Shinshu Med J, 70⑷：225～231, 2022

Combination Therapy of Cyclosporin A and Plasma Exchange
for Infants with Immunoglobulin-resistant Kawasaki Disease
Saori Yokota, Noriko Motoki＊, Shoko Yamazaki and Masafumi Utsumi
Department of Pediatrics, Shinshu University School of Medicine

Kawasaki disease (KD) is an acute childhood febrile illness that is classified as a systemic vasculitis syndrome.
Combination intravenous immunoglobulin (IVIG) and acetylsalicylic acid is the standard initial and second-line
therapy for KD to resolve inflammation and reduce the occurrence of coronary artery lesions (CALs). The goalof treatment in the acute phase of KD is to decrease inflammation and arterial damage to prevent CALs. For
IVIG-resistant KD, however, additional treatments should be administered promptly before CAL formation, suchas steroids, infliximab, cyclosporin A (CsA), and plasma exchange (PE). Although the effectiveness of PE on
refractory KD is well known, it is highly invasive, especially in infants. Therefore, safer treatments are needed to
avoid or minimize the number of PE courses in severe infantile cases. We herein report the clinical outcomes of
2 infants with IVIG-resistant KD who were treated successfully with a combination therapy of CsA and PE as
third-line treatment, thereby possibly reducing the number of PE sessions. Shinshu Med J 70 : 225―231, 2022
(Received for publication January 24, 2022 ; accepted in revised form April 25, 2022)
Key words : Kawasaki disease, infant, refractory, cyclosporin A, plasma exchange

Ⅰ Introduction

therapy5）.
The Japanese Kawasaki Disease Treatment Guide­

Kawasaki disease (KD) is an acute childhood febrileline was recently revised in 20205）. However, addi­

illness that is classified as a systemic vasculitis syn­tional treatments for the third line and beyond a-drome. Histologically, the earliest changes in KD aregainst IVIG-resistant KD remain unestablished. In

seen in the tunica media of the vessel walls on day

the standard initial treatment of KD, patients re­

6-8 of illness. Inflammation in the intima and adven­ceive a single dose of IVIG (2 g/kg infused over 12-24

titia emerges by day 10, and then coronary artery

hours) accompanied by high-dosage ASA (30-50

1）dilation occurs around day 12 . It has been report­

mg/kg/day orally). Prednisolone (PSL) and cyclospo­

ed that coronary artery lesions (CALs) develop in

rin A (CsA) have been newly described as first-line

2）

versus only 1 ％ in

intensive therapy in combination with the standard

promptly treated patients3）4）. Thus, the therapeutic

treatment for high-refractory risk cases identified bygoal in acute-phase KD is to reduce inflammation

the IVIG refractory prediction score6）. If the patientand arterial damage as soon as possible to prevent

exhibits a persistent or recurrent fever within 48

CALs. Currently, combined intravenous immunoglo­

hours of the initial therapy, second line treatment

bulin (IVIG) and acetylsalicylic acid (ASA) is the stand­will be given next ; an additional dose of IVIG is cur­ard initial and second-line therapy for KD. Approxi­

rently the most recommended method. For third-line

mately 15-20 ％ of patients do not respond to initial KD

treatments and beyond, IVIG, steroids, infliximab

20-25 ％ of untreated patients＊

Corresponding author : Noriko Motoki
Department of Pediatrics, Shinshu University School of
Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan
E-mail : nmotoki@shinshu-u.ac.jp

No. 4, 2022

(IFX ; a tumor necrosis factor-alpha inhibitor), CsA,
and plasma exchange (PE) have all been suggested
for monotherapy or in combination with other regi­mens. Ultimately, it is the decision of each clinician
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Yokota・Motoki・Yamazaki et al.
Table 1

Characteristics of the patients
Laboratory data

Clinical symptoms as diagnostic criteria (at diagnosis/at initiation of PE)

Age atCase

Sex

to IVIG

onset(months)

Laboratory data

immediately prior immediately prior

Fever

Conjunctival

Cervicalinjection

lymphadenopathy

Changes inChangesthe lips andin theoral cavity

extremities

to PE

Polymorphous

WBC

CRP

WBC

CRP

rash

(/μL)

(mg/dL)(/μL)(mg/dL)

1

M

8

(＋/＋)

(＋/＋)

(＋/＋)

(－/＋)

(＋/＋)

(＋/－)

7,450

19.47

26,200

24.74

2

M

8

(＋/＋)

(＋/＋)

(-/＋)

(＋/＋)

(＋/＋)

(＋/＋)

