4. • 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)
18. History of Present Illness
A
2D-Echo
4/17
Trivial MR
Left Atrial Enlargement
Normal coronary artery size
Proximal Distal
RCA 0.18/0.2 0.17cm/0.2
LCA 0.16 0.16
Normal PAP by PAT
Good LV systolic function with EF of
72%
Left sided aortic arch
Minimal pericardial Effusion
29. o (+) Hypertension: Maternal
o (-) Diabetes
o (-) Bronchial Asthma
o (-) Heart Disease
o (-) Cancer
30. • 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.
31. • Born to a 21 year old G1P1 (1001)
• Live
• Fullterm
• via NSD
• Chinese General Hospital
• (-) fetomaternal complications
32. • (+) 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
33. • fullterm,
• cephalic,
• NSD
• Chinese General
Hospital.
• BW : 2900g
• (+) good suck
• (+) good cry
• (+) spontaneous
activity
• (-) jaundice
• (-) cyanosis
34. • 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
35. Growth and
Development
• 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
37. 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
39. • 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
40. • 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
41. Neurologic exam: awake, active, GCS 15
CN I – able to smell
CN II - pupils 1-2mm equally reactive to light, (+)
ROR
CN III, IV, VI – intact extraocular muscle movements
CN V – no facial asymmetry
CN VII – no facial asymmetry with facial expressions
CN VIII – able to hear
CN IX, X – good gag
CN XI – good shoulder shrug
CN XII – no tongue deviation
Motor Sensory DTR
42.
43. 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
45. Differential Diagnosis
Rule IN Rule OUT
Prolonged fever No hepatosplenomegaly
(+) CLAD No weight loss
Swelling and joint pains No bleeding tendencies
Malignancy
50. Differential Diagnosis
Connective 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
51. Differential Diagnosis
Connective 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
56. 5/8/2012
Trivial MR
Left Atrial Enlargement
Normal coronary artery size
Proximal Distal
RCA 0.21/0.4/.37 0.17/0.24/0.29
LCA 0.2/0.3 0.2/0.31 cm
Normal PAP by PAT
Fair LV systolic function with EF of 55%
Left sided aortic arch
Minimal pericardial Effusion
7HD
Swelling of LE
Perianal
desquamation
Red lips
D3 AntibioticsD3 Antibiotics
63. • “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
64. • 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.
65. 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
66. 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
67. • US: ˜3,000 annually
Japan: 200,000
cases since the 1960s
68.
69. – 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.
70. • 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.
73. • high (≥101F)
• Unremitting
• unresponsive to antibiotics
without treatment is generally 1-2
weeks but may persist for 3-4
weeks.
Clinical presentation
79. 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
80. Phase 2 – Lasts 2 Weeks
• Thrombocytosis
• Desquamation
• Swollen and joint
pains
• Devt of coronary
aneurysms
• Highest risk of
sudden death
81. Phase 3 – convalescent
• All clinical
signs
disappeared
• ESR returns to
normal (6-8
weeks)
82. Associated Signs and Symptoms
Respiratory
Rhinorrhea, cough, pulmonary infiltrate
GI
Diarrhea, vomiting, abdominal pain, hydrops of
the gallbladder, jaundice
Neurologic
Irritability, aseptic meningitis, facial palsy,
hearing loss
Musculoskeletal
Myositis, arthralgia, arthritis
84. 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
85. • 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
86. • 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.
87. 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
88. • 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.
91. Complications
Coronary Artery
Aneurysm
Size
Small = <5 mm diameter
Medium = 5-8 mm
Giant = ≥ 8 mm
Highest risk for sequelae
Shape
Size
Small = <5 mm diameter
Medium = 5-8 mm
Giant = ≥ 8 mm
Highest risk for sequelae
Shape
93. 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
95. 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
96. 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
97. treatment
1. 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
98. • 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
99. 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.
100. 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
Kawasaki disease was first described in 1967 by Dr Tomisaku Kawasaki, who reported 50 cases of a distinctive illness in children seen at the Tokyo Red Cross Medical Center in Japan.1 In 1976, Melish et al first reported Kawasaki disease in the United States, in a group of 12 children from Honolulu examined from 1971-1973.2 Kawasaki disease is now recognized worldwide, although the greatest number of cases has been in Japan. It is the leading cause of acquired heart disease in children in the developed world and may be a risk factor for adult ischemic heart disease. In the United States, Kawasaki disease has surpassed acute rheumatic fever as the leading cause of acquired heart disease in children younger than 5 years.3
It is the leading cause of acquired heart disease in children in the developed world and may be a risk factor for adult ischemic heart disease. In the United States, Kawasaki disease has surpassed acute rheumatic fever as the leading cause of acquired heart disease in children younger than 5 years.3
Kawasaki disease is predominantly a disease of childhood although cases have been reported in adults. Around 80% of cases occur in children under 5 years of age. It occurs more often in boys than girls with a male/female ratio of about 1.5:1. An estimated 3,000 cases are diagnosed annually in the United States. In Japan, almost 200,000 cases have been reported since the 1960s.
