Skip to main content

The “Intermediate” CD14 + CD16 + monocyte subpopulation plays a role in IVIG responsiveness of children with Kawasaki disease



Kawasaki disease (KD) is an acute, self-limited febrile illness of unknown cause. Intravenous immunoglobulin (IVIG)-resistance are related to greater risk for permanent cardiac complications. We aimed to determine the correlation between monocytes and the phenotype of KD in relation to IVIG responsiveness in children.

Materials and methods

The study cohort included 62 patients who were diagnosed with KD, 20 non febrile healthy controls (NFC), and 15 other febrile controls (OFC). In all enrolled patients, blood was taken at least 4 times and laboratory tests were performed. In addition, subtypes of monocytes were characterized via flow cytometry.


The numbers of intermediate monocytes were significantly lower in IVIG-resistant group compared to IVIG-responsive group before IVIG infusion (p < 0.0001). After infusion, intermediate monocytes decreased in the responsive group, while a trend of increase was observed in the resistant group. Only intermediate monocytes were significant in logistic regression with adjusted OR of 0.001 and p value of 0.03.


CD14 + CD16 + intermediate monocyte may play an important role in IVIG responsiveness among KD children. Low starting levels of intermediate monocytes, followed by a dramatic increase post-IVIG infusion during acute phase of KD are associated with IVIG-resistance. Functional studies on intermediate monocyte may help to reveal the pathophysiology.


Kawasaki disease (KD) is an acute, self-limited febrile illness. It is the most common cause of acquired heart disease in children in developed countries, but the causes of this illness are still unknown [1].

If undiagnosed or untreated, permanent cardiac complication such as coronary arterial dilatation (CAL) can occur. The duration of fever and timing of the first treatment is known to contribute to permanent cardiac complications in KD patients. The probability of acquiring this permanent cardiac complication increases if the patient is resistant to intravenous Immunoglobulin (IVIG), which is approximately 10–20 % of the KD population [2, 3].

Although the inflammatory cascade during the acute phase of KD has been extensively studied and associated with monocyte/macrophage activation [4,5,6,7,8,9] the immune characteristics of IVIG-resistant patients remain to be elucidated regarding IVIG responsiveness. In addition, the role in subtypes of monocytes are limited.

The aim of this study was to determine if there is a correlation between monocytes and the phenotype of KD regarding the responsiveness to IVIG through characterization of KD children immune profiles.

Materials and methods

Study population

The study cohort included patients who were diagnosed with KD and required hospital admission. We excluded patients who were transferred for the treatment of refractory KD after the first treatment of KD. Non febrile, healthy controls (NFC) and other febrile controls (OFC) were also included. NFC were those who visited the hospital for routine blood exams including: (i) no history of acute fever within 2 months, (ii) those who came for routine checkups such as antibody check of hepatitis B or anemia check-ups, (iii) prematurity (> 35 weeks). OFC were those who came to the emergency department or outpatient clinic for evaluation of acute febrile illness, such as pneumonia, urinary tract infections, meningitis, and otitis media. All subjects were enrolled at Chonnam National University Children’s Hospital, a tertiary, university-based hospital, from May 1, 2017 to Apr. 30, 2019. The study protocol was approved by the institutional Review Board (CNUH-2017-257) and written informed consent was obtained from all guardians in accordance with the Declaration of Helsinki.

KD was defined with the American Heart Association criteria [3] All hospitalized patients were treated with 2 g/kg of IVIG of single infusion, and with 30–50 mg/kg aspirin during the acute phase which was lowered to 3–5 mg/kg/day 2–3 days after the patients were afebrile. We defined IVIG-resistant patients as those who had persistent fever 36 h after completion of the first IVIG infusion. For patients who are IVIG-resistant, 2nd IVIG of the same dosage was infused. If fever persists 36 h after completion of 2nd IVIG infusion, intravenous methylprednisolone pulse therapy (30 mg/kg/dose) was performed for 3 consecutive days. If fever persists after 3 days of methylprednisolone infusion, 5 mg/kg infliximab was infused.

In all enrolled patients, demographic data including age at diagnosis, sex, body weight, symptomatic phenotype, infused drug, and date of each treatment were recorded. All enrolled patients underwent echocardiography at least 4 times to identify any KD-related cardiac complications.

