Systemic lupus erythematosis & Kawasaki disease

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Transcript of Systemic lupus erythematosis & Kawasaki disease

Page 1: Systemic lupus erythematosis & Kawasaki disease

الرحيم الرحمن الله بسم

Systemic Lupus Erythematosus&

Kawasaki disease

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Systemic Lupus Erythematosus

Abbreviations: SLE or LupusAlternative Names: Disseminated lupus erythematosus; Discoid lupus

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Definition

• SLE is a chronic multisystem inflammatory disease of autoimmune origin

• Mostly affects females of childbearing age • Female to male ratio 9:1

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SLE

• A complex disorder of multifactorial origin resulting from interactions among genetic, hormonal and environmental factors

• The activation of helper T cells and B cells results in the formation of autoantibodies

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Genetic & other factors1. Female hormones

-90% are female-unclear how sex hormone promotes SLE

2. Drug-induced lupus-best known : procainamide, hydralazine, quinidine

Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939

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Genetic & other factors3. Antecedent viral-like illness : EBV4. Ultraviolet radiation 5. Gene : 8 susceptibility loci

Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939

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GENETIC

Mary K Crow.Developments in the clinical understading of lupus.Arthritis Research & Therapy 2009;11:245

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GENETIC

Mary K Crow.Developments in the clinical understading of lupus.Arthritis Research & Therapy 2009;11:245

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Autoantibodies in lupusAutoantibodies in lupus

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Autoantibodies in lupusAutoantibodies in lupus

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Source of autoantigens in lupus

1. cellular debris (as result of apoptosis)-apoptotic bleb on surface of dying cell

Ag within cell expose on surface of blebs

Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939

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Source of autoantigens in lupus

Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939

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Source of autoantigens in lupus

2. Removal of apoptotic debris-C1q play role in phagocytosis-phagocytes in lupus pt. engulf less than phagocytes in healthy people

3. Deficiency of complement poor “waste disposal”

Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939

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Tissue damage by autoantibody

-Two main theories1. extracellular dsDNA bind to autoAb

enter bloodstream

complexes settle in renal glomerular basement membrane

Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939

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Tissue damage by autoantibody

2. Autoantibodies cross-react with cellular proteins

(Ag with similar epitopes or similar charge)

direct pathogenic effect on cells

Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939

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Cytokines in lupus1. IL-10

-high level in lupus pt. correlate with activity of disease-stimulate of polyclonal populations of B cells

2. Interferon(IFN-)3. TNF-

Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939

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Cytokines in lupus4. B-lymphocyte stimulator

-member of TNF-ligand superfamily-promote proliferation & survival of B cells -there is overexpression of stimulator in lupus pt.

Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939

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SLE

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Aetiology/PathogenesisInate Susceptibility

•HLA type•Immunoregulatory genes•Hormonal levels•Complement levels

Environmental Stimuli•UV exposure•Microbial response•Medication

Autoimmune Proliferation•Hyperactive B-cell/T-cell activation•High ratio of CD4:CD8 T-cells•Defective immune complex clearance •Impaired tolerance

Autoantibody Production

•Apoptosis and self exposure•Self-recognition•Foreign-Ab cross reaction

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SLE

• Genetic factors• Hormonal Influences• Environmental Triggers• Immune Dysregulation

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• Most visceral lesions are mediated by immune complexes (Type III hypersensitivity)

• Autoantibodies against red cells, white cells and platelets mediate their effects via( Type II hypersensitivity )

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Is this Lupus??!

fever, rash, arthritis, alopecia and renal involvement

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Clinical Features____________SymptomsOccurrence

Achy joints (arthralgia)95%

Fever more than 38 degrees C90%

Arthritis90%

Prolonged or extreme fatigue81%

Skin rashes74%

Anaemia71%

Renal involvement50%

Pain in the chest on deep breathing (pleurisy)45%

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Clinical Features____________SymptomsOccurrence

Butterfly-shaped rash across the cheeks and nose42%

Sun or light sensitivity (photosensitivity)30%

Hair loss27%

Abnormal blood-clotting problems20%

Raynaud’s phenomenon (fingers turning white and/or blue in the cold)

17%

Seizures15%

Mouth or nose ulcers12%

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Butterfly Rash

Oral Ulcers

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Raynaud’s Phenomenon

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Diagnostic criteria (11)FeaturesCharacteristics

1-Malar rashFixed erythema, flat or raised, sparing the nasolabial folds

2-Discoid rashErythematous raised patches with adherent keratotic scarring and follicular plugging

3-PhotosensitivitySkin rash as a result of unusual reaction to sunlight

4-Oral ulcersOral or nasopharyngeal ulceration; may be painless

5-ArthritisNon-erosive, involving two or more peripheral joints

6-Serositisa. Pleuritis (convincing history of pleuritic pain, rub or pleural effusion) or

b. Pericarditis (rub, ECG evidence of effusion)