The etiology of Kawasaki disease remains unknown. Over the years, multiple infectious agents have been implicated; however, to date, no single microbial agent has surfaced as the prevailing cause.4 However, autoimmune reactions and genetic predisposition have been suggested as possible etiologic factors.
KD is a vasculitis that predominantly affects the medium-sized arteries, with a striking predilection for the coronary arteries. Pathologic examination of fatal cases in the acute or subacute stages reveals edema of endothelial and smooth muscle cells with intense inflammatory infiltration of the vascular wall. In the most severely affected vessels, inflammation involves all three layers of the vascular wall, with destruction of the internal elastic lamina.
In the most severely affected vessels, inflammation involves all three layers of the vascular wall, with destruction of the internal elastic lamina. Loss of structural integrity weakens the vessel wall and results in dilation (ectasia) or saccular or fusiform aneurysm formation.
Fever is characteristically high (≥101F), unremitting, and unresponsive to antibiotics. The duration of fever without treatment is generally 1-2 weeks but may persist for 3-4 weeks.
In the absence of treatment, KD can be divided into 3 clinical phases. The acute febrile phase is characterized by fever and the other acute signs of illness and usually lasts 1-2 weeks. The subacute phase is associated with desquamation, thrombocytosis, the development of coronary aneurysms, and the highest risk of sudden death in patients in whom aneurysms have developed, and generally lasts about 2 weeks. The convalescent phase begins when all clinical signs of illness have disappeared and continues until the erythrocyte sedimentation rate (ESR) returns to normal, typically about 6-8 weeks after the onset of illness.
The complete list of associated symptom is too long to go into in detail here,but virtually every organ system can be involved. Patients can have cough, rhinorrhea, or a pulmonary infiltrate. They can have diarrhea, vomiting, abdominal pain, hydrops of gallbladder, mild jaundice, and mild increase of serum transaminase levels. They can have striking irritability and an aseptic meningitis with a mononuclear pleocytosis in cerebrospinal fluid as well as a facial palsy and hearing loss. Finally, they can develop myositis, arthralgias, and arthritis.
There is no diagnostic test for Kawasaki disease. Primarily, it is diagnosed based on the presence of characteristic clinical signs. For classic Kawasaki disease, the diagnostic criteria require the presence of fever for at least 5 days and at least four of five of the other characteristic clinical features of illness. In atypical or incomplete Kawasaki disease, the patient has persistent fever but with fewer than four other features of the illness while IVIG resistant Kawasaki disease is defined as persistent or recrudescent fever 36 hours after completion of the initial IVIG infusion and occurs in approximately 15% of patients.
Kawasaki disease has certain characteristic laboratory findings. The leukocyte count is normal to elevated with a predominance of neutrophils and immature forms. Elevated ESR, CRP, and other acute phase reactants are almost universally present in the acute phase of illness and may persist for 4–6 wk. Normocytic, normochromic anemia is common. The platelet count is generally normal in the 1st week of illness and rapidly increases by the 2nd–3rd week of illness, sometimes exceeding 1,000,000/mm3. Tests for antinuclear antibody and rheumatoid factor are negative. Sterile pyuria, mild elevations of the hepatic transaminases, and cerebrospinal fluid pleocytosis may be present.
Risk Factors for IVIG Resistance 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 200510. This increase did not appear to be related to any changes in the formulations of IVIG used. In comparison, in 2006, the incidence of refractory KD in Boston was 8 percent. The same IVIG brands and lots administered in San Diego to treat patients with KD were also used in Boston.
Retrospective studies have identified potential factors that predict which patients will require further therapy for refractory disease. The first study utilized the database of patients treated in 2003 and 2004 included in the 18th nationwide survey of KD in Japan11. Of the 15,940 patients with KD, 20 percent did not respond to initial IVIG therapy. 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
Other retrospective studies have reported that the following clinical factors increased the likelihood of patient’s nonresponsiveness to initial IVIG therapy12: • Young patient age, children less than one year of age • Early diagnosis, with initial treatment at or before the 4th day of illness • Elevated C-reactive protein (≥10 mg/dL or ≥8 mg/dL) • Elevated liver enzymes (aspartate aminotransferase, AST and alanine aminotransferase, ALT) • Platelet count ≤300,000/mm2 • Elevated band count • Serum sodium ≤133 mmol/L • Low serum albumin
In a study done by Young-Sun Do, et.al, the 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.