Laboratory blood tests and flow cytometric analysis of monocyte subtypes

Blood was taken at each stage of the disease course for all KD patients, and laboratory tests were performed including complete blood counts (CBC), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR). Flow cytometric analysis of monocyte subtypes was also carried out for both KD patients and controls. The cells were stained with BV421-conjugated anti-CD14, PE-conjugated anti-CD16, all from Becton Dickinson Biosciences; San Diego, CA, USA. The subtypes of monocytes were then classified into the classical (CD14 + CD16-), the intermediate (CD14 + CD16+), and the nonclassical (CD14 + CD16++) monocytes.

Statistical analysis

Continuous variables are expressed as means ± standard deviations. The independent t-test (for normally distributed data) and the Mann–Whitney test (for non-normally distributed data) were used to compare continuous variables between the groups. ANOVA (for normally distributed data) and Kruskal-Wallis test (for non-normally distributed data) were used to compare continuous variables among three groups. For post-hoc analyses, Tukey method was used. In all analyses, p-values < 0.05 were considered to be statistically significant. All analyses were performed using MedCalc Statistical Software ver. 19.1 (MedCalc Software bvba; Ostend, Belgium;; 2019).


A total of 222 KD patients were diagnosed and admitted to the hospital during the study period. Among them, 62 patients were enrolled and compared to NFC and OFC.

Clinical characteristics regarding IVIG responsiveness

The demographics and treatment methods are described in Table 1. Amongst the 62 KD patients, 50 patients were IVIG responsive and 12 patients were IVIG-resistant. Rash (90.3 %) and conjunctivitis (90.3 %) were the most commonly seen manifestations in enrolled KD patients followed by red lip/red tongue (88.7 %), Edema of extremities (66.1 %), desquamation (58.3 %) and cervical lymphadenopathy (54.8 %). However, no statistical difference between IVIG responsive and resistant groups was observed. The total incidence of coronary artery dilatation was 9.7 %, and it was significantly higher in IVIG-resistant group (n = 3, 25 %) compared to IVIG responsive group (n = 3, 6 %).

Table 1 Clinical information of children with Kawasaki disease regarding IVIG responsiveness at admission day

Laboratory findings regarding IVIG responsiveness

Laboratory findings of the 62 patients are summarized in Table 1, comparing between IVIG-responsive and -resistant groups at diagnosis. The absolute counts for total white blood cells (WBC), lymphocytes, and monocytes were not significantly different between groups. The neutrophil counts and the neutrophil to lymphocyte ratio (NLR) were significantly higher in the IVIG-resistant group than IVIG-responsive group (p = 0.01 and p = 0.01, respectively). The level of albumin was significantly lower (3.3 ± 0.4 g/dL) in IVIG-resistant group compared to IVIG-responsive group (3.7 ± 0.5 g/dL, P = 0.001). There was no difference in the levels of hemoglobin, total bilirubin, platelet, ESR, and CRP between the groups.

Monocytes in children with Kawasaki disease

Comparison of monocyte subtype proportions between KD and controls

The proportion of monocyte subtypes was compared between KD patients and controls. (Fig. 1; Table 2) The classical monocytes were significantly higher in KD patients and OFC compared to NFC. A lower level of intermediate monocytes was also observed in NFC, while OFC reported the highest level followed by KD patients. No differences were observed for nonclassical monocytes between all groups.

Fig. 1
figure 1

Flow cytometric analyses of monocytes. a IVIG-responsive Kawasaki disease, b IVIG-resistant Kawasaki disease, c Other febrile controls and d Non febrile healthy controls

Table 2 Monocytes in children with Kawasaki disease and controls

Comparison of monocyte proportions in children with Kawasaki disease regarding IVIG responsiveness at diagnosis, before IVIG

As summarized in Table 3, only CD14 + CD16 + intermediate monocytes were significantly different between IVIG-responsive and IVIG-resistant groups. Before IVIG infusion, the levels of CD14 + CD16 + monocytes in IVIG-responsive group (0.8 ± 0.6) was significantly higher than IVIG-resistant group (0.3 ± 0.1, p < 0.001).

Table 3 Monocytes in children with Kawasaki disease regarding IVIG responsiveness

Changes of intermediate monocytes: from acute phase (before (D0) and after IVIG infusion (D2)) to convalescent phase (D56)

The changes of CD14 + CD16 + intermediate monocytes during acute phase (before and after IVIG) and convalescent phase in relation to IVIG responsiveness are described in Fig. 2. The percentage of CD14 + CD16 + intermediate monocytes decreased after IVIG infusion in the responsive group, while in the resistant group no significant changes were observed. The intermediate monocytes in both responsive and resistant groups increased to similar levels during the convalescent phase (after 2 months of disease onset).

