ivig resitant kawasaki

IVIG Resistant Kawasaki Disease:

Xenia Katrina Lucero

• Patient A• 2 years old • Male• Filipino• R. Catholic• born on April 7, 2009 • from 17 Little Tagaytay, Marulas Valenzuela• admitted for the 2nd time in JRRMMC (May 2,

2012)

Chief Complaint

History of Present Illness

Day of Illness

Paracetamol

History of Present Illness

Day of Illness

Val Gen: UTICefuroximeIbuprofen

History of Present Illness

Day of Illness

Red lips

Dysuriavomiting

History of Present Illness

Day of Illness

Red lips

Dysuriavomiting

VGHVGH

History of Present Illness

Day of Illness

vomiting

Swelling on LE

History of Present Illness

Day of Illness

vomiting

Swelling on LE

History of Present Illness

Day of Illness

vomiting

History of Present Illness

Day of Illness

A

KD

History of Present Illness

History of Present Illness

SE Post correction

Na+ 135.7K+ 4.76

History of Present Illness

Acute phase

reactants

Result

ESR 62CRP 108

Urinalysis 4/17Color yellowCharacteristics clearpH 8.5SG 1.010Sugar/Protein (-)RBC -WBC -

History of Present Illness

Day of Illness

A ASA (30)

History of Present Illness

A

2D-Echo4/17

Trivial MRLeft Atrial EnlargementNormal coronary artery size Proximal DistalRCA 0.18/0.2 0.17cm/0.2LCA 0.16 0.16Normal PAP by PATGood LV systolic function with EF of 72%Left sided aortic archMinimal pericardial Effusion

History of Present Illness

Day of Illness

AASA

History of Present Illness

Blood GS/CS 4/21/2012Heavy Growth S. coagulase negative organismSensitive ResistanceChloramphenicol ClindamycinErythromycin OxacillinTetracycline PenicillinVancomycin

History of Present Illness

Day of Illness

A

History of Present Illness

Day of Illness

AASA

History of Present Illness

Day of Illness

AASA

History of Present Illness

Day of Illness

AASA

MGHASA (5)

History of Present Illness

Day of Illness

AASA

MGHASA (5)

History of Present Illness

Day of Illness

AASA

MGHASA (5)

Swelling of LE, painful extremities

Red Lips

Perianal desquamation

History of Present Illness

Day of Illness

AASA

MGHASA (5)

Swelling of LE, Painful extremities

Red lipsPerianal desquamation

(-) AGE (-) Pneumonia (-) Measles (-) PTB (-) Bronchial Asthma

o (+) Hypertension: Maternalo (-) Diabeteso (-) Bronchial Asthmao (-) Heart Diseaseo (-) Cancer

• only child of the couple

• Father: 25 year-old, HS graduate, factory worker

• Mother: 23 year-old HS graduate, housewife

• lives in two-storey semi-concrete house

• no rooms, portions are divided only by cabinets

• 1 pour-flush toilet

• Water supply: NAWASA

• garbage is collected 2x a week.

• Born to a 21 year old G1P1 (1001)• Live• Fullterm• via NSD• Chinese General Hospital• (-) fetomaternal complications

• (+) regular PNCU c/o CGH starting 2 mos AOG

• (+) regular intake of MVS and FESO4, FA

• (+) maternal URTI: 9mos AOG: Amoxicillin

• (-) exposure to radiation/ intake of teratogenic drugs

• fullterm,

• cephalic,

• NSD

• Chinese General Hospital.

• BW : 2900g

• (+) good suck• (+) good cry• (+) spontaneous

activity• (-) jaundice• (-) cyanosis

• Breastfed: up to 1 week, per demand

• bottle-fed with Promil at 1:1 dilution

• Complementary feeding: 6mos with cereals

• Currently: milk, rice, meat and vegetables

Growth andDevelopment

• 1month: social smile

• 3 months: controls head

• 5 months: rolls over

• 7 months: crawls

• 10 months: sit and stands with support

• 11 months: walks with support

• 1 yr 4 months: walks alone

Immunization History

1 BCG

3 DPT

OPV

Hepa B

measles

General: no weight loss, decreased in appetite

Respiratory: no difficulty of breathing, no cough, no

colds

Cardiovascular: no easy fatigability, no orthopnea

Gastrointestinal: no diarrhea, no constipation

Genitourinary: no hematuria, no frequency, no

oliguria

Neurological: no seizures, no loss of consciousness,

Review of Systems

Physical Examination:

• Vital signs:

• HR- 136bpm • RR- 38/min • Temp- 38.8 C • BP- 100/70mmHg• Weight: 9.5kg• Height: 85 cm

