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Henoch Schonlein Purpura and
Kawasaki Disease
Peter Henning, DO
MAJ, MC, USA
2 December 2008
Overview
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Summary
Epidemiology
Etiology and Pathogenesis
Clinical Manifestations
Diagnosis
Treatment
Henoch Schonlein Purpura (HSP)
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Most common systemic vasculitis in children
Etiology - Unknown
Pathogenesis – End organ IgA immune complex (IC) deposition
Diagnosis - Clinical
– Palpable purpura
– Renal disease
- Abdominal pain
- 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 PLTs
AND
• 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
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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
– Gross hematuria
– Concominant proteinuria
11% (n=37)
5% (n=12)
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
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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.
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)
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Mucocutaneous lymph node syndrome
2nd most common childhood vasculitis
< 5 year old, Asian
Acute, self-limited medium-vessel vasculitis
– Fever
– Rash
– Extremity changes
- Conjuctivitis
- Mucositis
- 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
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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
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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?
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– NO substantiated specific infectious association
Pathogenesis
• Aberrant immune response
– Activated macrophages
• Subendothelial inflammation
• Transmural inflammation
• Destruction of the media and aneurysm
formation
Clinical Manifestations
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Fever
Bilateral conjunctivitis
Mucositis
Polymorphous rash
Extremity changes
Cervical LAD
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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
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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
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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
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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
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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
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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
– Fever > 14 days
– HCT < 35%
- Male
- Na+ < 135 mEq/L
- WBC > 12K / mm3
• Prognosis dependant on size, shape
– Best small (<8mm), fusiform (vs. saccular)
• Complications
– Rupture
– MI
- Thrombosis
- 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
Supplemental Lab Criteria:
•Albumin 3.0
• Anemia for age
•Elevated ALT
•PLT > 450K after 7 days
•WBC >15K
•UA with > 10 WBC / HPF
Newburger, JW. Pediatrics 2004; 114:1708.
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
Therapy
CA at 30 days
CA at 60 days
ASA alone
26%
18%
IVIG 1gm/kg
16%
10%
IVIG 2gm/kg
4%
4%
• Why? Efficacy; 6 RCTs, 1626 pts
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
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
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Gold standard
Invasive
Expensive
Increased risk
Cannot define wall
pathology
• Other diagnostic tests
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TTE
TEE
MRI/MRA
Intracoronary u/s
Evaluation of Coronary Artery Aneurysms
• Transthoracic
echocardiography
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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