7-Renal disordera. Persistent proteinuria >0.5 g/day, or b. Cellular casts (red cell, granular or tubular)

8-Neurological disorder

Seizures or psychosis in the absence of offending drugs or metabolic derangement

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FeaturesCharacteristics

9-Haematological disorder

a. Haemolytic anaemia orb. Leucopenia (<4000/mm3) orc. Lymphopenia (<1500/mm3) ord. Thrombocytopenia (<100 000/mm3) in the absence of

offending drugs

10-Immunology disorder

a. Anti-DNA antibodies in abnormal titre orb. Presence of antibody to Sm antigen or c. Positive antiphospholipid antibodies

11-Antinuclear antibody disorder

Abnormal titre of ANA by immunofluorescence

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• 4 of 11 clinical and laboratory criteria must be met

• Antinuclear antibody titer is the primary laboratory test

• Antinuclear antibody titer of 1:40 and characteristic multi-organ system involvement can diagnose SLE without additional testing

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• Patients with an antibody titer of 1:40 who fail to meet full clinical criteria should undergo additional testing:

including tests for antibody to double stranded DNA antigen and antibody to Sm nuclear antigen

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AUTOANTIBODIES IN SLEAntibody %Clinical Utility

ANA98Best screening test

Anti dsDNA70Specific for SLE; Correlate with disease severity

Anti-Sm25Specific for SLE

Anti-RNP40MCTD

Anti-Ro(SS-A)30Predisposes to Subcutaneous Lupus, Neonatal Lupus with Congenital Heart Blocks.Decreased risk of Nephritis

Anti-La(SS-B) 10Decreased risk of Nepritis

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Autoantibodies in SLE

Antibody %Clinical Utility

Anti Histone70Drug induced SLE

Antiphospholipid50Abortions, Thrombosis

Antierythrocyte60Hemolysis

Antiplatelet30Thrombocytopenia

Antineuronal60Active CNS lupus

Antiribosomal20Depression or Psychosis due to CNS lupus

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ANA

• Present in 4-5% of healthy population and up to 14% of chronically ill patients.

• Its sensitivity is high for SLE (98%) but specificity is low

• Diseases associated : SLE, MCTD, Systemic sclerosis, Drug induced SLE, Inflammatory myopathies, RA, Sjogrens, Thyroid ds, AI hepatitis, PBC, Hep C

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ANA PATTERNS

37A. Homogenous B. Speckled C. Centromere D. Nucleolar pattern

ANA by immunofluorescence

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International Society of Nephrology 2003 classification of lupus nephritis

Class IMinimal mesangialNormal light microscopy findings, abnormal electron microscopy findings

Class IIMesangial proliferative

Hypercellular on light microscopy

Class IIIFocal proliferative<50% of glomeruli involved

Class IVDiffuse proliferative>50% of glomeruli involved

Class VMembranousPredominantly nephrotic disease

Class VIAdvanced sclerosingChronic lesions and sclerosis

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SLE

• Difficult to diagnose• No single diagnostic marker; • identified through a combination of clinical and

laboratory criteria• Early diagnosis is important as it reduces morbidity

and mortality (lupus nephritis)

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Useful Investigations• General Investigations:

– TC, DC, Hb, PLT, ESR– Blood urea, Serum Creatinine– Urinalysis to check for protein, RBC and cellular casts– Spot urine test for Creatinine and protein concentration

(normal protein:creatinine ratio <0.2)– ANA

• Tests of SLE disease activity:– Anti-dsDNA, Complement determinations (C3, C4), CRP– Anti-nucleosome antibodies, anti-C1q antibodies

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TREATMENT

• Goals of treatment: - prevent flares - treat flares when they occur - minimize organ damage and complications

• Treatment plans are based on patient age, sex and disease severity– Fever, skin, musculoskeletal and serositis - milder disease– CNS and renal involvement – Life-threatening SLE

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TREATMENT - NON LIFE THREATENING SLE

• NSAIDS• Antimalarials – Hydroxychloroquine• Resistant cases – Low dose steroids (prednisolone 0.07 to 0.3mg/kg) - systemic immunosuppressants

• Dermatitis: Topical sunscreens, steroids, antimalarials or

Tacrolimus in resistent cases

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TREATMENT - LIFE THREATENING SLE

• Glucocorticoids : - Prednisolone - 0.5-1mg/kg orally or - Methylprednisolone 1g/d for 3 days f/b oral therapy 4-6 wks - Maintenance dose 5-10 mg/day

• Cytotoxic therapy :- Induction therapy : Cyclophosphamide - 500-750 mg/mt2 monthly for 6 months Mycophenolate mofetil (MMF) 2-3 gm/day- Maintanence therapy : Azathioprine(2mg/kg/d) or MMF(1.5-3 gm/d)

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TREATMENT

• Other drugs Chlorumbucil, Methotrexate, Leflunamide & Cyclosporine• Biological agents : used in resistant cases Rituximab (Anti CD20 Ab) Belimumab (Anti BLyS)

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Kawasaki Disease

Mucocutaneous lymph node syndrome

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What is Kawasaki Disease?