•Z scores:

•Height-for-age:

below -1 – -2 (Normal)•Weight- for-age:

below -3 (severely underweight)•BMI-for-age:

below -3 (severely wasted)

awake, comfortable, not in cardio-respiratory distress

• Skin: warm to touch, good skin turgor

• HEENT:anicteric sclerae, pink palpebral conjunctiva, no nasoaural discharge, no cervical lympadenopathy, no tonsillo-pharyngeal congestion, with red dry lips

• Lungs: symmetric lung expansion, no retractions, clear breath sounds

• Heart: adynamic precordium, normal rate, regular rhythm, PMI at 4th ICS L MCL, no murmur

• Abdomen: slightly globular, normoactive bowel sounds, soft, nontender, with perianal desquamation

• Extremities: grossly normal, no cyanosis, with edema on lower extremities, grade I, CRT <3s

Neurologic exam: awake, active, GCS 15CN I – able to smellCN II - pupils 1-2mm equally reactive to light, (+)

RORCN III, IV, VI – intact extraocular muscle movementsCN V – no facial asymmetryCN VII – no facial asymmetry with facial expressionsCN VIII – able to hearCN IX, X – good gag CN XI – good shoulder shrugCN XII – no tongue deviation

Motor Sensory DTR

Salient features

• 2 yo male

• Previously admitted with a diagnosis of KD– given IVIG on 11 day of illness

– Afebrile phase noted 5 days post IVIG

• 3 days post discharge/ 13 days post IVIG– Recurrence of fever

– Recurrence of swelling on LE, perianal desquamation

and red lips

Differential Diagnosis

TB

Typhoid fever

HRCI (Sepsis)

IVIG Resistant KD

Recurrent KD

Differential Diagnosis

Rule IN Rule OUT

Prolonged fever No hepatosplenomegaly

(+) CLAD No weight loss

Swelling and joint pains No bleeding tendencies

Malignancy

Differential Diagnosis

TB

Typhoid fever

HRCI (Sepsis)

IVIG Resistant KD

Recurrent KD

Differential Diagnosis

Infectious

TB

Rule IN Rule OUT

Fever No cough

Loss of appetite Weight loss

CLAD No exposure

(-) CXR

Differential Diagnosis

Infectious

Typhoid fever

Rule IN Rule OUT

Fever (-) diarrhea/ constipation

Loss of appetite (-)Abdominal pain

vomiting (-) Blood culture

Differential Diagnosis

Infectious

Health Care Related Infection (Sepsis)

Rule IN Rule OUT

Admitted for 14 days

(+) recurrence of fever 3 days post

discharge

Differential DiagnosisConnective Tissue Disease

Recurrent Kawasaki Disease

Rule IN Rule OUT

13 days post IVIG, Recurrence of:

Recurrence of fever 13 days post IVIG transfusion

fever no available criteria which defines recurrent KD

Perianal desquamation

Majority of cases recurs at 2 years post IVIG

Red lips

Edema of LE

Differential DiagnosisConnective Tissue Disease

IVIG-Resistant Kawasaki Disease

Rule IN Rule OUT

(+) IVIG transfusion

Afebrile phase noted 5 days post IVIG

13 days post IVIG:

(+) fever

(+) red lips

(+) edema of LE

(+) perianal desquamation

Course in

the Ward

Course in

the Ward

CBC 5/2/12

ABO A +Hgb 85Hct 0.28RBC 3.62WBC 15.7

2Neutro 65.8Lympho 27.2Platelet 665

Urinalysis 5/2/212

Color L. yellowCharacteristics S. turbid

pH 6.5SG 1.020

Sugar/Protein (-)RBC 0-2WBC 10-25

Antibiotics

ASA (30)

1HD

Swelling of LEPerianal desquamationRed lips

Acute phase reactants5/6/2012 Result NV

ESR 142 0-9CRP >384 <6 mg/l

5HD

Swelling of LEPerianal desquamationRed lips

D1 AntibioticsD1 Antibiotics

D2 AntibioticsD2 Antibiotics

Culture and sensitivity

Final result

Urine (5/7) No growth

6HD

Swelling of LEPerianal desquamationRed lips

5/8/2012Trivial MRLeft Atrial EnlargementNormal coronary artery size Proximal DistalRCA 0.21/0.4/.37 0.17/0.24/0.29LCA 0.2/0.3 0.2/0.31 cmNormal PAP by PATFair LV systolic function with EF of 55%Left sided aortic archMinimal pericardial Effusion

7HD

Swelling of LEPerianal desquamationRed lips

D3 AntibioticsD3 Antibiotics

Culture and sensitivity

Final result

Blood (5/9) No growth

8HD

Swelling of LEPerianal desquamationRed lips

IVIG ordered IVIG ordered

11HD

Swelling of LEPerianal desquamationRed lips

IVIG

DISCUSSION

• “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 in the United States and Japan.”

