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

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



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?


• 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


• 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


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

six weeks– Massive hemopericardium– Death


• Thrombosis and recanalization– Increased platelet count– Enhanced platelet aggregation– Sluggish flow pattern– Arteriae in arteria

• Localized stenosis– Tend to progress– Ischemic heart disease


• 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


• 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


• Magnetic resonance imaging and angiography– Non-invasive– Limits in imaging – Difficulty in examining young patients

• Intracoronary ultrasonography– Wall pathology visualized– Highly invasive research tool

Documents

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