infect Dis Jour. 2006; 25(3):241.

53. AHA / AAP Guidelines: Evaluation of Incomplete KD Newburger, JW. Pediatrics 2004; 114:1708. Supplemental Lab Criteria: Albumin 3.0 Anemia for age Elevated ALT PLT > 450K after 7 days WBC >15K UA with > 10 WBC / HPF

54. Treatment - IVIG Only proven definitive therapy Which patients should be treated? Multiple risk (CA) scoring algorithms – none validated All patients DX with KD or incomplete KD Why? Efficacy; 6 RCTs, 1626 pts TherapyCA at 30 daysCA at 60 days ASA alone26%18% IVIG 1gm/kg16%10% IVIG 2gm/kg4% Teraj, M. Jour Ped 1997; 131(6):888.

55. Treatment - IVIG Dose: 2mg/kg over 8-12 hours – Despite dose response, lack of evidence > 2gm/kg – Studies support single infusion CA, fever, length of hospitalizaion Administer during first 10 days of illness – Lack of studies TX after 10 days Effectiveness after 10 days? Patients can be re-treated at same dose Oates-Whitehead RM. Cochrane Db Syst Rev. 2003; (4):DC004000

56. Treatment IVIG – Adverse Drug Effects - 1994 Hep C cases – $$ however cost / benefit analyses clearly favorable – Volume ASA – No benefit in reducing CA – All studies include ASA – Improves clinical, lab markers of inflammatory response Corticosteroids – Conflicting results from 2 multicenter RCTs

58. Long-term Management Echo during acute phase and 6-8 weeks later – Risk stratification for MI and long-term complications Based on risk, AHA / AAP guidelines for – Medical TX (ASA, warfarin, LMWH) – Physical activity – Follow up schedule Vaccinations – Postpone all live virus (MMR, varicella) vaccines for 11 months after IVIG

59. Questions?

60. Coronary Artery Aneurysm Regression – 50-70% regress spontaneously over 6 months to 2 years – Fusiform aneurysms more likely to regress than saccular – Aneurysm size Giant aneurysm (internal diameter >8mm) are less likely to regress

61. Coronary Artery Aneurysm Mechanism of regression – Inward migration and proliferation of smooth muscle cells from the media layer – Proliferation of intimal cells – Persistently thickened intima – Residual endothelial dysfunction – Impaired myocardial perfusion

62. Coronary Artery Aneurysm Rupture – Very rare – All documented cases have occurred during first six weeks – Massive hemopericardium – Death

63. Coronary Artery Aneurysm Thrombosis and recanalization – Increased platelet count – Enhanced platelet aggregation – Sluggish flow pattern – Arteriae in arteria Localized stenosis – Tend to progress – Ischemic heart disease

64. Coronary Artery Aneurysm Myocardial infarction – Main cause of death in KS – Most deaths from AMI occur within one year of disease onset – 37% with silent MI – 22% mortality with first event – 63% with second event – 83% with third event

65. Cardiovascular Complications Signs and symptoms – Increased irritability, pallor – Cyanotic digits – Tachycardia, gallops, muffled heart sounds – Cardiomegaly – EKG changes Prolongation of PR and QT intervals Low voltage ST-T wave changes

66. Predictors of coronary artery aneurysm

67. Evaluation of Coronary Artery Aneurysms Coronary angiography – Gold standard – Invasive – Expensive – Increased risk – Cannot define wall pathology Other diagnostic tests – TTE – TEE – MRI/MRA – Intracoronary u/s

68. Evaluation of Coronary Artery Aneurysms Transthoracic echocardiography – Primary technique – Readily available – Non-invasive – Sensitive in pediatric population – Only proximal anatomy seen Transesophageal echocardiography – Not as readily available – Invasive – More sensitive in adult population – Better visualization of coronary anatomy

69. Evaluation of Coronary Artery Aneurysms Magnetic resonance imaging and angiography – Non-invasive – Limits in imaging – Difficulty in examining young patients Intracoronary ultrasonography – Wall pathology visualized – Highly invasive research tool