Clinical features and short- and mid-term follow-up of refractory Kawasaki disease in children

doi:10.21203/rs.3.rs-1452324/v1

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Clinical features and short- and mid-term follow-up of refractory Kawasaki disease in children

https://doi.org/10.21203/rs.3.rs-1452324/v1

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Objective To investigate the clinical manifestations, laboratory data and coronary artery lesions of refractory Kawasaki disease, and to follow up the patients in the near to medium term.

Methods Patients with refractory KD admitted to Guangzhou Women and Children's Medical Center between January 1, 2016 and December 31, 2020 were collected and their clinical data were retrospectively analyzed.

Results A total of 42 patients were diagnosed with refractory KD, including 31 (73.81%) and 11 (26.19%) were male and female, respectively, with a median age of 26.7±19.3 (2-99) months. The average time, from onset to diagnosis and IVIG use, was 5.8±0.9 (4-12 ) days, while the fever lasted for 14.8±4.0 (8-34) days. A total of 29 patients exhibited coronary artery disease complications. All patients exhibited persistent or recurrent fever after two doses of IVIG therapy. A total of 41 patients were given a methylprednisolone regimen for up to three consecutive days as follows, while one patient continued to receive IVIG. The diameter of coronary arteries returned to normal 10 patients during the follow-up period, patients with medium and huge tumors exhibited shrunken diameter of coronary arteries, although they were not completely normal. Follow-up observations are still ongoing.

Conclusion There is no unified diagnostic criteria and treatment plan for children with refractory KD. For patients that still experience fever after two IVIG treatments, clinicians need to consider the possibility of this type of KD. Development of an effective treatment plan is imperative to shortening fever time and prevention of progressive aggravation of coronary artery disease. Longer follow-up observation is also needed for this group of patients with coronary artery outcomes.

refractory Kawasaki disease

complications

therapy

follow-up

Kawasaki disease (KD), a systemic vasculitis first reported by Dr. Kawasaki in 1974 in English from Japan, mainly affects children less than 5 years old worldwide. Notably, Asia, Japan, Korea and Taiwan have the highest KD incidence worldwide. In 2010 alone, KD incidence ranged from 239.6/1000,000 to 264/100,000 in children less than 5 years old ^[1,2]. At present, intravenous immunoglobulin(IVIG) is the standard treatment for KD, and has been shown ti lower the risk of coronary artery aneurysm(CAA) from 3 to 5%^[3]. However, studies have shown that 10–15% of KD patients exhibit persistent fever despite high dose IVIG treatment(2 g/kg). Moreover, they do not respond to IVIG, while children with IVIG non-response were found to have significantly higher incidence of coronary artery lesions(CALs)than those who responded to IVIG^[4]. Between 3 and 4% of children with KD fail to respond to IVIG after initial treatment failure^[5]. In the past, IVIG non-responsive KD was also known as refractory KD, but with the increasing number of cases of treatment failure of KD, refractory KD tended to be separated from the definition of IVIG non-responsive KD. Previous studies have reported persistence or recurrence of fever (≥ 38.0℃), at least 36 hours after the last of more than 2 doses of IVIG therapy and high-dose aspirin, condition known as refractory KD^[6]. In the present study, we retrospectively analyzed clinical characteristics of refractory KD patients with a short-to-mid-term follow-up.