18,61010.03

28,90018.05＋ : positive clinical symptom, － : negative clinical symptom
PE, plasma exchange ; IVIG, intravenous immunoglobulin ; WBC, white blood cell count ; CRP, C-reactive protein.

or institution to decide which treatment to select5）.

echocardiography. Kobayashi risk score as a predic­

Since IFX is restricted for infants under 1 year of

tor of the response to IVIG therapy was 8 points,

age in Japan, the treatment options for infant cases

which indicated high IVIG refractory risk6）. He wasof KD are limited. The effectiveness of PE for refrac­initially administered IVIG (2 g/kg) over 12 hours

tory KD is well known. However, PE in infants isand oral flurbiprofen (5 mg/kg/day) instead of ASA

highly invasive since it requires deep sedation anddue to high transaminase levels (Fig. 1). 48 hours

intensive care during vascular access and through­after the start of treatment, his fever persisted, and7）

out the exchange . CsA has been adopted as an im­

blood tests showed strong inflammatory findingsmunosuppressant for various infant diseases. The(WBC 10.4×103/μL and CRP 18.6 mg/dL). Although a

use of CsA for IVIG-resistant KD is reportedly safe

second dose of IVIG (2 g/kg) was given on day 6, he

8）
9）

and well tolerated, even for infantsremained febrile with a further increase in CRP to.

We herein report the clinical outcomes of two 8month-old male infants with IVIG-resistant KD whowere treated successfully with a combination therapyＡ

as an additional treatment on day 8.
After the first course of PE, his CRP level dropped
temporarily from 24.7 mg/dL to 10.9 mg/dL, but byof CsA and PE for third-line treatment.
Ⅱ

22.0 mg/dL. He was referred to our hospital for PE

the next day increased to 26.2 mg/dL. Since his re­Cases

sponse to PE alone was insufficient, we added contin­uous infusion of CsA (4 mg/kg/day) from day 9.

Case 1
An 8-month-old male infant exhibited a high-grade

After 2 additional courses of PE combined with CsA,

fever, followed 3 days later (day 4 of illness) by bilat­

his CRP level had decreased to 6.9 mg/dL, whicheral conjunctival infection, cervical lymphadenopa­

enabled a switch from intravenous to oral CsA medi­

thy, hardened edema and erythema of the finger andcation (4 mg/kg/day divided into 2 doses). After

toe tips, and a polymorphous rash (Table 1). There

completing the third course of PE, he became afe­

was no medical or family history of note, and he wasbrile, and his CRP gradually decreased to 1.72 mg/

fully immunized. The patient was first admitted to adL. On day 15, however, in addition to a fever ofmunicipal hospital with a diagnosis of KD. Laboratory

38.2 ℃ , echocardiography revealed mild coronary

investigation at the time revealed hemoglobin (Hb)artery dilation, and so an additional course of IVIG

3

8.9 g/dL, white blood cell count (WBC) 7.45×10 /μL,4

was commenced. The coronary arteries were dilated

3

neutrophils (Neu) 86.8 ％ , platelets 36.3×10 /mm ,up to the left main trunk (LMT) at 3.2 mm (Z-scoreaminotransferase (AST) 69 U/L, alanine aminotrans­2.65), left anterior descending branch (LAD) at 2.5

ferase (ALT) 69 U/L, albumin 3.1 g/dL, sodium 132.5mm (Z-score 2.76), and right coronary artery (RCA)mEq/L, and C-reactive protein (CRP) 19.4 mg/dL.

at 2.7 mm (Z-score 2.50) but only transiently andNo dilation of the coronary artery was present on

without aneurysms. Since he remained afebrile with

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ol. 70Combined cyclosporin A and plasma exchange for Kawasaki disease

Fig. 1 Clinical course of case 1
IVIG, intravenous immunoglobulin ; PE, plasma exchange ; CsA, cyclosporin A ; div, drip intravenous ;po, per os ; ASA, acetylsalicylic acid ; CRP, C-reactive protein ; BT, body temperature.

normal CRP by day 21, we discontinued CsA. He was

was 6 points, indicating high risk of IVIG resistance.

discharged on day 23 with low-dosage (5 mg/kg/

IVIG (2 g/kg) and high-dosage (30 mg/kg/day)day) ASA without any complications associated with

ASA treatment was applied (Fig. 2). After 2 cour­PE or CsA. His CALs progressively regressed, andses of IVIG resulting in poor response (body temper­

follow-up echocardiography 2 years after the onset

ature 39 ℃, WBC 26.6×103/μL, and CRP 20.8 mg/dL),of KD revealed normal findings of LMT 2.5 mm (Z-he was transferred to our hospital for additionalscore 0.53), LAD 2.3 mm (Z-score 1.77), and RCA 2.5

treatment on day 9.
Initial continuous infusion of CsA (2.4 mg/kg/day)

mm (Z-score 1.76).
Ｂ

provided limited results, with further increases inCase 2
An 8-month-old male infant suffered a high-grade

fever and CRP. On day 10, we combined CsA withfever, followed 3 days later (day 4 of illness) by bilat­

