1. Kawasaki Disease: History and Clinical Practice
Richard D. Andersen, MD
Former Medical Director, Infectious Disease and Director of Med Student Education
Children’s Minnesota

2. Disclosures
I have no relevant financial relationship with the manufacturers of any commercial product and/or provider of commercial services discussed in this CME activity.
Following college tuition expenses for 3 children, I have no relevant finances of any kind.
I may discuss an investigative use of an approved commercial product in my presentation.

3. One Night on Call…..
You and your Children’s Minnesota hospital ward team are on call, cross-covering the 2-year-old girl admitted yesterday with Kawasaki Disease. The evening nurse calls to report that the patient just vomited today’s 4th aspirin dose. “Do we have to repeat the dose?” Later, the night nurse calls to inform you that the IV has infiltrated…the patient has received 80% of the IVIG. “Do we have to restart the IV?”

4. In the Beginning…. Karl Rokitansky (1852)
“Rosary Sign” – Worm etiology?

5. Clinical and Pathologic Description Kussmaul and Maier (1866)….
Adolf Kussmaul – eminent clinician – ophthalmoscope, endoscopy, respiration in DKA
Kussmaul and Maier describe “periarteritis nodosa” in adults
(“Kussmaul-Maier Disease”)
Detailed microscopic description
Arterial dilatation with transmural inflammation described

6. Pediatric Periarteritis Nodosa in the 20th Century
In the first half of the 20th century, pediatric periarteritis nodosa was recognized and reported as a distinct entity, “a constant clinical syndrome.”
Most cases were diagnosed at autopsy, generally in young children

7. Keith & Baggenstoss, 1941, Emphasized Coronary Disease in Childhood Periarteritis Nodosa

9. “Mucocutaneous Ocular Syndrome”
Itoga & Yamagishi 1960 published report of non-fatal “mucocutaneous ocular syndrome,”
All cases were between 2 mo and 7 yrs of age
20 cases – all treated with corticosteroids.
They believed it to be a variant of Stevens-Johnson Syndrome (E. multiforme exudativum)

11. Emergence of a Pediatrician: Tomisaku Kawasaki
Born in 1925, the youngest of seven children
“I was very interested in plants and fruit….I wanted to continue studying mutation.”
“My mother wanted me to become a doctor.”
Enrolled in Chiba Medical School
“Adult patients were full of complaints, but sick children said little. Basically, I liked children.”

12. Emergence of A New Entity 1961-67
Dr. Tomisaku Kawasaki
Pediatric Acute Febrile Mucocutaneous Lymph Node Syndrome
Saw first case in 1961
Presentation to a skeptical Japanese Pediatric Society (Chiba)
1964 at Central Japan Ped. mtg labeled them MCOS
1967 abandoned MCOS , emphasized cervical adenopathy (68%)

13. Kawasaki’s Position:
The entity MCLS is distinct from MCOS, emphasized adenopathy.
The constellation of findings are unrelated to Steven’s-Johnson Syndrome.
The syndrome is benign and self-limited.
The cardiac abnormalities observed in similar patients are not related to MCLS.

14. Mucocutaneous Lymph Node Syndrome in USA
First cases in USA are described in Hawaii
Described by Melish and Hicks in 1974
Autopsy diagnoses and new clinical cases

15. MCLS: Case Definition

16. Late 1970’s: Unifying Clinical Concepts
U. Hawaii ped. resident David Morens  to CDC
Skepticism at CDC re new diagnostic entity
Creates case definition for CDC surveillance, based on J.R.C.
“Kawasaki Disease” --term unifies MCOS, pediatric PN, MCLS

17. Kawasaki Disease: A Clinical Portrait

19. Rash may be Morbilliform

20. Age Distribution of Kawasaki Disease

21. Extremity Swelling May Be Subtle…. or not

22. What Else Could This Be? Measles Adenovirus Enteroviruses &EBV
Stevens-Johnson Syndrome
Staph aureus infection
Group A strep infection
Leptospirosis & RMSF
Systemic onset JIA
Other

