The Japanese Connection

“

The Japanese Connection”

“The Japanese Connection” • J.K.K, 1 year 3 month old, male, Catholic from Cainta, Rizal was admitted because of prolonged fever • He was apparently well until eighteen days prior to admission when he developed remittent fever (maximum 400C) temporarily lysed by Paracetamol at 10 mk/dose. There were no accompanying symptoms. No consult was done

History • Fourteen days PTA with persistence of fever now accompanied by dry, fissured lips, they consulted at UERM Hospital. CBC was normal. He was diagnosed with Acute Otitis Media and Acute Tonsillitis and was prescribed CoAmoxiclav at unrecalled doses to be taken for 7 days

Q1: Are you agreeable with the management given at the hospital? Would you modify the management?

Answer to Q1: • The most frequent etiologic agents involved in Acute Otitis Media of this age group are: S. pneumoniae, H. influenzae and Moraxella catarrhalis (developed countries) or S. aureus (developing countries) • For this group of agents the most costeffective drugs would be Amoxicillin or Cotrimoxazole depending on the sensitivity pattern in the community • For a more definitive diagnosis, tonsillar swab culture or rapid serological tests could have been requested (depending on the financial capacity of the patient)

History • Thirteen days PTA, there was note of increased lacrimation of both eyes with associated cough prompting consult at a local clinic. An impression of acute viral illness was given and he was prescribed Chloramphenicol for 7 days. There was minimal relief of symptoms however

Q2: At this point, what disease entity/entities will you entertain?

Answer to Q2 • The history of 4 days fever with lacrimation and cough in the absence of measles vaccination should make a physician consider Measles as a likely diagnosis

History • Nine days PTA , there was note of edema of both hands and feet and increased dryness and cracking of the lips. They sought consult at Salve Regina Clinic where CBC showed Hgb 100, Hct 0.30, WBC 15.7; Segmenters 0.38, Lymphocytes 0.62, Platelet 256, Na 130.9, K 3.95; Typhidot IgG (-), IgM (-). Chest x-ray showed bronchopneumonia prompting subsequent admission. He was given Chloramphenicol and Paracetamol affording lysis of fever. He was discharged after 3 days afebrile and apparently well

Q3: Would you have managed the child in the same manner?

“The Japanese Connection” • Survey

FUO • At this time with 9 days fever, the patient should have been thought of having Fever of Unknown Origin thus more exhaustive efforts to identify the possible causes of FUO should have been done. Antibiotics for the management of the condition given prophylactically have no practical indication

History • Five days PTA, there was recurrence of fever for one day accompanied by truncal rash and periungual desquamation. They were advised to continue the previously prescribed meds which afforded no change in symptoms .

History • They consulted another pediatrician who requested CBC the results of which showed Hgb 10.2, Hct 0.30, WBC 8.7, segmenters 35, lymphocytes 61, Platelet 402, eosinophils 04. They were referred to a Pediatric cardiologist who advised admission

Q4: How would you interpret the laboratory examination?

Interpretation (answer)

Days PTA 18

17

16

15

14

13

12

11

10

9

8

7

6

5 4 3 2

1

fever Dry, fissured lips

Consult: Acute Otitis/Tonsillitis

Increased lacrimation

Co-amoxyclav Consult: Measles Chloramphenicol

Edema of both Hands and feet

Consult Labs CXR: Bronchopneumonia Chloramphenicol

Truncal rash

Continue chloramphenicol

Periungual desquamation

Consulted: probable Kawasaki Disease Labs Pedia Cardio

IMMUNIZATIONS • • • •

BCG – ® deltoid scar DPT- 3 doses OPV- 3 doses No Measles, MMR, Hib, Varicella

• All immunizations given at a local health center, dates unrecalled

PHYSICAL EXAMINATION

• Alert, awake, fairly nourished, irritable, not in cardiorespiratory distress • CR: 110 bpm, RR: 24 breaths/min, T: 36.3C • Weight: 10 kg (P25), Length 76 cm (P25) • Warm skin, (+) multiple maculopapular rash, posterior trunk

Bilateral exudative conjunctivitis

Physical exam • (+) lacrimation (B) eyes, pink palpebral conjunctiva, anicteric sclerae, mm ERTL, no injection • non hyperemic external auditory canal, (+) impacted cerumen, AU

Physical Exam • (+) red, dry, fissured lips, moist buccal mucosa, smooth tongue, nonhyperemic posterior pharyngeal wall and tonsils • supple neck, palpable cervical lymph node, (L) submandibular area approx 0.5-1 cm, firm, non-tender • Adynamic precordium, AB 4th LICS MCL, no murmurs

• Globular abdomen, normoactive bowel sounds, soft, nontender, liver and spleen not palpable • Extremities: (+) periungual desquamation, (+) edema • Pulses full and equal, no cyanosis • genitalia: grossly male, bilaterally descended testes

Periungual desquamation

SALIENT FEATURES • • • • • • •

1 yr 3 month old, male, previously well fever of 13 days Dry, fissured lips Edema of both hands and feet Maculopapular truncal rash Periungual desquamation Palpable cervical lymph node, (L) submandibular area

Q5: With the Clinical findings, what is your impression?