We obtained medical records for 2292 KD patients that were hospitalized at the Guangzhou Women and Children’s Medical Center, Guangzhou, China, between January 1, 2016 and December 31, 2020. KD was diagnosed using criteria described in the 6th Edition of the Kawasaki Disease Diagnostic Guidelines issued by the Japanese Academy of Pediatrics in 2020^[7]:(1) Fever was diagnosed based on the following 5 main clinical features: bilateral bulbar conjunctival injection, chapped lips as well as changes of bayberry tongue and extremities (initial stage reddening of palms and soles, edema, and periungual desquamation of convalescent stage), pleomorphic rash including redness at the site of Bacille Calmette-Guèrin (BCG) inoculation and non-suppurative cervical lymphadenopathy. For patients who exhibit more than 4 main clinical symptoms, especially those whose hands and feet are flushed and swollen, the heat course can be diagnosed within 4 days. It is important to exclude other febrile diseases at the time of diagnosis. Patients who satisfied criteria for 5 or 6 clinical features were diagnosed as complete KD; (2) Patients with 4 clinical features and echocardiogram showing CALs were also diagnosed as complete KD; (3) Patients with 3 principal clinical features and CALs. Patients with fever and rashes, were diagnosed with complete KD; (4) The patients who fulfilled 3 or 4 in the principle clinical features without coronary artery dilation but exhibited some features from the list of “other significant clinical features” were diagnosed as incomplete KD, if other disease are rule out; (5) The condition was considered KO if other diseases were excluded and only 1 or 2 principal clinical features. The diagnostic criteria for refractory KD were as follows: the condition was classified as refractory KD if after two high doses of IVIG combined with aspirin treatment, fever persisted for at least 36 hours or reappeared ≥ 38.0℃^[8].This study was performed with ethical approval from the Institutional Committee of Guangzhou Women and Children’s Medical Center (224A01).

Criteria for diagnosing CALs followed: the JCS/JSCS2020 guidelines recommend the Z value evaluation CAL criteria as: (1) No disease: Z value is always < 2; (2) Coronary artery dilation (CAD) only: 2 ≤ Z value < 2.5; or Initial Z value < 2, Z value decreased during follow-up > 1; (3) Small CAA: 2.5 ≤ Z value < 5; (4) Medium CAA: 5 ≤ Z value < 10, or absolute value inner diameter < 8mm; (5) Giant CAA (GCAA): Z value ≥ 10, or absolute value inner diameter ≥ 8mm. And Z value ≥ 2.5 is defined as long-term significant CAL (sequelae)^[9].

Upon diagnosis, children with KD were given an intravenous injection of high-dose IVIG (2 g/kg) combined with aspirin (30–50 mg/kg). If the fever persisted for at least 36 hours after IVIG treatment or reappeared after subsiding, IVIG treatment was administered again ^[10]. Patients who still exhibited fever, after the second IVIG treatment, were given methylprednisolone or a third IVIG treatment.

2.1 Clinical manifestations and laboratory tests results

A total of 42 patients, with an incidence rate of 1.8%, were diagnosed with refractory KD. Among them, 31 (73.81%) and 11 (26.19%) were male and female, respectively, with a median age of 26.7 ± 19.3 (2–99) months. The average time, from onset to diagnosis and IVIG use, was 5.8 ± 0.9 (4–12) days, while the fever lasted for 14.8 ± 4.0 (8–34) days. A total of 29 patients exhibited coronary artery disease complications. These include 3 patients who developed coronary artery dilatations (CAD) (7.14%), 7 exhibited coronary artery small aneurysms (SCAL) (16.67%), 6 developed coronary artery medium aneurysms (MCAL) (14.29%), while 13 had giant coronary artery aneurysms (GCAL) (30.96%). Moreover, 7 patients exhibited non-cardiac complications, including 4 with arthritis (9.52%), 1 who developed KD shock syndrome (2.38%), 1 with capillary leak syndrome (2.38%) and 1 with facial nerve paralysis (2.38%). Results from blood routine, erythrocyte sedimentation rate, serum ferritin and pro-BNP test before IVIG (Table 1 and Table 2). The age of refractory KD is distributed within 24 months, especially under 12 months ( Fig. 1).

