We conducted a study to determine which factors may be useful as predictive markers in identifying Kawasaki disease (KD) patients with a high risk of resistance to intravenous immunoglobulin (IVIG) and developing coronary artery lesions (CAL).
We enrolled 287 patients in acute phase of KD at a single center. The demographic, clinical and laboratory data were collected retrospectively.
There were 34 patients in the IVIG resistant group. The IVIG resistant group had significantly higher serum
Serum NT-proBNP levels and PMN percentage were significantly elevated in patients with KD with IVIG resistance and CAL. Thus, they may be useful predicting markers for IVIG resistance and development of CAL in KD patients.
Kawasaki disease (KD) is an acute febrile illness of childhood, a vasculitis of unknown etiology
Coronary artery complications develop in 20% to 25% of untreated KD patients
Recent studies have investigated factors for predicting resistance to intravenous immunoglobulin (IVIG) as well as coronary artery lesions (CALs) in patients with KD, but the results have been conflicting.
The purpose of our study was to determine which factors can be useful as predictive markers for patients with KD who are at higher risk of IVIG resistance and developing CAL.
KD was diagnosed according to the criteria published by the American Heart Association (AHA) in 2004. Diagnosis of incomplete KD was based on the diagnostic criteria established by AHA
All patients received 50 mg/kg/day acetylsalicylic acid until they were afebrile and 2 g/kg of IVIG over 12 hours. The onset of KD including incomplete (atypical) KD was defined as the day of fever onset.
We conducted a retrospective review of medical records for 287 KD patients, admitted to Inje University Haeundae Paik Hospital between September 2010 and December 2015.
IVIG resistance was defined as persistent or recrudescent fever (temperature>38.0℃) after more than 36 hours following completion of IVIG infusion (2 g/kg). CALs were assessed by performing serial echocardiography, primarily by quantifying the internal coronary artery dimension as per the Japanese Ministry of Health criteria: a maximum absolute internal diameter >3 mm in children <5 years of age, or >4 mm in children 5 years and older, or segment 1.5 times greater than an adjacent segment, or the presence of luminal irregularity. We also diagnosed the presence of CAL whenever body surface area-adjusted Z score of any coronary artery was ≥+2.5, including left main, left anterior descending, and right coronary arteries
All laboratory data used in this study were obtained at admission before the initiation of IVIG therapy. The laboratory investigations included white blood cell count, polymorphonuclear neutrophil (PMN) percentage, albumin, total bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), C-reactive protein (CRP),
Statistical analysis was performed using IBM SPSS Statistics ver. 21.0 (IBM Co., Armonk, NY, USA). A univariate analysis was performed on the clinical data of the KD patients in the IVIG resistant and CAL groups, in which categorical data were presented as as either significantly different or correlated. To assess the ability of laboratory factors for percentages and were analyzed using the Student
Two hundred eighty-seven children (159 male and 128 female), age range: 2 months to 13 years 3 months (median age, 2.2 years), presenting with acute phase of KD were enrolled in this study. Patients with typical KD and incomplete KD accounted for 88.2% (n=253) and 11.8% (n=34), respectively.
Out of the 287 patients, 253 (88.2%) responded to IVIG treatment, whereas 34 (11.8%) did not respond to the therapy. There were no significant differences between the IVIG resistant and IVIG responding groups based on gender (male/female, 19/15 and 140/113, respectively) and age (36.24±21.76 and 29.07±21.57 months,
The number of patients who developed CAL was significantly higher in the IVIG resistant group, 65% (21 of 34) in IVIG resistant group vs. 0.04% (9 of 253) in IVIG responding group (
The NT-proBNP cutoff value of 628.6 pg/mL yielded a sensitivity of 78.8%, a specificity of 58.2% for predicting IVIG resistant group in the acute phase of KD. The CRP cutoff value of 6.81 mg/dL yielded a sensitivity of 81.8% and a specificity of 54.2% for predicting IVIG resistance. The PMN cutoff value of 80.3% yielded a sensitivity of 60.6% and a specificity of 90% for predicting IVIG resistance.
The NT-proBNP levels significant for predicting IVIG resistance in KD patients were assessed by a ROC curves analysis (
Thirty patients from the total study population of 287 patients developed CAL, despite receiving IVIG. There were significant differences in age between the CAL and non-CAL groups (39.1±22.36 and 28.84±21.38 months,
An NT-proBNP cutoff value of 853.4 pg/mL yielded a sensitivity of 73.3%, a specificity of 67.9% for predicting CAL in the acute phase of KD. The CRP cutoff value of 9.4 mg/dL yielded a sensitivity of 63.3% and a specificity of 71.6% for predicting CAL. The PMN percentage cutoff value of 80.3% yielded a sensitivity of 56.7% and a specificity of 88.9% for predicting CAL.
The NT-proBNP level for predicting CAL in patients with KD was assessed by an ROC curves analysis (
The diagnostic criteria of KD were set forth over 40 years ago. Despite several revisions over the years, they are still insufficient for adequate diagnosis of the disease. Unfortunately, there are no diagnostic tests currently available that help early diagnosis of KD patients. Our results suggest that the serum NT-proBNP levels and PMN percentage are significantly elevated in patients with KD with IVIG resistance and CAL and may be useful predicting markers.
Some patients with KD fail initial IVIG therapy for reasons that are not clear. Retrospective studies have identified potential factors that could predict which patients will require further therapy for refractory disease. The presence of one or more of these risk factors for treatment failure should alert clinicians to an increased likelihood that the patient may not respond adequately to the initial IVIG therapy. The ability to predict a lack of response to IVIG before initiating therapy, would allow clinicians to identify these patients because they might benefit from more aggressive treatment.