KAWASAKI DISEASE

• Fever > 5 days • Presence of at least 4 principal features – Cervical lymphadenopathy – Rash primarily truncal: polymorphic, non vesicular – Bilateral non purulent conjunctivitis – Changes in lips and oral cavity • Erythema, lips cracking, strawberry tongue, diffuse injection of oral and pharyngeal mucosa – Changes in extremities • peripheral edema, erythema, periungual desquamation Illness not explained by other known disease process

Rheumatic Diseases Pediatric Medicine edited by Mary Ellen Avery and Lewis First

• The rheumatic diseases are a group of disorders sharing the common property of inflammation of connective tissues throughout the body • Inflammation is characteristically chronic or recurrent and is of unknown cause • Immunologic aberrations are frequently associated with these disorders • Because the musculoskeletal system is made up of predominantly connective tissues, the rheumatic diseases all share the property of prominent musculoskeletal involvement

Rheumatic Diseases These diseases include: • Acute rheumatic fever - a poststreptococcal state best characterized by inflammation of the endocardium resulting in valvular carditis • Juvenile rheumatoid arthritis – characterized by chronic inflammation of synovial tissues; several different diseases are included under this umbrella term e.g. Systemic Onset JRA • Ankylosing spondylitis and the spondyloarthropathies – characterized by chronic synovitis and inflammation of connective tissues around bones and joints which affect the axial skeleton more than the peripheral joints

Rheumatic Diseases • Systemic lupus erythematosus – multisystem disease characterized by inflammation in a number of organs and by the presence of a number of host immunologic aberrations • Dermatomyositis – characterized by inflmmation of skeletal muscle and skin, resulting in myositis and a distinctive skin rash • Various Vasculitis Syndromes:  Henoch-Schonlein vasculitis – a disease of inflammation of very small blood vessels  Kawasaki disease – a febrile illness that is associated with inflammation of large coronary and other large blood vessels

Rheumatic Diseases • Scleroderma – characterized by fibrosis of the skin and subcutaneous tissue and of internal organs; can exist in localized cutaneous forms or as a systemic disease • Mixed connective tissue disease – a multisystem overlap disease characterized by the presence of a certain antinuclear antibody reactive with nucleoprotein • Fasciitis – a condition resulting from inflammation of the fascial tissues

Basic Science • The basic causes of the inflammation and the explanation for mechanisms that perpetuate the chronicity of this inflammatory process remain to be found • Various lab observations have led to the idea that the diseases are in some way caused by “autoimmunity” however the situation seems to be more complicated than simple autoimmunity • Recent findings suggest that several factors are interrelated in the causation of some of the rheumatic diseases:  Genetic predisposition  Exposure to environmental agents and  Aberrant host immune responses

DIAGNOSTIC CRITERIA for Kawasaki Disease

• Fever > 5 days • Presence of at least 4 principal features – Cervical lymphadenopathy – Rash primarily truncal: polymorphic, non vesicular – Bilateral non purulent conjunctivitis – Changes in lips and oral cavity • Erythema, lips cracking, strawberry tongue, diffuse injection of oral and pharyngeal mucosa – Changes in extremities • peripheral edema, erythema, periungual desquamation Illness not explained by other known disease process

Historical Perspective & Epidemiology

• First Described in Japan in 1967 by

Tomisaku Kawasaki • Now #1 cause of acquired heart disease in U.S. children – 6-9 cases/100,000 children aged <5 years in U.S. – 2,000 cases/year in U.S.