The commonest and potentially most life threatening complication of KD is the development of CAA. In untreated KD, up to 25% of patients develop CAA and in a small number this may result in coronary thrombosis, myocardial infarction and death14. Most aneurysms will develop within 6–8 weeks from the onset of the illness.
In untreated KD, up to 25% of patients develop CAA and in a small number this may result in coronary thrombosis, myocardial infarction and death14.
Aneurysms are classified as small, medium and giant. Giant aneurysms have the greatest risk for complications and have an incidence of 0.8 % in the latest Japanese survey. The aneurysms are also classified as saccular, if they have axial and lateral dimensions being of about equal size, or fusiform, if there is dilation with proximal and distal tapering.
The most useful test to identify and monitor potential development of coronary artery abnormality is by two-dimensional echocardiography. It should be performed on the onset of diagnosis and again after 2–3 weeks of illness. If both are normal, a repeat study should be performed 6–8 wk after onset of illness. If coronary abnormalities are not detected by 6–8 wk after onset of illness, and after the ESR has normalized, additional follow-up studies are optional.
Ectasia is defined as coronary artery size larger than normal for age but without discrete aneurysm.
Echocardiographic finding include myocarditis and depressed function, pericarditis with an effusion, valvular insufficiency, or coronary artery changes. The most common finding is mild coronary artery changes. Echo is 80-90% sensitive for the diagnosis of proximal coronary artery aneurysms
The score The Harada score was developed in the early 1990s to select patients who were at higher risk of developing CAA. This scoring is based on; 1) WBC count: equal to or more than 12 ×103/μl, 2) Platelet count: less than 35×104/μl, 3) CRP: equal to or more than 4 mg/dl, 4) Hematocrit: less than 35%, 5) Serum albumin: less than 3.5 g/dl, 6) Gender: male, 7) Age: equal to or less than 12 months. When the patient with KD satisfies 4 or more of the above 7 criteria within the 9th day of illness, treatment with IVIG should be started, hence, this patient has a high risk of developing coronary artery lesions.
Patients with acute Kawasaki disease should be treated with intravenous immunoglobulin (IVIG) and high-dose aspirin as soon as possible after diagnosis and, ideally, within 10 days of disease onset. The mechanism of action of IVIG in Kawasaki disease is unknown, but treatment should result in rapid defervescence and resolution of clinical signs of illness in 85–90% of patients. With therapy, the CRP normalizes much more quickly than the ESR, which will often increase immediately after IVIG therapy. IVIG reduces the prevalence of coronary disease from 20–25% in children treated with aspirin alone to 2–4% in those treated with IVIG and aspirin within the 1st 10 days of illness. Consideration should even be given to treatment of patients diagnosed after the 10th illness day if fever has persisted, because the anti-inflammatory effect may be helpful, although the effect of such therapy on the risk of developing coronary aneurysms is unknown. The dose of aspirin is decreased from anti-inflammatory to antithrombotic doses (3–5 mg/kg/day as a single dose) on the 14th illness day or after the patient has been afebrile for at least 3–4 days. Aspirin is continued for its antithrombotic effect until 6–8 wk after onset, when the ESR has normalized in patients that have not developed abnormalities detected by echocardiography.
Patients with acute Kawasaki disease should be treated with intravenous immunoglobulin (IVIG) and high-dose aspirin as soon as possible after diagnosis and, ideally, within 10 days of disease onset. The mechanism of action of IVIG in Kawasaki disease is unknown, but treatment should result in rapid defervescence and resolution of clinical signs of illness in 85–90% of patients. With therapy, the CRP normalizes much more quickly than the ESR, which will often increase immediately after IVIG therapy. IVIG reduces the prevalence of coronary disease from 20–25% in children treated with aspirin alone to 2–4% in those treated with IVIG and aspirin within the 1st 10 days of illness. Consideration should even be given to treatment of patients diagnosed after the 10th illness day if fever has persisted, because the anti-inflammatory effect may be helpful, although the effect of such therapy on the risk of developing coronary aneurysms is unknown. The dose of aspirin is decreased from anti-inflammatory to antithrombotic doses (3–5 mg/kg/day as a single dose) on the 14th illness day or after the patient has been afebrile for at least 3–4 days. Aspirin is continued for its antithrombotic effect until 6–8 wk after onset, when the ESR has normalized in patients that have not developed abnormalities detected by echocardiography.
Patients receiving long-term aspirin therapy are candidates for annual influenza vaccination to reduce the risk of Reye syndrome. Varicella vaccination should be strongly considered, since the risk of Reye syndrome in children who take salicylates and who receive varicella vaccine is likely to be lower than with wild-type varicella. Patients treated with 2 g/kg IVIG should have measles-mumps-rubella and varicella vaccinations delayed for 11 mo because the specific antiviral antibody in IVIG may interfere with the immune response to live-virus vaccines.