In Kawasaki disease (KD) patients, coronary artery complications, incomplete and refractory types occur more frequently in patients with streptococcal or other bacterial/viral infections. Recently, we observed a higher incidence of coronary lesions in KD patients with high anti-streptolysin O (ASO) titer. Therefore, we hypothesized that KD patients diagnosed with concurrent streptococcal infection have poor prognoses, with respect to treatment response and development of coronary artery lesions.
A retrospective review was performed in 723 patients with KD who were admitted to 2 major hospitals between June 2010 and September 2017.
Among 723 patients with KD, 11 initially showed an elevated ASO titer (>320 IU/mL) or elevated follow-up ASO titer after treatment. Of these patients, 5 showed no response to the first intravenous immunoglobulin treatment, 3 had abnormalities of the coronary arteries. This is a significantly higher proportion of patients with a high ASO titer (n=3, 27.3%) than those with a normal ASO titer (n=53 [7.4%],
It is not certain whether acute streptococcal infection may cause KD, but this study revealed that KD with high ASO titers showed higher rates of severe clinical course. It may be helpful to analyze concurrent streptococcal infection in patients with a severe clinical course.
Kawasaki disease (KD) is an acute systemic inflammatory disease involving multiple organs and tissues [
Despite many investigations and many candidates, no unique infectious agents have been identified as the sole etiologic agent responsible for KD. The role of viral infections in the pathogenesis of KD has been controversial [
Here, we investigated the coronary artery lesions and response to intravenous immunoglobulin (IVIG) in relation to the level of anti-streptolysin O (ASO) in patients with KD.
We retrospectively reviewed KD patients admitted to Kyung Hee University Medical Center and Kyung Hee University Hospital at Gangdong between June 2010 and September 2017. The clinical data of a total 723 KD patients were reviewed. Only patients for whom ASO titer and echocardiography data were available were included in the study. The Institutional Review Board of Kyung Hee University Hospital at Gangdong approved this study (approval number: 2018-08-047) and waived the need for written informed consent.
Laboratory data including microbiology results, imaging studies, and echocardiography examinations were collected and reviewed. A standardized set of laboratory tests was performed before and 36 hours after the end of IVIG infusion, including complete blood count, white blood cell differential count, erythrocyte sedimentation rate, C-reactive protein, albumin, alanine aminotransferase, aspartate aminotransferase, bilirubin, creatinine, ASO, and urine analysis. All except one patient diagnosed with KD received IVIG (2 g/kg) for 12 hours and these blood tests were performed 36 hours after the end of treatment. Only 1 patient did not receive IVIG, because he was referred to our hospital without a fever. Blood culture, throat swab, respiratory viral polymerase chain reaction (PCR), and serum Mycoplasma antibody tests were performed in patients who were suspected of having an infection. Respiratory viral PCR can detect 12 respiratory viruses and subtypes included the following: adenovirus, respiratory syncytial viruses A and B, influenza viruses A and B, parainfluenza 1,2, and 3, rhinovirus, metapneumovirus, and coronaviruses 229E, NL63, OC43, and HKU1. Serial echocardiography exams were performed during hospitalization by an expert pediatric cardiologist. By correcting for BSA, a z score system provided by Kobayashi et al. [
The diagnosis of KD depends on the clinical manifestations according to the defined criteria of the presence of fever for at least 5 days, with at least 4 of the 5 principal clinical features [
We enrolled patients if their ASO titer had increased 4 fold in 2 measurements [
A good clinical course group is defined as fever subsiding within 36 hours after the end of first IVIG treatment without any coronary artery abnormalities. On the other hand, relatively severe KD groups were defined as follows; (1) no response to the first IVIG treatment, and a second IVIG treatment or methylprednisolone (MPD) pulse therapy were required, or (2) KD patients with coronary artery abnormalities.
Fisher exact test was used to compare data using IBM SPSS Statistics ver. 20.0 (IBM Co., Armonk, NY, USA). and values of
A total of 723 patients were diagnosed with KD between June 2010 and September 2017. Patients were admitted to the hospital on average 5.9 days after the onset of fever. These patients’ clinical data are summarized in
Of the 11 KD patients with elevated ASO levels, 5 were boys and 4 were girls (ratio, 0.83:1), with a mean age of 65.5 months (range, 10–131 months) at the time of the KD diagnosis. Ten patients had complete KD, while 1 had incomplete KD. One of the patients (female, 73 months) experienced a KD relapse 15 days after the first treatment.
At the time of diagnosis, all 11 patients had a fever, (mean duration, 9.2 days; range, 5–21 days) and a nonexudative eye injection. 10 patients (90.9%) had a polymorphous rash, 9 patients (81.8%) displayed noticeable changes in the lips or oral mucosa, 8 patients (72.7%) had erythema and edema of the extremities, and 7 patients (63.6%) had cervical lymphadenopathy. The mean fever duration was 9.4 days in the severe KD group and 8 days in the good clinical course group. All patients in the good clinical course group had complete KD, fevers that subsided within 36 hours after the first IVIG treatment, and normal coronary arteries. At the time of diagnosis, 4 patients (36.4%) had a confirmed concurrent infection, the most common pathogens being
Four patients with a high ASO titer did not receive any antibiotics despite a sustained fever, whereas the other 7 did receive antibiotics. However, the prevalence of coronary artery lesions did not differ between them.
As for seasonal patterns, 4 cases were diagnosed in early summer (2 in May, 1 in June, and 1 in July), while 3 were diagnosed in winter (1 in January, 2 in February). No cases were diagnosed in the fall.