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

Kawasaki Disease:Mucocutaneous Lymph Node

Syndrome

• 1967: Dr Tomisaku Kawasaki– 50 cases of a distinctive illness in children at

Tokyo Red Cross Medical Center in Japan.1

• 1976: Melish et al – United States, in a group of 12 children from

Honolulu examined from 1971-1973.2

1. Kawasaki T. Acute febrile mucocutaneous syndrome with lymphoid involvement with specific desquamation of the fingers and toes in children. Arerugi. Mar 1967;16(3):pp 178-222.

2. Melish ME, Hicks RM, Larson EJ. Mucocutaneous lymph node syndrome in the United States. Am J Dis Child. Jun 1976;130(6):599-607.

Leading cause of acquired heart disease in children in the developed world

In the US, KD has surpassed acute rheumatic fever as the leading cause of acquired heart

disease in children younger than 5 years

Newburger JW, et al. Summary and abstracts of the Seventh International Kawasaki Disease Symposium: December 4-7, 2001, Hakone, Japan. Pediatr Res. Jan 2003;53(1):pp 153-7

Kawasaki Disease

• Leading cause of acquired heart disease

• disease of childhood • 80%: < 5 years of age• Boys: girls 1.5:1• Highest incidence in Japan

• US: ˜3,000 annually

Japan: 200,000 cases since the 1960s

– One case report in the literature documents a 35-day-old infant who developed Kawasaki disease after his second hepatitis B vaccination. 6

6. Miron D, Fink D, Hashkes PJ. Kawasaki disease in an infant following immunization with hepatitis B vaccine. Clin Rheumatol. Dec 2003;22(6):pp 461-3.

• 2007: FDA

– required the makers of RotaTeq rotavirus vaccine to report in the package insert that 9 cases of Kawasaki disease had occurred in children who had received the vaccine.

• However, most believe that there is no connection between the vaccine and the disease. 5

5. Hua W, Izurieta HS, Slade B, Belay ED, Haber P, Tiernan R, et al. Kawasaki disease after vaccination: Pediatr Infect Dis J. Nov 2009;28(11):pp 943-7.

Pathology

vasculitis Med-sized arteries

Med-sized arteries

Coronary Arteries

Acute/subacute: Edema of endothelial smooth muscle cells with intense inflammatory infiltration of the vascular wall

Severe: involves all layers, with

destruction of internal elastic lamina

Pathology

Severe: involves all layers, with destruction of internal elastic lamina

Vessel wall

weakensdilatation

• high (≥101F)• Unremitting• unresponsive to antibiotics

without treatment is generally 1-2 weeks but may persist for 3-4 weeks.

Clinical presentation

Five principal clinical criteria of KD

Clinical Manifestations

Initial Phase - lasts 2 weeks

• 101° temperature for 5 days

• Red eyes

• Sore throat

• Swollen lymph nodes

Skin Reactions

Skin ReactionsRashes on the

body

Skin Reactions

• Palms of hands swell• Soles of feet swell• Red - purple in color

• Palms of hands swell• Soles of feet swell• Red - purple in color

Phase 2 – Lasts 2 Weeks• Thrombocyto

sis• Desquamatio

n• Swollen and

joint pains• Devt of

coronary aneurysms• Highest

risk of sudden death

Phase 3 – convalescent

• All clinical signs disappeared

• ESR returns to normal (6-8 weeks)

Associated Signs and Symptoms

RespiratoryRhinorrhea, cough, pulmonary infiltrate

GIDiarrhea, vomiting, abdominal pain,

hydrops of the gallbladder, jaundiceNeurologic

Irritability, aseptic meningitis, facial palsy, hearing lossMusculoskeletal

Myositis, arthralgia, arthritis

Diagnostic Test

Laboratory findings

• WBC: normal to elevated with neutrophilic predominance

• Elevated ESR, CRP, may persist for 4–6 wk• Normocytic, normochromic anemia• platelet count: normal- 1st week, rapidly increases

by the 2nd–3rd week (1,000,000/mm3)• ANA/rheumatoid factor: Negative• Sterile pyuria• mild elevations of the hepatic transaminase

• The incidence of KD refractory to initial IVIG therapy increased to 38 percent in 2006 from a range of 10 to 20 percent between 1998 and 2005.

– This increase did not appear to be related to any changes in the formulations of IVIG used.