Idiopathic multisystem disease characterized by vasculitis of small & medium blood

vessels, including coronary arteries

*Burns, J. Adv. Pediatr. 48:157. 2001.

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Kawasaki Disease (KD)

• A self-limited vasculitis of unknown etiology that predominantly affects children younger than 5 years.

• It is now the most common cause of acquired heart disease in children

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• Coronary artery aneurysms develop in 15% to 25% of untreated children & can lead to– ischemic heart disease or– sudden death

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Background• 1967 - Tomisaku Kawasaki reports a series of 50

patients and establishes the clinical criteria for diagnosis (in Japanese)

• 1974 - first English language report of Kawasaki syndrome by Kawasaki

• 1976 - first series of American patients reported by Melish, Hawaii

• 1977 - landing and Larson establish that Kawasaki disease and infantile polyarteritis nodosa are pathologically indistinguishable

• 1988 - American academy of pediatrics endorses high does IVIG plus ASA as recommended therapy for Kawasaki disease

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Dr Tomisaku Kawasaki

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Epidemiology

• More prevalent in Japan and in children of Japanese ancestry (annual incidence of 112 cases per 100 000 children <5 years old)

• 80% of cases in children < 4 yrs• Males:females = 2:1• Annual incidence of 4-15/100,000 children

under 5 years of age

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Aetiology and Pathogenesis

• Aetiology of KD remains unknown, (although clinical and epidemiological features strongly suggest an infectious

cause)

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• Most children are under age 5– Most common in Asian boys

• 10 day “window” to diagnosis– Heart problem occurrences increase after 10 days

• Estimated 80% fully recover– 1 % will die from Kawasaki disease

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Pathology

• Generalized systemic vasculitis involving blood vessels throughout the body

• Aneurysms may occur in coronary artery, celiac, mesenteric, femoral, iliac, renal, axillary, and brachial arteries)

• Active inflammation is replaced over several weeks to months by progressive fibrosis, with scar formation

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May 1, 2023

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Clinical Features

1. Prolonged fever – FUO/PUO2. Bilateral non exudative conjunctivitis3. Erythema of the lips and oral mucosa4. Changes in the extremities – oedema, peeling5. Rash – non-vesicular6. Cervical lymphadenopathy – unilateral

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Trager, J. D. N Engl J Med 333(21): 1391. 1995.

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Kawasaki diseaseAcute febril phase Subacute phase Convalescent phase

1- 2 wk 2 – 4 wk 6 – 8 wk 1- 2 wk

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Phases of Disease

• Acute (1-2 weeks from onset)– Febrile, irritable, toxic appearing– Oral changes, rash, edema/erythema of feet

• Subacute (2-4 weeks from onset)– Desquamation, may have persistent arthritis or

arthralgias– Gradual improvement even without treatment

• Convalescent (Months to years later)

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Phase 1 – Phase 1 – LastsLasts 2 Weeks2 Weeks• 39° temperature for

5 days

• Red eyes

• Sore throat

• Swollen lymph nodes

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Skin&m.m.Skin&m.m. ReactionsReactions

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SkinSkin ReactionsReactions• Red rash on body

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• Palms of hands swell

• Soles of feet swell

• Red - purple in color

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Phase 2 – Phase 2 – LastsLasts 2 Weeks2 Weeks• Skin peels from

hands and feet

• Swollen painful

joints

• VomitingDiarrheaAbdominal pain

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Differential Diagnosis

• Infectious– Measles & Group A beta-hemolytic strep – Bacterial: severe staph infections w/toxin release– Viral: adenovirus, enterovirus, EBV, roseola

• Immunological/Allergic– JIA (systemic onset)– Hypersensitivity reactions

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Other clinical features of KD• Irritability

– Aseptic meningitis (~25% ) (CSF - ↑ lymph's, N glucose/protein)

– Arthritis - probably less common since IVIG treatment– Hydrops of the gallbladder (RUQ pain, seen on USS)– Sterile pyuria, urethritis and diarrhoea– Pulmonary infiltrates or pneumonitis

• Inflammation at site of BCG scar– Cross-reactivity of T cells in KD patients with BCG

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Kawasaki Disease: Diagnostic CriteriaCriterionDescription

FeverDuration of 5 days or more plus 4 of the following:

1ConjunctivitisBilateral, bulbar, non-suppurative

2LymphadenopathyCervical, >1.5 cm

3RashPolymorphous, no vesicles or crusts

4Changes of lips or oral mucosa

Red cracked lips; "strawberry" tongue; or diffuse erythema of oropharynx

5Changes of extremities

Initial stage: erythema and oedema of palms and solesConvalescent stage: peeling of skin from fingertips

KD may be diagnosed with fewer than 4 of these features if coronary artery aneurysms are detected.