Table 1

clinical and laboratory data of children with refractory KD
Characteristic		Laboratory data	Mean
Sex(cases)		White blood cell counts(×103/uL)	19.91 ± 8.29
Male	31(73.81%)	Hemoglobin(g/L)	96.41 ± 14.42
Female	11(26.19%)	Platelets(×103/uL)	445.05 ± 173.87
Diagnosis of KD(cases)		C-reactive protein(mg/dL)	112.76 ± 48.54
complete KD	38(90.48%)	Erythrocyte sedimentation rate(mm/hour)	53.07 ± 16.68
incomplete KD	4(9.52%)	Albumin(g/dL)	29.57 ± 3.15
Age of onset(months)	26.7 ± 19.3(2–99)	Sodium(mmol/L)	134.00 ± 2.38
Diagnosis and use of IVIG from the onset(days)	5.8 ± 0.9(4–12)	N-terminal-pro-brain natriuretic peptide(pg/ng)	1925.90 ± 2164.69
Complications(cases)
coronary abnormalities	29(69.05%)
arthritis	4(9.52%)
Kawasaki shock	1(2.38%)
facial paralysis	1(2.38%)
capillary leakage	1(2.38%)

Table 2

Coronary artery lesions of children with refractory KD
Coronary artery lesions	patients
CAD ^a	3(7.14%)
SCAL^b	7(16.67%)
MCAL^c	6(14.29%)
GCAL^d	13(30.96%)
Number of coronary artery lesions	patients
1	4
2	24
3	1

a Kawasaki disease patients with coronary artery dilatations. b Kawasaki disease patients with small aneurysms. c Kawasaki disease patients with coronary artery medium aneurysms. d Kawasaki disease patients with coronary artery giant aneurysms.

2.2 Treatment

All patients exhibited persistent or recurrent fever after two doses of IVIG therapy, the third choice of treatment. A total of 41 patients were given a methylprednisolone regimen for up to three consecutive days as follows: 32 of them were treated with 15 mg/kg per day, 6 were given 2 mg/kg per day, whereas 2 and 1 were administered with 10 and 30 mg/kg per day respectively. One patient continued to receive IVIG.

2.3 Follow-up

The 42 patients with refractory KD had an average fever regression time of 14.8 ± 4.0 days. In the acute phase, the number of children with inflammatory indicators such as white blood cells and rapid C-reactive protein returned to normal. Notably, 13 patients (30.95%) exhibited normal white blood cells, whereas 11 (26.19%) had normal rapid C-reactive protein. Upon stabilization of clinical symptoms, the patients were discharged from hospital, and followed up regularly. During follow-up, their conditions were monitored via color Doppler echocardiography and electrocardiogram, for a period of 6 months. Consequently, the patients exhibited no symptoms myocardial ischemia, myocardial infarction, or death. The diameter of coronary arteries returned to normal 10 patients (23.81%) during the follow-up period. Patients with medium and huge tumors exhibited shrunken diameter of coronary arteries although they were not completely normal. Follow-up observations are still ongoing.

KD, also called mucocutaneous lymph node syndrome, is one of the most common vasculitides in children^[11]. Typically, this self-limited condition manifests as fever and acute inflammation that last for an average of 12 days without therapy. High doses IVIG have shown efficacy in suppressing inflammation and reducing prevalence of coronary artery abnormalities when administered during early stages of KD development^[12]. In the present study, about 1.6% of children with KD still exhibited fever even after two IVIG treatments, which was lower than the 3–4% reported in previous studies ^[5]. These children are at a high risk of developing coronary artery disease and long-term sequelae ^[13–15]. Previous studies have shown that the main risk factors for KD coronary artery disease are C-reactive protein, duration of fever and time course of gamma globulin use^[16]. The present group patients had a high incidence of coronary artery disease ( 69.05%) with about 90.48% of the children diagnosed with complete KD. Notably, the patients exhibited no response to IVIG treatment, while their fever lasted as long as 14.8 ± 4.0 days. Laboratory test data revealed that they had elevated levels of white blood cells, C-reactive protein, and erythrocyte sedimentation rate, suggesting that children with refractory KD not only have severe inflammatory reactions, but also exhibited thrombocytosis, hypoalbuminemia, and anemia. In this group of patients, disease onset mainly occurres within 12 months, which is consistent with previous reports that found 12 months to be the peak age of KD development^[17].