Several previous studies reported increased patient serum NT-proBNP levels in acute phase of KD, thus providing useful markers for diagnosing KD
The NT-proBNP is a prohormone with a 76 amino acid
The mechanisms by which the elevated levels of serum NT-proBNP occur in the acute phase of KD are not clear at the present time, however there is a possibility that proinflammatory cytokines such as tumor necrosis factor-α or interleukin-1 beta, known to be increased in the acute phase of KD, induce the secretion of BNP from myocytes
The serum concentration of NT-proBNP may be useful for predicting IVIG resistance and CAL in patients with the acute phase of KD. It is worthwhile to consider and evaluate risk stratified strategies for patients at a higher risk of developing severe KD, based on the serum concentration of NT-proBNP.
Kaneko K et al.
By using larger data in our study, we further confirmed that the serum NT-proBNP levels are also increased in children with KD, having CAL and IVIG resistance.
By the AUC, the serum levels of PMN percentage, NT-proBNP, and CRP were considered to be good predictors for IVIG resistance in KD patients. The serum levels of NT-proBNP and PMN percentage were considered to be good predictors for developing CAL in KD patients. These results were compared to previous study. In that study, the serum level of NT-proBNP and serum CRP were considered to be better single predictor for IVIG nonresponders. And the serum level of NT-proBNP was considered to be the best single predictor for CAL among these biochemical markers in patients with KD
Moreover, our study also revealed significantly higher levels of total bilirubin and ALT. However serum albumin levels were significantly lower in both IVIG resistant and CAL groups (
In our study, PMN percentage was an important laboratory predictive factor in addition to NT-proBNP. Our results correlated with the findings of Ha et al.
While controversy remains as to which risk factors predict patient resistance to IVIG, and treatment regimens to reduce the risk of developing CAL, the presence of several predictive factors in our study, especially proBNP and PMN percentage, should alert clinicians to the increased probability of the patient not responding adequately to initial IVIG therapy and developing CAL.
In conclusion, the serum NT-proBNP, PMN percentages, CRP and total bilirubin are increased significantly in KD patients with IVIG resistance and CAL. Serum NT-proBNP levels and PMN percentage may be useful for predicting IVIG resistance and CAL in KD.
Characteristic | IVIG responsive (n=253) | IVIG resistant (n=34) | |
---|---|---|---|
Sex | 0.952 | ||
Male | 140 (55.3) | 19 (55.9) | |
Female | 113 (44.7) | 15 (44.1) | |
Age (mo) | 29.07±21.57 | 36.24±21.76 | 0.07 |
Fever of IVIG (day) | 4.87±1.15 | 4.74±.90 | 0.525 |
Cervical lymphadenitis | |||
No | 134 (53.0) | 10 (29.4) | 0.010 |
Yes | 119 (47.0) | 24 (70.6) | |
PMN (%) | 60.31±16.19 | 76.75±14.31 | <0.0001 |
Albumin (mEq/L) | 3.60±.39 | 3.28±.51 | <0.0001 |
Total bilirubin (mg/dL) | .65±.76 | 1.34±1.16 | <0.0001 |
ALT (IU/L) | 97.57±164.21 | 166.88±192.81 | 0.024 |
CRP (mg/L) | 7.82±6.00 | 10.46±5.28 | 0.015 |
NT-proBNP (pg/mL) | 1,127.10±2,033.60 | 2,255.02±3,150.97 | 0.005 |
Values are presented as number (%) or mean±standard deviation.
IVIG, intravenous immunoglobulin; PMN, polymorphonuclear neutrophil; ALT, alanine aminotransferase; CRP, C-reactive protein; NT-proBNP,
Variable | A | B |
---|---|---|
PMN | 0.802 | 0.773 |
Albumin | 0.293 | 0.322 |
Total bilirubin | 0.668 | 0.698 |
ALT | 0.660 | 0.621 |
CRP | 0.671 | 0.676 |
NT-proBNP | 0.712 | 0.739 |
A, the resistance to IVIG treatment; B, the prediction of CAL; IVIG, intravenous immunoglobulin; CAL, coronary artery lesion; PMN, polymorphonuclear neutrophil percentage, ALT, alanine aminotransferase; CRP, C-reactive protein; NT-proBNP,
Characteristic | CAL− | CAL+ | |
---|---|---|---|
Sex | |||
Male | 138 (53.7) | 21 (70.0) | 0.089 |
Female | 119 (46.3) | 9 (30.0) | |
Age (mo) | 28.84±21.38 | 39.1±22.36 | 0.014 |
Fever before IVIG (day) | 4.82±1.12 | 5.10±1.13 | 0.197 |
Cervical lymphadenitis | |||
No | 135 (52.5) | 9 (30.0) | 0.020 |
Yes | 122 (47.5) | 21 (70.0) | |
PMN (%) | 60.75±16.09 | 75.22±17.67 | <0.0001 |
Albumin (mEq/L) | 3.59±.40 | 3.27±0.51 | <0.0001 |
Total bilirubin (mg/dL) | 0.65±0.76 | 1.45±1.20 | <0.0001 |
ALT (IU/L) | 97.59±162.74 | 176.00±205.19 | 0.016 |
CRP (mg/L) | 7.75±5.76 | 11.39±6.86 | 0.001 |
NT-proBNP (pg/mL) | 1,087.58±1,963.10 | 2,743.94±3,462.45 | <0.0001 |
Values are presented as number (%) or mean±standard deviation.
CAL, coronary artery lesion; IVIG, intravenous immunoglobulin; PMN, polymorphonuclear neutrophil; ALT, alanine aminotransferase; CRP, C-reactive protein; NT-proBNP,