Fig. 2
figure 2

Serial measurement of CD14 + CD16 + intermediate monocytes in IVIG- responsive and IVIG-resistant groups. The time of measurements were D0 (acute phase, at diagnosis, before IVIG infusion), D2 (acute phase, after resolution of fever, after IVIG infusion) and D56 (convalescent phase, 2 months after diagnosis). * <0.01

Logistic regression and ROC curve at admission day regarding IVIG responsiveness

Only intermediate monocytes were significant in logistic regression with adjusted OR f < 0.01 and p value of 0.02 (Table 4).

Table 4 Logistic regression of variables at admission day between IVIG- responsive and -resistant group


This study provided immunophenotypes related to the monocyte subtype by IVIG responsiveness for KD. As innate immune cells initiate and propagate the immune responses, monocytes were therefore investigated. We revealed statistically lower proportions of intermediate monocytes in children with IVIG-resistant KD.

The monocyte population is heterogenous that plays an important role as the first line of immune defense and they migrate to inflammatory or infected tissues and can differentiate into macrophages or dendritic cells [10, 11]. Monocytes are recruited by chemokines (such as CD192 or CCDR2) that bind to receptors (CD14, CD16 or CD64) expressed on their cell surface. In human, we have 3 subtypes of monocytes which have different roles in immunity, the classical (CD14 + CD16-), the intermediate (CD14 + CD16+), and the nonclassical (CD14 + CD16++) monocytes [12, 13]. Each subtypes have characteristics unique to their key functions. The classical monocytes have high phagocytic ability, effectively produces inflammatory mediators in response to bacterial products, repairs tissues, and migrates to sites of inflammation. The intermediate monocytes are a newly defined subset which were previously identified within the nonclassical subset. They also produce inflammatory mediators in response to bacteria and has the ability to expand during infection and antigen presentation. The intermediate monocytes have proportionally increased in inflammatory and chronic conditions such as cardiovascular disease, rheumatoid arthritis, and Crohn’s disease, however, the role of intermediate monocytes in such disease has not been investigated [14,15,16,17,18]. Intermediate monocytes actively produce proinflammatory cytokines such as TNF-α, IL-1β and IL-6. Lastly, nonclassical monocytes produce TNF-α, IL-1β and CCL3 in response to viral and immune complex stimulation and they have the ability of FcƔ mediated phagocytosis [19].

Some researchers have demonstrated the role of monocyte/macrophage in KD. In affected tissues in autopsy cases and skin biopsy specimens of KD patients, infiltration of monocytes/macrophages is notable and the number of CD14 + monocytes/macrophages in peripheral blood augmented with increased activation of CD14 + CD23 + monocytes/macrophages during the acute stage of KD [20,21,22]. In addition, increased peripheral blood CD14 + monocytes/macrophages and secretion of TNF-α, IL-6, and IL-1 were observed more dominantly in KD patients with CAL [9, 22,23,24,25]. Koga et al. [7] have demonstrated CD14 + monocytes/macrophages were activated in peripheral blood in the acute stage of KD with exaggerated phagocytosis and strong expression of TNF-α which became weakly expressed in the convalescent stage.

IVIG is a classic treatment modality in KD and those who received IVIG within 10 days of onset have decreased probability of having CAL, but if the patient is resistant to IVIG treatment, the patients have increased probability of developing CAL. The action mechanism of IVIG is not yet fully understood. IVIG plays a role in immune homeostasis by suppressing the activation of innate and adaptive immunity and inhibiting inflammatory mediators to enhance the anti-inflammatory processes [26, 27]. Das et al. have revealed that IVIG induces autophagy in peripheral blood monocytes, monocyte derived from dendritic cells, and M1 macrophages but not in M2 macrophages of healthy donors [28]. Autophagy, a regulated mechanism for clearance of damaged/dysfunctional cells or components to warrant regeneration of new and healthy cells. This process plays a fundamental role in the regulation of innate and adaptive immune responses, lymphocyte differentiation, survival, and homeostasis [29,30,31]. Furthermore, the concept of autophagy is also important in regulating autoimmune and inflammatory diseases including systemic lupus erythematosus, inflammatory bowel diseases, rheumatoid arthritis, psoriasis, multiple sclerosis and myositis and some report autophagy as a potential target to treat for such diseases [31,32,33,34,35].