23. 1970’s: Steroids and Aspirin

24. 1978: Kawasaki Arrives

25. Treatment Consensus – late 1970’s
Rheumatologic opinion favored high dose aspirin for anti-inflammatory effect
Hematologic opinion favored low dose aspirin for antithrombotic effect on platelets
Conclusion: high-dose ASA during intense inflammatory period (2 weeks) and low-dose ASA during convalescence
Steroids appear to be contraindicated

26. 1978-1980 Disruption of Conceptual Clarity
Todd et al (1978) describe “toxic-shock syndrome” in 3 boys, 4 girls with mucosal phage group 1 Staph aureus
Report met with skepticism (Denver/USA) and rejection (N.E.J.M.), published in the Lancet
Simultaneous reports of “Adult Kawasaki Disease” – more acute than pediatric Kawasaki Disease
1980--emergence of tampon association (Minn/Wisc)
“ Toxishaki?” (unpublished term)

27. Lessons of the Kawasaki Disease Story 1940-1980
Lesson #1 -- Discoveries of new clinical constellations are often met with skepticism by the medical community.
Lesson #2 -- Rigorous study of pathologic anatomy tends to clarify clinical confusion.
Lesson #3 – There may be “critical periods” to answer important therapeutic questions, after which “conventional wisdom” dictates care.

28. Lesson #4:
Listen to your mother…..

30. Infants with Kawasaki Disease are Different than Older Children (1980)
K.E. was a 6 mo. old girl with 3 weeks of high fever with minimal physical findings.
Cardiovascular deterioration and death occurred at 3 weeks.
Post-mortem exam revealed generalized vasculitis, including larger vessels, and myocardial/endocardial involvement
Post-mortem conference debate: Kawasaki Disease = Periarteritis Nodosa?

31. Clustering and Seasonality

32. Outbreak -- An Important Clue?

33. Living near a Body of Water -- Epidemiologic Factor?

34. 1980’s – Intravenous Gamma Globulin
Emergence of IVIG in the 1970’s led to successful treatment of ITP in 1981.
Early 1980’s -- Furusho and Furukawa in Japan reported successful treatment of Kawasaki Disease with IVIG.
U.S.A. investigators launched controlled national collaborative study, by 1986 showed dramatic reduction of coronary aneurysms with IVIG (~5%) vs. placebo (20+%)

35. IVIG Impact on Aneurysms

36. Intravenous Gamma Globulin (cont.)
Original study used 400 mg/kg/day X 4 days
New national collaborative study (1986 to 1991) compared 4-day IVIG course with mg/kg in a single dose
Slight superiority and convenience of single dose therapy established it as the currently recommended regimen.
Usual course is ~12 hours, sometimes with pre-medication.

37. IVIG – Late 1980’s: What are We Doing?
The presumption of an undiscovered microbial etiology led to hypothesis that IVIG was neutralizing microbes or their toxins.
Other investigators believed that IVIG played an immunoregulatory role, perhaps binding Fc receptors on inflammatory cells.
Observed efficacy intensified study of inflammatory mediators in Kawasaki Syndrome

38. LATE 1980’S FOOTNOTE:
Dr. James Todd receives prestigious Infectious Disease Society of America Award at annual meeting for his investigations of Toxic Shock Syndrome and its pathogenesis.
Award is presented by Infectious Disease Society member who was the reviewer for the New England Journal of Medicine, and who recommended rejection of the article.