PE. After the second course of PE, he became afe­

eral conjunctival infection, erythematous lips andbrile, and his CRP level had decreased to 3.33 mg/

strawberry tongue, hardened edema and erythemadL. During CsA tapering and discontinuation, a mildof the finger and toe tips, and a polymorphous rash

fever and increases in inflammatory findings were(Table 1). He was fully immunized and had no rele­

detected. However, no CAL formation was observed,

vant medical history, although his cousin earlier had

and so IVIG treatments were added accordingly. He

KD. He was first admitted to a municipal hospital

was discharged on day 36 with low-dosage ASA,

with a diagnosis of KD. Laboratory investigation on

without any complications associated with CsA or

3admission revealed Hb 11.3 g/dL, WBC 18.6×10 /μL,
4

3

PE. Repeated echocardiography showed no dilation

Neu 73.6 ％ , platelets 41.8×10 /mm , AST 59 U/L,of the coronary artery during the clinical course or

ALT 47 U/L, albumin 3.6 g/dL, sodium 132 mEq/L,

at 2 years of follow-up.

and CRP 10.03 mg/dL. Coronary artery dilatation was
absent on echocardiography. Kobayashi risk scoreNo. 4, 2022

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Yokota・Motoki・Yamazaki et al.

Fig. 2 Clinical course of case 2
IVIG, intravenous immunoglobulin ; PE, plasma exchange ; CsA, cyclosporin A ; div, drip intravenous ;po, per os ; ASA, acetylsalicylic acid ; CRP, C-reactive protein ; BT, body temperature.

contra-indications to IFX, including patients under 1

Ⅲ Discussion

year old, those vaccinated against BCG within 6This study described the clinical outcomes of 2

months prior or given a live vaccine within 1 monthinfants with IVIG-resistant KD who were managed

prior, and those already with CALs5）. Accordingly,

successfully with combination therapy of CsA andCsA or PE is likely to be chosen as the third-line

PE. Neither CsA nor PE alone was effective in boththerapy and beyond in infants less than 1 year ofpatients. By combining the therapies, however, weage. In 2013, Kobayashi et al. demonstrated that thewere able to minimize the number of PE sessions, aincidence of CALs and the need for additional treat­highly invasive treatment especially in infants under

ment were significantly lower for PSL＋IVIG than

1 year of age.

for IVIG alone12）. However, PSL can mask fever and

The therapeutic aim in acute-phase KD is the re­

CRP elevation, making it difficult to predict CAL

duction of inflammation and arterial damage to pre­progression. Long-term steroid administration may

vent CALs. Even in IVIG-refractory cases, additional

also weaken arterial walls5）; we have encounteredtreatments aim for successful symptom resolution by

several cases of giant aneurisms and coronary artery5）

day 9, before the onset of coronary artery dilation .

rupture during and after steroid use. Thus, from theAt our institution, the first- and second-line treat­

viewpoint of safety and effectiveness that can bements for KD are IVIG with high-dosage ASA, fol­

judged in a short time, we have adopted a protocol

lowed by IFX. The advantage of IFX is that it takes

using IFX from the third line of treatment onward.

only 2 hours for administration and that the efficacy

In Europe and the U.S., the first line of treatment

can be determined after a single dose. The averagefor KD is IVIG (2 g/kg) and ASA, whose efficacy istime for fever alleviation is as short as 16.6 hours,

determined at 48 hours. For the second line, addition­and the antipyretic rate at 48 hours after administra­al IVIG or combination with methylprednisolone

tion is 77.4-83.6 ％ 10）11）. However, there are several(MP) or PSL is considered, with CsA, PE, and IFX as

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Vol. 70

Combined cyclosporin A and plasma exchange for Kawasaki disease

options for third line and beyond. MP or PSL is also

semia without arrhythmia, elevated blood pressure,considered for high-risk patients. However, sincenausea, vomiting, tremor, and in long-term use cases,

evidence on additional treatments are lacking andtemporary hirsutism5）8）9）.

risk scores are less accurate, steroids are not highly

Additional indications for CsA were added for KD

recommended in such cases13）14）. Our therapeutic strate­

in 2020 after the publication of the KAICA trial22）,

gy is comparable to that of general treatment in Europe

which proved the significant effect of the drug on

and the U.S.