Although the mechanism of IVIG action has not been fully elucidated, one proposed mechanism is a blockade of Ig Fc receptors (FcγRs). The bound IgG prevents immune complex from phagocytosis and also from delivering activating signals to the target cells [36]. Abe et al. [36] have reported the correlation of FcγRs expression and KD without sub-dividing them in to IVIG responsive and resistant. In this study, FcγRII expression on monocytes (n = 12) was not significantly changed before vs. after IVIG therapy and was not significantly elevated in KD patients compared with febrile controls. FcγRIII expression (n = 6) was also down-regulated by IVIG treatment but there was no significant difference in FcγRIII expression levels between pre-IVIG KD patients and controls. The Fc receptor on CD 16 is FcγRIII and this has correlation with intermediate monocyte (CD14 + CD16+) and KD [36].

According to current literatures, approximately 10–20 % of patients are IVIG-resistant, and further research efforts are required to better characterize and predict IVIG-resistant patients [37,38,39,40]. Risk factors of IVIG resistance include younger age, male, higher neutrophil count, C-reactive protein (CRP), total bilirubin (TB), aspartate aminotransferase (AST), alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) [2, 37,38,39, 41]. Scores related to IVIG resistance have been developed using the above variables, but there are discrepancies of performance between Japanese cohorts and North American cohorts [42].

IVIG for acute KD decreases the absolute number of circulating monocytes/macrophages [43]. NF-κB activation in peripheral CD14 + monocytes/macrophages also significantly decreased after IVIG therapy in acute stage of KD, [44] Katayama et al.[8] also observed increased number of CD14 + CD16 + monocytes/macrophages in acute stage of KD which decreased after IVIG infusion.

In this present study, we have evaluated the monocyte subtypes to determine the role of it regarding IVIG responsiveness. The Intermediate monocytes in patients with KD were significantly higher than NFC but significantly lower than OFC. Regarding IVIG responsiveness, the intermediate monocytes were significantly lower in the IVIG-resistant group compared to IVIG-responsive group. This implies that to activate IVIG therapy, a certain number of intermediate monocyte might need initially, however, the decreased numbers and percentage of intermediate monocyte might have weakened the activation of IVIG. Lower level of intermediate monocyte could play a role in IVIG-resistant condition which needs further research whether the intermediate monocyte interfere the action of IVIG. After resolution of fever (after IVIG infusion), the intermediate monocyte decreased significantly in the IVIG-responsive group and while they were increased in the IVIG-resistant group. Decreased percentage of intermediate monocytes in IVIG-responsive group after the resolution of fever was because the proportion of classical monocyte and intermediate monocyte has been changed. While the changes of intermediate monocytes are more noticeable during the acute and subacute phase of KD, the level of intermediate monocytes became similar at convalescent phase of KD. This finding may also imply some interaction between IVIG and the intermediate monocytes and further research is needed.

This study had limitations. First, the small enrollment number of patients with IVIG-resistant, which could limit the statistical analyses. Second, the monocyte profiles between IVIG-responsive and -resistant in KD children were only assessed by the number/proportion of monocyte subtypes. Further functional studies, on the intermediate monocytes in particular, are needed. However, further evaluation into the intermediate monocytes could warrant a step forward to reveal the pathophysiology of KD, especially IVIG-resistant KD.


In conclusions, the intermediate monocyte may play an important role in IVIG responsiveness. Low starting levels of intermediate monocytes, followed by dramatic increase post-IVIG infusion during acute phase of KD are associated with IVIG-resistance. Functional studies on intermediate monocyte may help to reveal the pathophysiology of KD.

Availability of data and materials




Complete blood counts


C-reactive proteins


Coronary arterial dilatation


Erythrocyte sedimentation rate


Intravenous Immunoglobulin


Kawasaki disease


Neutrophil to lymphocyte ratio


Non febrile, healthy controls


Other febrile controls


White blood cells


  1. Kawasaki T, Kosaki F, Okawa S, Shigematsu I, Yanagawa H. A new infantile acute febrile mucocutaneous lymph node syndrome (MLNS) prevailing in Japan. Pediatrics. 1974;54(3):271–6.

