Urine Proteomics in Kawasaki Disease

Pawan Sharma15th October 2013

Kawasaki Disease• Uncommonly common systemic vasculitis.• 6 months to 4 years age.• Significant mortality and morbidity esp with delayed

diagnosis.• No pathognomic test for early diagnosis.

GOAL

To discover and validate diagnostic markers of KD in a prospective cohort..

Study participants• Over 39 months in Tertiary care hospital.• Approved by Boston Children’s Hospital

Committee.• Patients under the age of 18 with possible

diagnosis of KD.• Exclusion criteria: neoplastic, renal or urologic

disease.• Total patients mentioned 236 (234).

Study design • Discovery phase.• Validation phase:

First cohort based on possible KD, but before determination of final diagnosis.

Second cohort utilized serum specimens collected as a part of Pediatric Heart Network Study of KD.

Out come measures• Paediatric Rheumatologist • Use of Published Diagnostic Criteria for KD.• Atypical KD was established using American Heart

association guideline.

DF candidate diagnostic marker• Analysed 15 patients.• 6 KD patients (3 with and 3 without Coronary heart

disease).• 6 non-KD patients (2 non specific, 3 adeno and 1

Pyelonephritis).• 3 matched specimen from treated patients with KD

(after 1 month).• 190 proteins specific to KD.• Meprin A and Filamin C chosen.

Urine proteomics for discovery of improved diagnostic markers of Kawasaki disease

EMBO Molecular MedicineVolume 5, Issue 2, pages 210-220, 20 DEC 2012 DOI: 10.1002/emmm.201201494http://onlinelibrary.wiley.com/doi/10.1002/emmm.201201494/full#fig1

Validation • Prospectively measured concentration in urine.• Investigators blinded to Final diagnosis.• Mean age 3 years.• 53 (49%) final diagnosis of KD.• All treated with IVIg and Aspirin, 30% required

repeat treatment.• All studied patients received a Final Outcome.

Table 2. Final diagnosis of the 107 study patients

Final diagnosis Number of patients

Kawasaki disease 53 (49%)

Viral syndrome 33 (61%)

Adenovirus 6

Serum sickness 3

Pyelonephritis 2

group A streptococcal pharyngitis 2

Cytomegalovirus 1

Epstein-Barr virus 1

Group A streptococcal pharyngitis 1

Lyme disease 1

Otitis media 1

Pneumonia 1

Respiratory syncytial virus 1

Systemic arthritis 1

KD Non KD

Filamin C 19.2 3.7

Meprin A 50.2 5.6

Atypical KD Non KD

Filamin C 17 3.7

Meprin A 41.5 5.6

Mean values

Blinded case control study

Response to treatment

2nd Cohort• 112 archived samples collected from KD patient

analysed.• Compared them with Non-KD febrile illness.• Serum samples used.• Results were:

KD Non KD

Filamin C 217 6.6

Meprin A 1363 14.8

Mouse model

What do we think• Clear question for study address?• Was there a comparison with appropriate

standard? • Did all patients get diagnostic test and reference

standard?• Could the result have been influenced?• Is disease status clearly described?• Were methods described in clear details?• What are the results?• Can the results be applied to our patients?

Summary• Potential approaches for improving diagnosis.• Discover phase: very small group.• Mechanism of how this markers accumulate shall

be important direction for future work.• Limitations: Renal or Urologic disease, sever

dehydration or ? Shock.

• Thank you!

The Receiver Operating Characteristic Curve.• true positive rate (Sensitivity) is plotted in function of the

false positive rate (100-Specificity) for different cut-off points.

• Each point on the ROC curve represents a sensitivity/specificity pair corresponding to a particular decision threshold.

• A test with perfect discrimination has a ROC curve that passes through the upper left corner (100% sensitivity, 100% specificity). Therefore the closer the ROC curve is to the upper left corner, the higher the overall accuracy of the test .

ROC Chart