Henoch Schonlein Purpura and Kawasaki Disease

Peter Henning, DOMAJ, MC, USA

2 December 2008

Overview

• Summary• Epidemiology• Etiology and Pathogenesis• Clinical Manifestations• Diagnosis• Treatment

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

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

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.

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

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.

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 PLTsAND

• Diffuse abd pain• Arthritis or arthralgia• BX with IgA deposition

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

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

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%

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

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 proteinuria 57% (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.

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

Clinical Findings in Adults with HSP

• Less common• Similar to children• Exceptions– Intussusception rare– Increased risk of renal involvement

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)

Skin Biopsy• Superficial dermis sufficient• BX < 24 hour-old lesion

– Older lesions with less specific changes• Leukocytoclastic vasculitis in post capillary venules• IgA deposition

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

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

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

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 neededWeiss PF. Pediatrics 2007; 120(5):1079.

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.

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

Kawasaki Disease (KD)

Kawasaki Disease (KD)• 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.

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

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

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

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

Pathogenesis

• Aberrant immune response– Activated macrophages

• Subendothelial inflammation• Transmural inflammation• Destruction of the media and aneurysm

formation

Clinical Manifestations

• Fever • Bilateral conjunctivitis• Mucositis• Polymorphous rash• Extremity changes• Cervical LAD

• Arthritis• Lipid abnormalities• Renal/urinary findings• Vasculitis– Coronary artery

aneurysm– Cardiac complications

Fever

• 100% of patients– Consider KD in children with unexplained fever > 5 days

• 38o to > 40o C• Persistent ; > 5 consecutive days– Untreated, usually lasts 1-2 weeks– Fever > 4 weeks, suspect other etiology

• Unresponsive to antibiotics, antipyretics

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.

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.

Name two other diseases in which you can see a “strawberry” tongue?

Scarlet fever and toxic shock syndrome

Rash

• POLYMORPHOUS

• 80% of pts• Within 1-5 days of fever onset• Trunk and extremities• Frequently pruritic• Disappears when fever subsides

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

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

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.

Lymphadenopathy

• Least consistent feature– Absent in 50-75%

• Frequently unilateral• Usually anterior cervical– NOT generalized LAD

• > One lymph node>1.5cm

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

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

Differential Diagnosis

• Viral– Measles, EBV, echo and adenovirus

• Toxin Mediated– Toxic shock syndrome, scarlet fever

• RMSF, leptospirosis• Drug Reaction– Steven’s Johnson

• Systemic JIA

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

Coronary Artery Aneurysm

• 20-25% untreated vs. 4-13% treated• Findings associated with CA– Age < 1 or > 6 - Male– Fever > 14 days - Na+ < 135 mEq/L– HCT < 35% - WBC > 12K / mm3

• Prognosis dependant on size, shape– Best small (<8mm), fusiform (vs. saccular)

• Complications– Rupture - Thrombosis– MI - Stenosis after regression

Coronary Artery Aneurysm

Coronary Artery Aneurysm

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

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

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.

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

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 Therapy CA at 30 days CA at 60 days

ASA alone 26% 18%

IVIG 1gm/kg 16% 10%

IVIG 2gm/kg 4% 4%

Teraj, M. Jour Ped 1997; 131(6):888.

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

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

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

Questions?

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

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

Coronary Artery Aneurysm

• Rupture– Very rare– All documented cases have occurred during first

six weeks– Massive hemopericardium– Death

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

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

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

Predictors of coronary artery aneurysm

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

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

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