Tremoulet AH, Best BM, Song S, et al. Resistance to intravenous immunoglobulin in children with Kawasaki disease. J Pediatr 2008; 153:117

• Risk factors associated with the need for retreatment included:

• Initial treatment at or before the fifth day of illness

• Recurrent episodes of KD

• Male sex

Tremoulet AH, Best BM, Song S, et al. Resistance to intravenous immunoglobulin in children with Kawasaki disease. J Pediatr 2008; 153:117.

Risk Factors for unresponsiveness to IVIG

• Young patient age, < 1 yo

• Early diagnosis, with initial treatment < 4DOL

• Elevated C-reactive protein (≥10 mg/dL )

• Elevated liver enzymes (AST/ALT)

• Platelet count ≤300,000/mm2

• Elevated band count

• Serum sodium ≤133 mmol/L

• Low serum albumin

Sundel, Robert, Treatment of refractory Kawasaki disease, UpToDate, June 17, 2011

• In a study done by Young-Sun Do, et.al, they found out that IVIG resistant group has significantly longer febrile period and hospital days than those IVIG-responsive groups.

• Serum levels of albumin and sodium were significantly lower in the IVIG-resistant group.

• Fewer lymphocytes was observed during the subacute phase in the IVIG-resistant group.

• Coronary arterial dilatations (CADs) were observed in 10.9% (7/64) of IVIG-responders and 38.5% (5/13) of IVIG-resistant patients.

Complications

Coronary Artery Aneurysm

commonest

Most life threatening

25% untreated KD

6-8 wks from onset of illness

Complications

Coronary Artery Aneurysm

Coronary thrombosis

death

M I

Complications

Coronary Artery Aneurysm

SizeSmall = <5 mm diameter Medium = 5-8 mmGiant = ≥ 8 mm

Highest risk for sequelaeShape

SizeSmall = <5 mm diameter Medium = 5-8 mmGiant = ≥ 8 mm

Highest risk for sequelaeShape

Echocardiography

Onset of DX

2–3 wks of illness

N6-8 wks of

illness

(-) CAA/ ESR: Normal

2D- echo:optional

Coronary Artery Changes

• 15% to 25 % of untreated patients develop coronary artery changes

• 3-7% if treated in first 10 days of fever with IVIG

• Most commonly proximal, can be distal

• Left main > LAD > Right

Echocardiographic Findings

•Myocarditis with dysfunction

•Pericarditis with an effusion

•Valvar insufficiency

•Coronary arterial changes

The HARADA score

• 1) WBC count: >12 ×103/μl, • 2) Platelet count: < 35×104/μl, • 3) CRP: > 4 mg/dl, • 4) Hematocrit: <35%, • 5) Serum albumin: < 3.5 g/dl, • 6) Gender: male, • 7) Age: equal to or less than 12 months.

> 4 :high risk of developing coronary artery lesions

treatment

1. IVIG 2g/kg as a single infusion over 12H

2. Aspirin 30-50 mg/kg/day in four doses (in USA 80-100mg/kg/day in 4 doses) until afebrile for 2-3 days

3. Aspirin 3-5 mg/kg/day once daily for 6-8 weeks minimum

treatment1. Second dose of IVIG 2 g/kg

2. Third dose of IVIG or

3. Methylprednisolone 30mg/kg for 3 days or prednisolone 2 mg/kg/day orally and tailored based on clinical/ inflammatory marker improvement

Fever persists after 48H or recrudescent fever within 2 weeks

4. Cyclophosphamide, cyclosporin, plasmapheresis and monoclonal antibodies to TNFalpha have been reported

Tizard E.J., Complications of Kawasaki disease, Current Pediatrics, 2005 Volume 15, pp 62-88

• Patients receiving long-term aspirin therapy– annual influenza vaccination– Varicella vaccination

• Patients treated with 2 g/kg IVIG

delay measles-mumps-rubella and varicella vaccinations delayed for 11 mo

prognosis

Recovery is complete and without apparent long-term effects for patients who do not develop coronary disease

In Japan, fatality rates are very low, about 0.01%. Overall, 50% of coronary artery aneurysms resolve as assessed by echocardiogram 1–2 yr after the illness.

prognosis

Recurrence of the disease has been previously noted with reported rates varying between 0.8% in the United States to 3% in Japan.

The proportion of patients suffering a recurrence increases with age, while the majority of recurrences occur within 2 years of the initial attack.

9. Pemberton1, I M Doughty2, R J Middlehurst3 & M H Thornhill4, British Dental Journal 186, 270 - 271 (1999), Case study: Recurrent Kawasaki disease

KT H A N

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