Cardiac involvement was screened for in all patients using echocardiography. A significantly higher proportion of patients with a high ASO titer (n=3, 27.3%) than those with a normal ASO titer (n= 53; 7.4%) showed abnormalities of the coronary arteries (
Here we reported the severity of KD with streptococcal infections among 723 KD patients. Among them, 11 had elevated ASO levels before or after IVIG treatment. Of those, 9 had high ASO titers or 4-fold increased titers, and clinical findings for them were worse than those for the other KD patient. Five patients showed no response to the first IVIG treatment (45.5%,
Jordan-Villegas et al. [
In temperate climates, the incidence of group A streptococcal infection peaks during the winter and early spring. In Japan, several group A streptococcal serotypes showed a bimodal distribution, with peaks in December to February and again in May to June and a prominent nadir of infections in September [
Measurement of ASO is relatively inexpensive and easy to perform because the proceeds, along with other blood tests. However, there are significant difficulties assigning a “normal” ASO titer value. The only upper normal limit is >320 IU/mL, presented in a recent study and many other studies [
In our study, 4 of the 11 patients with a high ASO titer did not receive any antibiotics despite a sustained fever, whereas the other 7 did receive antibiotics. However, the prevalence of coronary artery lesions did not differ between them. In 2018, Han and Lee [
Despite its many limitations, our study’s main strength is that we treated all patients using a relatively constant protocol. A series of blood tests was performed at the time of diagnosis, including the ASO titer, because the tests are simple and do not require additional specimens. IVIG 2 g/kg was administered slowly over 12 hours as soon as KD was diagnosed and discontinued whenever a patient’s temperature exceeded 38°C. Thirty-six hours after the end of the IVIG administration, the blood tests, including the ASO titer, were repeated to exclude acute streptococcal infection and the fever pattern was closely observed. In addition, echocardiography was performed by an expert pediatric cardiologist at the admission, 2–3 weeks later, 2 months later, or 1 year later depending on each patient’s status to monitor for coronary artery or other transient lesions.
In this study, we do not know whether acute streptococcal infection or past infection caused the KD. However, in KD with acute streptococcal infection, the fever duration was longer than average and the frequency of coronary artery aneurysms was higher. In cases of incomplete KD or prolonged fever, it may be necessary to diagnose acute streptococcal infection using ASO titer or culture; therefore, more aggressive therapy is needed to prevent coronary artery lesions. Prospective studies with larger samples are needed to further examine the relationship between KD with coronary lesions and elevated ASO titers.
No potential conflict of interest relevant to this article was reported.
Clinical and laboratory data of the 11 patients with Kawasaki disease and a high ASO titer
No. | Sex | Age (mo) | F | Ei | L | R | E | LN | Type | BNP (pg/mL) | Echo |
ASO (initial/peak) | IVIG MPD pulse | Associated pathogen | Antibiotics administered |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
1 | F | 100 | 10 | + | - | - | - | + | Incomplete | 569.6 | 1.85 | 274/773 | 2 | ||
2 | F | 73 | 7+5 |
+ | + | + | + | + | Complete | 328.0 | 2.37 | 55/487 | 2 | Cefotaxime | |
3 | M | 55 | 21 | + | + | + | + | - | Complete | - | 3.91 | 506 | 0 | Influenza B | Oseltamivir |
4 | F | 42 | 9 | + | + | + | + | + | Complete | 381.0 | 2.28 | 35.3/514 | 2 | ||
5 | F | 52 | 7 | + | + | + | + | - | Complete | 191.5 | -0.7 | 594/1,020 | 2 | ||
6 | M | 63 | 9 | + | + | + | + | - | Complete | 140.0 | 0.65 | 1,023/2,611 | 1 | Augmentin | |
7 | M | 49 | 6 | + | + | + | + | + | Complete | 1235.0 | 2.5 | 971/1,957 | 1 | ||
8 | F | 10 | 10 | + | - | + | + | + | Complete | 67.0 | 0.4 | 7/348 | 2 | Rhino virus | Augmentin |
9 | M | 131 | 10 | + | + | + | - | + | Complete | 66.0 | 3.52 | 267/714 | 1 | Cefotaxime | |
Augmentin | |||||||||||||||
10 |
F | 58 | 9 | + | + | + | + | + | Complete | 43.0 | 0.36 | 52/430 | 1 | Mycoplasma pneumoniae | Clarithromycin |
11 |
M | 87 | 7 | + | + | + | - | + | Complete | 524.0 | 0.56 | 556 | 1 | Mycoplasma pneumoniae | Clarithromycin |
ASO titers were determined before and after IVIG treatment.
ASO, antistreptolysin O; F, fever days; Ei, nonexudative eye injection; L, changes in the lips or oral mucosa; R, polymorphous rash; E, erythema and edema of the extremities; LN, cervical lymphadenopathy; BNP, brain natriuretic peptide; IVIG, intravenous immunoglobulin; MPD, methylprednisolone; Augmentin, amoxicillin/clavulanic acid.
Patients 10 and 11 had a relatively good clinical course in which the fever subsided within 36 hours after the first IVIG treatment. On the other hand, patients 1–9 had a worse clinical course in which the fever persisted for >36 hours after the first IVIG treatment.
Patient No. 2 experienced Kawasaki disease relapse 15 days after the first IVIG administration.
Comparisons of clinical outcomes of patients with Kawasaki disease having a high versus normal ASO titer
Variable | Total (n=723) | Elevated ASO (n=11) | Normal ASO (n=712) | |
---|---|---|---|---|
Coronary artery lesion | 56 (6.9) | 3 (27.3) | 53 (7.4) | 0.047 |
Initial IVIG nonresponse | 75 (10.4) | 5 (45.5) | 70 (9.8) | 0.003 |
Severe clinical course | 112 (15.5) | 9 (81.8) | 103 (14.5) | <0.001 |
Values are presented as number of patients (%).
ASO, antistreptolysin O; IVIG, intravenous immunoglobulin.