39. What Causes Kawasaki Disease
What Causes Kawasaki Disease? 1990’s: Still Searching for Infectious Etiology
CATEGORY
POSSIBLE CANDIDATES
BACTERI A
RICKETTSIA
VIRUSES
SPIROCHETES
ECTOPARASITES
Staph aureus
Group A Strep
Coxiella burnetii
Rickettsia conorii
Retroviruses
Parvoviruses
Borrelia
Leptospira
Carpet mites

40. Another False Start…
Dr. Jane Burns, leading Kawasaki Disease investigator, finds evidence of reverse transcriptase in supernatant fluid of lymphocyte cultures of KD patients.
Hypothesis emerges of a T-8-tropic retrovirus
Dr. Burns and other investigators are unable to reproduce results.

41. Kawasaki Disease in the 1990’S
Universal adoption of IVIG single dose
Aspirin use continues (high-dose X 2 weeks, followed by 6-8 weeks of low-dose); some question its necessity and its dosage.
Continued debate over microbial etiology, including Staph aureus, but growing evidence of immunologic dysregulation as central
Recognition of children with “Atypical” and “Incomplete” Kawasaki Disease.

42. Some Immunologic Alterations in Kawasaki Syndrome
T-cell imbalance during the acute phase
Increased cytokine production
Appearance of circulating antibodies to endothelial cells activated with IL-1, tumor necrosis factor-alpha, or interferon-gamma
Adhesion of leukocytes to endothelial wall, infiltration of neutrophils & mononuclear cells

43. Tumor Necrosis Factor: Central Role?

44. Kawasaki Disease in the 21st Century: The Central Questions
1. What are the criteria for diagnosis of Incomplete Kawasaki Disease ?
2. What do we do if treatment fails ?
3. Why are some individuals more likely to experience Kawasaki Disease ?
4. What can we learn about etiology and pathogenesis?
5. What is the long-term prognosis ?

45. Leading Centers for Kawasaki Disease Research
Japan Kawasaki Disease Research Center
Kawasaki Disease Research Center - U.C. San Diego

47. What do we do if IVIG/ASA Fails?
About 10-15% of children with Kawasaki Disease fail primary treatment – highlighted by persistent or recrudescent fever.
First choice is usually repeat IVIG dose
Corticosteroids role?
TNF inhibition - infliximab or etanercept?
IL-1 inhibition – anakinra or canakinumab?
Cyclophosphamide or cyclosporin?

49. KIDCARE Study
Study underway, planned for 250 patients who have refractory KD post-IVIG treatment
Study coordinated by UC San Diego and involves 28 children’s hospitals in USA
Randomization to 2nd IVIG vs infliximab
Completion by (?) unless terminated early by Drug Safety Monitoring Board

50. Genetic Studies Example
Planned study of 800 children (past/present) with Kawasaki disease
Study centered at Seattle Children’s Heart Center (also Montreal & Alabama)
Stated goal: Find genetic biomarkers that will predict which patients will not respond to the standard treatment

51. Is the Answer Blowin’ in the Wind?
“Analyses of the three major KD epidemics in Japan, major non-epidemic interannual fluctuations of KD cases in Japan and San Diego, and the seasonal variation of KD in Japan, Hawaii, and San Diego, reveals a consistent pattern wherein KD cases are often linked to large-scale wind currents originating in central Asia and traversing the north Pacific. Results suggest that the environmental trigger for KD could be wind-borne. Efforts to isolate the causative agent of KD should focus on the microbiology of aerosols.” (2011)

52. Long-term Prognosis?
“Guidelines have been developed by the AHA and AAP for subsequent therapy, physical activity, and follow-up visits (schedule and content) based upon the relative risk for myocardial infarction.”
“Patients without any cardiovascular abnormalities appear to be clinically healthy at long-term follow-up (range, 10 to 21 years). However, it is unknown whether they are at increased risk for atherosclerotic heart disease.”
(both quotations from UpToDate, 2019)

53. Back to the Night on Call….
“Do we need to repeat the dose of aspirin that the patient vomited?”
“Do we need to restart the IVIG if he has received 80% of the dose?”
Final lesson – the rationality of our clinical practice derives from the solidity of the literature on which we stand