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Kawasaki disease - AHA diagnostic criteriaFever of 5 days duration + four of five criteria

Oropharyngeal changes

(90%+ of cases)

1.

Changes in peripheralextremities

(90% +of cases)

2.

Cervical lymphadenopathy

~(75% of cases)

5.

Polymorphous rash

(95% +of cases)

4.

Bilateral non-purulent conjunctival injection

(90% +of cases)

3.

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Atypical or Incomplete Kawasaki Disease

• Present with < 4 of 5 diagnostic criteria• Compatible laboratory findings• Still develop coronary artery aneurysms• No other explanation for the illness• More common in children < 1 year of age

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Kawasaki Disease: Labs

• Early– Leukocytosis– Left shift– Mild anemia– Thrombocytopenia/

Thrombocytosis– Elevated ESR– Elevated CRP– Hypoalbuminemia– Elevated transaminases– Sterile pyuria

• Late– Thrombocytosis– Elevated CRP

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Cardiovascular Manifestations of Acute Kawasaki Disease

• ECG changes– Arrhythmias– Prolonged PR and/or QT intervals– Low voltage– ST-T–wave changes.

• CXR–cardiomegaly

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Coronary Arterial Changes

• Vary in severity from asymptomatic coronary artery ectasia to giant aneurysms

• May lead to myocardial infarction, sudden death, or ischemic heart disease

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Coronary Aneurysms

• Patients most likely to develop aneurysms– Younger than 6 months, older than 8 years– Males– Fevers persist for greater than 14 days– Persistently elevated ESR– Thrombocytosis– Pts who manifest s/s of cardiac involvement

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Newburger, J. W. et al. Circulation 2004;110:2747-2771

Coronary angiogram demonstrating giant aneurysm of the LAD with obstruction and giant aneurysm of the RCA with area of severe narrowing in

6-year-old boy

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Recommended guideline for the management of Kawasaki disease

• Establish diagnosis (1) Complete Kawasaki disease (any age) (2) Incomplete Kawasaki (<1 year)

• Treatment–IVIG 2 g/kg as a single infusion over 12 hours–Aspirin 80–100 mg/kg/day in 4 divided doses until afebrile x 48 hrs &/or decrease in acute phase reactants–Decrease to low dose (3-5 mg/kg/day) for 6-8 weeks or until platelet levels normalize–Echocardiography and ECG

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Disease defervescence:Repeat echocardiography at 2 and 6 weeks

No CAACAA <8 mm, no stenoses

CAA > 8 mm and/or stenoses

Stop aspirin at 6 weeks

Continue aspirinLifelong aspirin 3–5 mg/kg/day

Lifelong follow up at least every 2 years

Repeat echocardiography and ECG at 6 monthly intervals

Consider warfarin

 Discontinue aspirin if resolves

Consider coronary aneurysm angiography and exercise stress testing

 Consider exercise stress test if multiple aneurysms

Repeat echocardiography and ECG at 6 monthly intervals

 Specific advice on minimizing atheroma risk factors

Specific advice on minimizing atheroma risk factors

 Lifelong follow upLifelong follow up

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No disease defervescence within 48 hours, or disease recrudescence within 2 weeks: Seek expert advice to consider:

• Second dose of IVIG at 2 gm/kg/day• Pulsed methylprednisolone at 600 mg/m2 twice daily for 3 days or prednisolone 2 mg/kg/day once daily, weaning over 6 weeks

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May 1, 2023

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Evaluation of suspected incomplete Kawasaki disease

Supplemental laboratory criteria:

1. albumin 3.0 g/dL

2. anaemia for age

3. elevation of ALT

4. platelets after 7 day 450 000/mm3

5. WBC 15 000/mm3

6. urine - 10 WBC/HPF

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Diagnosis is the Key

• Kawasaki disease should be considered in the DD of every child with prolonged fever accompanied by rash and non-purulent conjunctivitis

• the age of the child :(those under 6 months with persistent fever for seven days and evidence of inflammation must have an echocardiogram even in the absence of positive clinical criteria)

Nelson19th edition

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Thank you

Dr Tai Al AkawyAlexandria University Children’s

Hospital