    Article  CAS  PubMed  Google Scholar 

  2. Tremoulet AH, Best BM, Song S, Wang S, Corinaldesi E, Eichenfield JR, et al. Resistance to intravenous immunoglobulin in children with Kawasaki disease. J Pediatr. 2008;153(1):117–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. McCrindle BW, Rowley AH, Newburger JW, Burns JC, Bolger AF, Gewitz M, et al. Diagnosis, treatment, and long-term management of Kawasaki Disease: a scientific statement for health professionals from the American Heart Association. Circulation. 2017;135(17):e927-e99.

  4. Yeung RS. Kawasaki disease: update on pathogenesis. Curr Opin Rheumatol. 2010;22(5):551–60.

    Article  PubMed  Google Scholar 

  5. Takahashi K, Oharaseki T, Yokouchi Y. Pathogenesis of Kawasaki disease. Clin Exp Immunol. 2011;164(Suppl 1):20–2.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Wang GB, Li CR, Zu Y, Yuan XW. [The role of activation of toll-like receptors in immunological pathogenesis of Kawasaki disease]. Zhonghua Er Ke Za Zhi. 2006;44(5):333–6.

    PubMed  Google Scholar 

  7. Koga M, Ishihara T, Takahashi M, Umezawa Y, Furukawa S. Activation of peripheral blood monocytes and macrophages in Kawasaki disease: ultrastructural and immunocytochemical investigation. Pathol Int. 1998;48(7):512–7.

    Article  CAS  PubMed  Google Scholar 

  8. Katayama K, Matsubara T, Fujiwara M, Koga M, Furukawa S. CD14 + CD16 + monocyte subpopulation in Kawasaki disease. Clin Exp Immunol. 2000;121(3):566–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Furukawa S, Matsubara T, Jujoh K, Yone K, Sugawara T, Sasai K, et al. Peripheral blood monocyte/macrophages and serum tumor necrosis factor in Kawasaki disease. Clin Immunol Immunopathol. 1988;48(2):247–51.

    Article  CAS  PubMed  Google Scholar 

  10. Swirski FK, Nahrendorf M, Etzrodt M, Wildgruber M, Cortez-Retamozo V, Panizzi P, et al. Identification of splenic reservoir monocytes and their deployment to inflammatory sites. Science (New York, NY). 2009;325(5940):pp. 612–6.

    Article  CAS  Google Scholar 

  11. Shi C, Pamer EG. Monocyte recruitment during infection and inflammation. Nat Rev Immunol. 2011;11(11):762–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ziegler-Heitbrock L, Ancuta P, Crowe S, Dalod M, Grau V, Hart DN, et al. Nomenclature of monocytes and dendritic cells in blood. Blood. 2010;116(16):e74–80.

    Article  CAS  PubMed  Google Scholar 

  13. Boyette LB, Macedo C, Hadi K, Elinoff BD, Walters JT, Ramaswami B, et al. Phenotype, function, and differentiation potential of human monocyte subsets. PloS one. 2017;12(4):e0176460.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Wong KL, Tai JJ, Wong WC, Han H, Sem X, Yeap WH, et al. Gene expression profiling reveals the defining features of the classical, intermediate, and nonclassical human monocyte subsets. Blood. 2011;118(5):e16–31.

    Article  CAS  PubMed  Google Scholar 

  15. Wong KL, Yeap WH, Tai JJ, Ong SM, Dang TM, Wong SC. The three human monocyte subsets: implications for health and disease. Immunol Res. 2012;53(1–3):41–57.

    Article  CAS  PubMed  Google Scholar 

  16. Grip O, Bredberg A, Lindgren S, Henriksson G. Increased subpopulations of CD16(+) and CD56(+) blood monocytes in patients with active Crohn’s disease. Inflamm Bowel Dis. 2007;13(5):566–72.

    Article  PubMed  Google Scholar 

  17. Rogacev KS, Seiler S, Zawada AM, Reichart B, Herath E, Roth D, et al. CD14 + + CD16 + monocytes and cardiovascular outcome in patients with chronic kidney disease. Eur Heart J. 2011;32(1):84–92.

    Article  CAS  PubMed  Google Scholar 

  18. Rossol M, Kraus S, Pierer M, Baerwald C, Wagner U. The CD14(bright) CD16 + monocyte subset is expanded in rheumatoid arthritis and promotes expansion of the Th17 cell population. Arthritis Rheum. 2012;64(3):671–7.