• Male: Female ratio of 1.5-1.7: 1 • Increased incidence in siblings of index cases – 2.1% occurrence in siblings within 1 year after first case in family 10 x rate in general Japanese population – 13% risk of occurrence in twins • 76% of affected children are < 5 years old • Peak age is in first year for boys & girls • More common in winter and early spring

• Reported in virtually all countries • Higher incidence in developed countries • Some association with socioeconomic status • Fatality Rate- 0.3%

• Local Statistics (Hospital of the Infant Jesus 1998-2003) • < 1 year old: 38 cases • 1-4 y/o: 87 cases • 5-9 y/o: 5 cases • Females: 34.6% • Males: 65.4%

• 10 year review at Chinese General Hospital 1989-1999 • 28 patients with Kawasaki disease • More common in males • Peak age below 1 year old • Most common manifestation: – polymorphous rash, – conjunctival injection, – cervical lymphadenopathy

• • • •

54% Filipinos 25% Filipino-Chinese 14% Chinese 7% Japanese-Filipino

– 38% of deaths occur in infants < 6 months old – 23% of deaths in infants 6-12 months of age – 77% of deaths in children < 2 years of age – 85% of deaths in children < 3 years of age – Myocardial infarction is principal cause of death

Race Specific Incidence of Kawasaki • United States – – – –

Asian and Pacific Islander African American Hispanic Caucasians

32.5 16.9 11.1 9.1

• Japan – Japanese ancestry

112

Incidence rates given in # of cases/100,000 children < 5 y/o

Etiology of Kawasaki Syndrome • Unknown • Infectious etiology – Seasonal occurrence – Age distribution – Community outbreaks with wavelike geographic spread

• Probable genetic susceptibility features • Bacterial superantigenic toxin • Immune response is oligoclonal (antigen driven) and IgA plasma cells play a central role

Pathology • Generalized systemic vasculitis involving blood vessels throughout the body • Aneurysms: – Celiac, mesenteric, femoral, iliac, renal, axillary, brachial arteries

Laboratory Findings Consistent with Acute Kawasaki Syndrome • Leukocytosis with neutrophilia and

• • • • • •

immature forms Anemia for age Platelets > 450,000 / mm3 after 7 days Elevated ESR Elevated CRP Urine > 10 WBC /high-power field Hyponatremia

Laboratory Findings Consistent with Acute Kawasaki Syndrome • Elevated serum transaminases • CSF Pleocytosis • Leukocytosis in synovial fluid • Elevated serum GGT • Albumin < 3

J.K.K’s Laboratory findings:

CBC Hgb Hct Platelet WBC Segmenters Lymphocytes Eosinophils

3/14/05 94 0.29 561 9.7 0.51 0.47 0.02

Urinalysis

3/14/05

color

Light yellow

transparency

clear

pH

6.5

Specific gravity

1.010

Pus cells

0-2/hpf

Squamous cells

Few

Bacteria

few

3/14/05 Na (meq/L)

137

K (meq/L)

3.8

ESR (mm)

119

CRP (mg/L)

24.74

• Serum sodium concentration of < 135 meq/L at the first patient’s hospital visit may be a predictor of giant coronary aneurysm due to Kawasaki disease. • 78% sensitivity and specificity of 58% • Positive predictive value of 5%

•

Nakamura, et al. Pediatrics International, (2004) 46, 33-38

• Predictive equation of cardiac sequelae including total protein, age, sex and serum sodium. Low serum sodium elevated the risk of cardiac sequelae

Other Clinical Findings

Cardiovascular – CHF, Myocarditis, Pericarditis, Valvular regurgitation – Coronary artery abnormalities – Aneurysms of medium-size noncoronary arteries – Raynaud’s phenomenon – Peripheral gangrene

• The major sequelae of Kawasaki disease related to the coronary arterial system

• Echocardiography is sensitive in detecting proximal coronary artery aneurysm • Unequivocal coronary lesions are not commonly present before 10 days

•

Cardiological issues, BMJ 2003; 327, 918

• Echocardiography – Initial study when diagnosis of Kawasaki disease first suspected, but do not delay treatment while awaiting echo – Serial echocardiograms recommended at 2 weeks and 6-8 weeks after onset – Echo at 1 year not likely to reveal abnormality if normal at 4-8 weeks • Histological evidence suggests that myocarditis is universal in acute Kawasaki disease

Increased Risk for Development of Coronary Artery Aneurysm Boys < 1 year of age Fever for > 16 days or recurrent fever Peripheral WBC count >30,000/mm2 Erythrocyte Sedimentation Rate > 101 mm/hr Elevated ESR or CRP for >30 days of illness Recurrence of elevated ESR or CRP ECG abnormality- Abnormal Q waves in leads II, III, aVF • Symptoms of Myocardial Infarction • • • • • • •

Asai et al, Japan J Ped, 1976

Cardiac Complication : Coronary Artery Aneurysm Development

• Media of affected vessels demonstrate edematous dissociation of smooth muscle cells • Endothelial cell swelling and subendothelial edema with intact internal elastic lamina • Neutrophil influx in early stages (7-9 days after onset)

• Rapid transition to large mononuclear cells in concert with lymphocytes (predominantly CD8+ T cells) and IgA plasma cells • Internal elastic lamina destruction and fibroblast proliferation occur • Matrix metalloproteinases prominent in remodeling process • Progressive coronary stenosis results from active remodeling with intimal proliferation and angiogenesis