preventing CALs, namely : 1) for predicted IVIG-

In the post-RAISE study, younger age (＜6 months

resistant KD as first-line intensive treatment in com­of age) was associated with a higher risk of CALs atbination with IVIG, and 2) for IVIG-resistant KD as

15）

1 month after onset . Another report also indicatedan additional treatment. Unlike IFX, CsA can bethat even in a low-risk group, younger age (＜12used in infants 4 months and older. As supplemental

16）months of age) was a risk factor for CALs . Consid­

treatment, CsA (5 mg/kg/day) is orally administeredering that “age under 12 months” is included in thein equally divided doses before morning and evening

Kobayashi risk score as well, aggressive treatment

meals. If oral intake is difficult, intravenous CsA can beshould be pursued to promptly resolve vasculitis,

administered at 3-4 mg/kg/day divided into 2 doses,

especially in infants.

and then switched to oral CsA whenever possible5）8）.

PE has been a treatment option for KD long before
7）

Since intravenous CsA often results in higher blood

IVIG and has a history of nearly 40 years . Since it

concentrations, we started with a lower dose (2.4

can remove excessive inflammatory cytokines in the

mg/kg/day) in Case 2. Trough value is measured

circulation, PE has become the last resort for IVIG-

before administration on the third day for adjusting

17）

resistant KD . PE has a wider range of therapeutic

the dose to reach the target concentration of 60-200

indications than other treatment options and can be

ng/mL. Five days are needed to determine the effectadapted to various pathological conditions, includingof CsA and decide whether to continue it for 10-14

infection and heart failure, even in infants. Despite its

days until CRP decreases sufficiently9）. In studies

effectiveness, however, PE can only be performed atwhereby CsA was given as additional treatment be­

specialized facilities in which intensive pediatric careyond the third line, the fever resolved within 5 daysis possible because invasive procedures, such as

and CRP decreased in many cases. CsA is also rec­catheter placement in the inguinal or external jugu­ommended as initial treatment in combination withlar vein, deep sedation, and artificial respiration, are

IVIG for high-risk patients5）. However, it should be

required in infants. The complications of PE havenoted that CsA requires a longer time to determine

been discussed in various studies

18）
-21）

. When theefficacy than other treatments, which may delay thetechnique is performed in children with a small body

start of second-line treatment. Nevertheless, CsA

size and low circulating blood volume, it is necessary

may be considered in high-risk infants for whomto ensure reliable vascular access, reduce priming

IFX is unavailable.

volume, prevent hypothermia, use anticoagulants,

The combination therapy of CsA and PE is also7）

and provide safe sedation . PE requires 2 hours perused for other immunosuppressive-resistant diseases,

procedure and can be performed up to 5 consecutive

such as autoimmune diseases23）-25） and after kidneydays, although shorter periods lead to fewer compli­transplantation26）, by exerting complimentary actions.

cations.

Shimada et al.27） reported that IFX prior to PE could

CsA is used relatively frequently in children sincedecrease the total duration of PE (median number ofit has long been indicated for nephrotic syndrome

PE sessions of the IFX＋PE group vs. the PE group :and post-organ transplantation. No serious side ef­

2.0 vs. 4.5) and reduce the physical and mental burden

fects have been reported to date, with minor compli­of patients related to vascular access, physical re­cations including pseudohyperkalemia, hypomagne­

straint, and deep sedation. Even if IFX therapy be­

No. 4, 2022

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Yokota・Motoki・Yamazaki et al.

fore PE alone seems clinically ineffective, it helps towhere CsA or PE alone is insufficient, combining thelower the levels of granulocyte colony-stimulating

therapies may shorten the febrile period and minimize

factor, monocyte chemotactic protein-1, human tumor

the number of invasive PE procedures as well as

necrosis factor alpha, and other cytokines, thus indi­

IFX prior to PE. Further studies are needed to eval­27）

cating an ability to rapidly suppress inflammation .

uate the effect and mechanism of CsA on PE.

In the 2 presented cases, the lack of a response to PE

Ⅳ

alone (Case 1) or CsA alone (Case 2) coincidentally
led to combination therapy. According to the study
27）

Conclusion

We successfully treated 2 infants with IVIG-resis­by Shimada et al. , we would like to prospectively

tant KD using a combination therapy of CsA and PE,

investigate the effectiveness of combination treatment

which may have reduced the number of invasive PE

by pre-administering CsA and adding PE based on

sessions. Combined CsA and PE may be a new treat­cytokine profiles.

ment strategy for infants with IVIG-resistant KD,

The therapeutic goal of acute-phase KD is rapid

which currently has few treatment options.

fever elimination without CAL formation. In cases
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