    Article  CAS  PubMed  Google Scholar 

  19. Gren ST, Grip O. Role of Monocytes and Intestinal Macrophages in Crohn’s Disease and Ulcerative Colitis. Inflamm Bowel Dis. 2016;22(8):1992–8.

    Article  PubMed  Google Scholar 

  20. Terai M, Kohno Y, Namba M, Umemiya T, Niwa K, Nakajima H, et al. Class II major histocompatibility antigen expression on coronary arterial endothelium in a patient with Kawasaki disease. Hum Pathol. 1990;21(2):231–4.

    Article  CAS  PubMed  Google Scholar 

  21. Sugawara T, Hattori S, Hirose S, Furukawa S, Yabuta K, Shirai T. Immunopathology of the skin lesion of Kawasaki disease. Prog Clin Biol Res. 1987;250:185–92.

    CAS  PubMed  Google Scholar 

  22. Furukawa S, Matsubara T, Yabuta K. Mononuclear cell subsets and coronary artery lesions in Kawasaki disease. Arch Dis Child. 1992;67(6):706–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Furukawa S, Matsubara T, Yone K, Hirano Y, Okumura K, Yabuta K. Kawasaki disease differs from anaphylactoid purpura and measles with regard to tumour necrosis factor-alpha and interleukin 6 in serum. Eur J Pediatr. 1992;151(1):44–7.

    Article  CAS  PubMed  Google Scholar 

  24. Maury CP, Salo E, Pelkonen P. Elevated circulating tumor necrosis factor-alpha in patients with Kawasaki disease. J Lab Clin Med. 1989;113(5):651–4.

    CAS  PubMed  Google Scholar 

  25. Leung DY, Cotran RS, Kurt-Jones E, Burns JC, Newburger JW, Pober JS. Endothelial cell activation and high interleukin-1 secretion in the pathogenesis of acute Kawasaki disease. Lancet. 1989;2(8675):1298–302.

    Article  CAS  PubMed  Google Scholar 

  26. Galeotti C, Kaveri SV, Bayry J. IVIG-mediated effector functions in autoimmune and inflammatory diseases. Int Immunol. 2017;29(11):491–8.

    Article  CAS  PubMed  Google Scholar 

  27. Séïté JF, Hillion S, Harbonnier T, Pers JO. Review: intravenous immunoglobulin and B cells: when the product regulates the producer. Arthritis Rheumatol (Hoboken, NJ). 2015;67(3):595–603.

    Article  CAS  Google Scholar 

  28. Das M, Karnam A, Stephen-Victor E, Gilardin L, Bhatt B, Kumar Sharma V, et al. Intravenous immunoglobulin mediates anti-inflammatory effects in peripheral blood mononuclear cells by inducing autophagy. Cell Death Dis. 2020;11(1):50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Bhattacharya A, Eissa NT. Autophagy and autoimmunity crosstalks. Front Immunol. 2013;4:88.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Pua HH, Dzhagalov I, Chuck M, Mizushima N, He YW. A critical role for the autophagy gene Atg5 in T cell survival and proliferation. J Exp Med. 2007;204(1):25–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Rockel JS, Kapoor M. Autophagy: controlling cell fate in rheumatic diseases. Nat Rev Rheumatol. 2016;12(9):517–31.

    Article  CAS  PubMed  Google Scholar 

  32. Rioux JD, Xavier RJ, Taylor KD, Silverberg MS, Goyette P, Huett A, et al. Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. Nat Genet. 2007;39(5):596–604.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Lin NY, Beyer C, Giessl A, Kireva T, Scholtysek C, Uderhardt S, et al. Autophagy regulates TNFα-mediated joint destruction in experimental arthritis. Ann Rheum Dis. 2013;72(5):761–8.

    Article  CAS  PubMed  Google Scholar 

  34. Yin H, Wu H, Chen Y, Zhang J, Zheng M, Chen G, et al. The Therapeutic and Pathogenic Role of Autophagy in Autoimmune Diseases. Front Immunol. 2018;9:1512.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Bonam SR, Wang F, Muller S. Autophagy. A new concept in autoimmunity regulation and a novel therapeutic option. J Autoimmun. 2018;94:16–32.

    Article  CAS  PubMed  Google Scholar 

  36. Abe J, Jibiki T, Noma S, Nakajima T, Saito H, Terai M. Gene expression profiling of the effect of high-dose intravenous Ig in patients with Kawasaki disease. J Immunol. 2005;174(9):5837–45.