At present, no unified standard for treatment of refractory KD has been developed. In fact, the choice of medicine is based on efficacious drugs against other vasculitis, including glucocorticoids, TNF inhibitors, other immunosuppressants, and plasma exchange^[18]. The use of glucocorticoids for treatment of Kawasaki disease remains controversial, although they are generally used as a remedy for IVIG resistance. Functionally glucocorticoids suppress KD-induced inflammations by inhibiting production of inflammatory mediators, inhibiting migration of white blood cells and reducing capillary permeability^[19]. To date, several glucocorticoid treatment options for children with refractory KD have been suggested, including high-dose methylprednisolone sodium succinate (30 mg/kg.d) intravenous pulse therapy for up to 3 days. In Japan, intravenous or oral administration of prednisolone (1–2 mg/kg.d) for at least 15 days has been reported^[20]. Numerous studies have reported the use of infliximab for treatment of refractory KD. Song^[6]et al. reported continuous and recurrent fever in 16 cases of children diagnosed with refractory KD, within 36 hours following after 2 sessions of adequate IVIG treatment. Notably, 15 of the cases developed coronary Arterial disease. However the authors observed that temperature of 13 children returned to normal after treatment with infliximab. Follow-up echocardiographic observation revealed no damage to the dilated coronary arteries. In the present study, 34 children were treated with medium-dose methylprednisolone sodium succinate, and found to have excellent therapeutic effect. Previous case reports have demonstrated that cyclosporine, cyclophosphamide and methotrexate are efficacious in treating KD, although high-dose sample data is lacking. These drugs were not used in this study.

During our short-term follow-up of the children, we found that their body temperature returned to normal after treatment with salvage drugs. Notably, only about 30.95 and 26.19% of the inflammatory indicators, such as white blood cells and rapid C-reactive protein, returned to normal levels in the acute phase, suggesting that these inflammatory indicators have potential in predicting disease severity as well as efficacy of IVIG^[21,22]. White blood cells and rapid C-reactive protein are expected to significantly reduce after acute treatment in children with KD. However, in this group of studies, not many children recover to normal in a short period of time. Considering that their children have severe inflammation, their recovery time is longer. In present study, 10 cases (23.81%) of the coronary artery diameter returned to normal during the 6-month follow-up period, while coronary aneurysms took longer to recover compared to coronary artery dilation.

In summary, there is no unified diagnostic criteria and treatment plan for children with refractory KD. For patients that still experience fever after two IVIG treatments, clinicians needs to consider the possibility of this type of KD. Development of an effective treatment plan is imperative to shortening fever time and prevention of progressive aggravation of coronary artery disease. Longer follow-up observation is also needed for this group of patients with coronary artery outcomes.

KD: Kawasaki disease; BCG: Bacille Calmette-Guèrin; IVIG: intravenous immunoglobulin; CAD: Coronary artery dilation; CAA: coronary artery aneurysm; CAL: Coronary artery lesions; SCAL: Kawasaki disease patients with coronary artery dilatations/small aneurysms; MCAL: Kawasaki disease patients with coronary artery medium aneurysms; GCAL: Kawasaki disease patients with coronary artery giant aneurysms

Acknowledgement

We would like to thank the patients and volunteers for their participation.

Authors’ contributions

All authors made important contributions to this work. J Y was responsible for the writing of the article. W L, Z-P W, Y-F W and X-F X performed the experiments and collected data. L Z and X Z analyzed the data, P H designed the research study. All authors have read and approved the final version of this manuscript.

Funding

No funding.

Availability of data and material

Data sharing is not applicable to this article, as no datasets were generated or analyzed during the current study. Please contact the author for data requests.

Ethics approval and consent to participate

This study was performed with the ethics approval from the Institutional Committee of Guangzhou Women and Children’s Medical Center.

Competing interests

The authors report no conflicts of interest.

Consent for publication

Not applicable.

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Clinical features and short- and mid-term follow-up of refractory Kawasaki disease in children

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