• Musculoskeletal – Arthritis/ Arthralgia • Gastrointestinal tract – Diarrhea, Vomiting, Abdominal pain – Hepatic dysfunction – Hydrops of gallbladder

• Central Nervous System – extreme irritability – Aseptic meningitis – Sensorineural hearing loss • Genitourinary System – Urethritis/ Meatitis

• Other – Otitis media – Erythema, induration at BCG inoculation site – Anterior uveitis (mild) – Desquamating rash in groin

Incomplete (Atypical) Kawasaki • Patients who do not fulfill the criteria • More common in young infants • Diagnosis depend on echocardiographic findings of coronary artery abnormalities • Considered in a child with unexplained fever for > 5 days associated with 2 or 3 of the principal clinical features of Kawasaki • Infant < 6 months with fever of > 7 days, laboratory evidence of systemic inflammation and no other explanation for febrile illness

Common Pitfalls in Diagnosis of Kawasaki Disease • Initial presentation may only include

fever and unilateral cervical lymph node. • Diagnosis frequently missed in children < 1 year and adolescents • Subsequent rash and mucosal changes may be attributed to a reaction to antibiotics.

• Sterile pyuria with subsequent negative cultures may be mistaken for partially treated UTI • Fever, rash and CSF pleocytosis may be misinterpreted as viral meningitis. • Occasionally may present with an acute abdomen

Clinical Findings Suggesting Illness Other than Kawasaki Disease • Exudative Conjunctivitis • Exudative Pharyngitis • Discrete Intraoral Lesions • Bullous or Vesicular Rash • Generalized Adenopathy

Treatment

Goals of therapy for Kawasaki disease Stop inflammation » Control fever » Alleviate clinical signs and symptoms » Prevent coronary artery damage

Acute Phase: ASPIRIN – 80-100

mg/kg/day administered in 4 doses/day during acute phase of illness. – Aspirin dose reduced to 3-5 mg/kg/day either: • 48-72 hours after fever resolves - or• Day 14 of illness with absence of fever for 48-72 hours – If no evidence of coronary artery abnormality by 6-8 weeks of illness, low dose aspirin may be discontinued – If coronary artery abnormality, aspirin may be continued indefinitely

Acute Phase: IVIG – Well-established reduction in prevalence of coronary artery abnormality • Without IVIG: 15-25% • With IVIG: 5% transient coronary dilatation, 1% giant aneurysms – Mechanism of action in treating Kawasaki Disease is unknown – Dose: 2 grams/ kg in a single infusion – Administer dose within 10 days of onset

• If

possible, administer within 7 days of onset • No advantage to administration of IVIG before day 5 compared to treatment on days 5-7 – Administer IVIG after day 10 if persistent fever without explanation or if documented coronary aneurysms with evidence of ongoing systemic inflammation – Measles and Varicella immunizations should be deferred for 11 months after high-dose IVIG

• Steroids: – Recommended only for children in whom >2 doses of IVIG have failed to alleviate symptoms – Most commonly used regimen: IV methylprednisolone 30 mg/kg over 2-3 hours once daily for 1-3 days

Convalescent • If no coronary lesions by 2D echo, discontinue aspirin after 2 months • Patients with coronary lesions – Continue aspirin 3-5 mg/kg/day – Dipyridamole 5 mg/kg/day in 3 doses – Heparin or coumadin together with antiplatelet therapy in severe thrombosis or past evidence of coronary thrombosis

Thrombosis Prevention in Patients with Coronary Artery Disease • •

• •

Mild and Stable Disease – Low-Dose Aspirin Mild-to-Moderate Disease – Combination of Low-Dose Aspirin with other Antiplatelet Agents (Clopidogrel, Dipyridamole) Severe Disease/Rapidly Expanding Aneurysms – Heparin with Aspirin Giant Aneurysms with or without Stenosis – Low-Dose Aspirin with Warfarin – Low-Dose Aspirin with Low-Molecular-Weight Heparin

Treatment of Coronary Thrombosis • Kawasaki disease-associated acute coronary thrombosis differs from atherosclerotic coronary occlusion • Thrombolytic treatment in Kawasaki disease should target multiple steps in coagulation cascade – Tissue Plasminogen Activator (tPA), TenecteplasetPA, streptokinase, urokinase each used in infants & children with varying success. All used with aspirin and heparin or low molecularweight heparin. • Balloon angioplasty generally not successful – May lead to late neoaneurysm formation

• Rotational ablation & stent placement > 80% success rate • Coronary artery bypass grafting may be effective • Cardiac transplantation- small number of patients

Thank You!