    Article  CAS  PubMed  Google Scholar 

  37. Kobayashi T, Inoue Y, Takeuchi K, Okada Y, Tamura K, Tomomasa T, et al. Prediction of intravenous immunoglobulin unresponsiveness in patients with Kawasaki disease. Circulation. 2006;113(22):2606–12.

    Article  PubMed  Google Scholar 

  38. Egami K, Muta H, Ishii M, Suda K, Sugahara Y, Iemura M, et al. Prediction of resistance to intravenous immunoglobulin treatment in patients with Kawasaki disease. J Pediatr. 2006;149(2):237–40.

    Article  CAS  PubMed  Google Scholar 

  39. Sano T, Kurotobi S, Matsuzaki K, Yamamoto T, Maki I, Miki K, et al. Prediction of non-responsiveness to standard high-dose gamma-globulin therapy in patients with acute Kawasaki disease before starting initial treatment. Eur J Pediatr. 2007;166(2):131–7.

    Article  CAS  PubMed  Google Scholar 

  40. Burns JC, Capparelli EV, Brown JA, Newburger JW, Glode MP. Intravenous gamma-globulin treatment and retreatment in Kawasaki disease. US/Canadian Kawasaki Syndrome Study Group. Pediatr Infect Dis J. 1998;17(12):1144–8.

    Article  CAS  PubMed  Google Scholar 

  41. Son MB, Gauvreau K, Ma L, Baker AL, Sundel RP, Fulton DR, et al. Treatment of Kawasaki disease: analysis of 27 US pediatric hospitals from 2001 to 2006. Pediatrics. 2009;124(1):1–8.

    Article  PubMed  Google Scholar 

  42. Sleeper LA, Minich LL, McCrindle BM, Li JS, Mason W, Colan SD, et al. Evaluation of Kawasaki disease risk-scoring systems for intravenous immunoglobulin resistance. J Pediatr. 2011;158(5):831–5.e3.

    Article  PubMed  Google Scholar 

  43. Furukawa S, Matsubara T, Jujoh K, Sasai K, Nakachi S, Sugawara T, et al. Reduction of peripheral blood macrophages/monocytes in Kawasaki disease by intravenous gammaglobulin. Eur J Pediatr. 1990;150(1):43–7.

    Article  CAS  PubMed  Google Scholar 

  44. Ichiyama T, Yoshitomi T, Nishikawa M, Fujiwara M, Matsubara T, Hayashi T, et al. NF-kappaB activation in peripheral blood monocytes/macrophages and T cells during acute Kawasaki disease. Clin Immunol (Orlando Fla). 2001;99(3):373–7.

    Article  CAS  Google Scholar 

Download references


This work was supported by the BCR120006 Biomedical institute of Chonnam National University Hospital.

Author information

Authors and Affiliations



HJC and ISJ conceptualized and designed the study, drafted the initial manuscript, and reviewed and revised the manuscript. HJC and ISJ equally contributed as corresponding authors. YSK and HJY reviewed and revised the manuscript and contributed equally as first authors. SJK, KKK, IC, and KH critically reviewed the manuscript for important intellectual content. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

Authors’ information

YSK is a pediatric cardiologist in a university hospital. HJY is a medical student in Chonnam National University Medical School and contributed in analyses/writing during a holiday program for medical students. SJK is a clinical pathologist and critically advised the design of the study. IC and KH, both pediatric cardiologists, also critically revised the manuscript. KKK, a basic researcher, critically analyzed and interpreted the results. ISJ, a cardiac surgeon, an intensivist conceptualized and designed the study. HJC, a pediatric cardiologist and pediatric intensivist also conceptualized and designed the study.

Corresponding authors

Correspondence to In Seok Jeong or Hwa Jin Cho.

Ethics declarations

Ethics approval

The study protocol was approved by the institutional Review Board (CNUH-2017-257) and was conducted in accordance with Good Clinical Practice guideline and ethical standards as laid down in the 1964 Declaration of Helsinki.

Consent for publication

Written Informed consent was obtained from all individual participants included in the study.

Competing interests

The authors declare that they have no conflict of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kim, Y.S., Yang, H.J., Kee, SJ. et al. The “Intermediate” CD14 + CD16 + monocyte subpopulation plays a role in IVIG responsiveness of children with Kawasaki disease. Pediatr Rheumatol 19, 76 (2021).

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: