Received: 19 February 2022

| Accepted: 25 April 2022

DOI: 10.1002/ppul.25950

CLINICAL CORRESPONDENCE

Elevated serum TARC/CCL17 levels associated withchildhood interstitial lung disease with SFTPC gene mutation
Yuto Otsubo MD|Yuji Fujita MD

George Imataka MD, PhD||Yusuke Ando MD, PhD|Shigemi Yoshihara MD, PhD

Department of Pediatrics, Dokkyo Medical University, Mibu, Tochigi, Japan
Correspondence: Yuto Otsubo, MD, Department of Pediatrics, Dokkyo Medical University, 880, Kitakobayashi, Mibu, Shimotsuga, Tochigi 321‐0293, Japan.
Email: otsubo.920315@gmail.com

Laboratory test results showed white blood cell count,

To the Editor,
Childhood interstitial lung disease (ILD) is a serious and often life‐

941 × 109/L; neutrophil count, 58%; C‐reactive protein level,

threatening disease that causes interstitial lung lesion formation.

0.01 mg/dl; lactate dehydrogenase level, 929 IU/L; Krebs von den

Several causative genes of childhood ILD, such as SFTPC, SFTPB, andLungen‐6 (KL‐6) level, 909 U/ml (normal range < 500 U/ml); surfac-ABCA3, have been identified in some children. The pathogenesis oftant protein A level, 319 ng/ml (normal < 43.8 ng/ml); and surfactant

ILD caused by SFTPC mutations may involve the accumulation ofprotein D level, 2770 ng/ml (normal < 110 ng/ml), which were

misfolded surfactant protein C (SP‐C) in vesicles, inhibition ofsuspicious findings for ILD (Table 1). ß‐D‐glucan level was 7.9 pg/ml

pulmonary surfactant reuptake, and decreased expression of SP‐C.

(normal < 20 pg/ml) and both IgG and IgM were negative forHowever, this pathogenesis remains to be confirmed.1

cytomegalovirus.

Thymus and activation‐regulated chemokine/C‐C motif chemo-

Chest

radiography

showedbilateral

diffuseground‐glass opacities (Figure 1). Chest computed tomography scankine ligand 17 (TARC/CCL17) is a known disease marker for atopic

showed bilateral diffuse frosted shadows (Figure 2), leading to ILD

dermatitis. Recently, it has been reported that plasma TARC/CCL17

diagnosis.

levels were upregulated in patients with idiopathic pulmonary fibrosis

Although prednisolone was started on Day 2 after admission, thecompared with those in normal controls.2 However, to date, there

patient's respiratory status did not sufficiently improve, andhas been no report on the association between childhood ILD andsupplemental oxygen therapy was required. Therefore, methylpred-TARC/CCL17.

nisolone (30 mg/kg/day) was administered two times for 3 consecu-Herein, we report our experience with a case of childhood ILD

tive days on Days 13–15 and 19–21. However, the patient'swith SFTPC mutation and elevated TARC/CCL17 levels at disease

respiratory status remained poor. Hydroxychloroquine (10 mg/kg/onset that decreased after patient improvement with treatment. Inday) was then started on Day 21, and azithromycin (10 mg/kg/day)children with SFTPC mutation, elevated TARC/CCL17 levels may bethree times a week was started on Day 56. Thereafter, herassociated with ILD, which is different from the pathogenesis ofrespiratory status gradually improved. Although posthospitalization

atopic dermatitis. Moreover, it was suggested that TARC/CCL17

treatment improved her hypercapnia and labored breathing, the childlevels could be used as a biomarker for ILD in patients with SFTPC

was still in need for oxygen therapy administration and could not bemutation.

weaned off it. On Day 66 after hospitalization, the patient was

An otherwise healthy 15‐month‐old girl was admitted to ourdischarged with home‐based oxygen. Chest X‐rays showed little

hospital for fever, breathing difficulty, and poor oral intake. Nine days

improvement in imaging findings between admission and discharge

before admission, nasal discharge and cough appeared and gradually(Figure 3). Respiratory status, oxygenation, and laboratory data of ILD

worsened; subsequently, poor oral intake appeared. No fine crackles

markers such as KL‐6 gradually improved after discharge (Table 1).

were heard. The patient required supplemental oxygen and was

Genetic analysis of SFTPB, SFTPC, ABCA3, CSF2RA, andadmitted to the hospital. She had no history of respiratory

CSF2RB showed SFTPC mutation and p.I73T (c.218T>C). There-impairment at birth. However, the patient had a family history offore, ILD was determined to be caused by this SFTPC mutation.

ILD in her maternal grandmother. Informed consent was obtained

The parents and grandparents of the patient did not wish tofrom the patient's guardians for the publication of this case report.

undergo genetic testing.

Pediatric Pulmonology. 2022;1–3.

wileyonlinelibrary.com/journal/ppul© 2022 Wiley Periodicals LLC.

|

1

2|

TABLE 1OTSUBO ET AL.

Patient biochemical analysis results since the first visit.

Days after visit

1

71318

26

40

47

61

75

83

103

131

TARC/CCL17 (pg/ml)––

10,270–––

10,630

–

–

7046

2962

2122

LDH (IU/L)

929

KL‐6 (U/ml)

909

SP‐A (ng/ml)–

SP‐D (ng/ml)

–

621

671

651

737

580

600

497

463

477

471

420

1003

942

1107

1011

1040

1001

925

935

890

769

319

–

244

493

462

–

300

300

–

241

209

2770

–

2580

3080

2220

–

1770

2000

–

1950

1000

–

Abbreviations: KL‐6, Krebs von den Lungen‐6; LDH, lactate dehydrogenase; SP‐A, surfactant protein A; SP‐D, surfactant protein D; TARC/CCL17, thymus
and activation‐regulated chemokine/C‐C motif chemokine ligand 17; –, no data.

F I G U R E 3 Chest X‐ray at discharge showing remaining uniformground‐glass opacities at bilateral lung fields.

Additional examination revealed elevated TARC/CCL17 level at
10,270 pg/ml. However, IgE (24.2 IU/ml, normal < 173 IU/ml) and IL‐4
F I G U R E 1 Chest X‐ray revealing uniform ground‐glass opacities
at bilateral lung fields.

(2.7 pg/ml, normal < 6 pg/ml) levels were not elevated in the early stagesof treatment. TARC/CCL17 level decreased to 2122 pg/ml on Day 131
after admission. Granulocyte‐macrophage colony‐stimulating factor(GM‐CSF) level was measured two times on Days 11 and 83 and on
both days, its level was under 5 pg/ml without significant elevation.
Anti‐GM‐CSF antibody (0.3 U/ml, normal < 1.7 U/ml) was negative.
Although it has been hypothesized that many of these effector
cell populations, such as macrophages and lymphocytes, are recruited
by TARC/CCL17 and act profibrogenically, the details remain largely
unknown.3 SFTPC mutations increase the number of abnormal
alveolar type 2 epithelial cells (AT2) due to impaired metabolism ofSP‐C. A knock‐in mouse model capable of regulating the expressionof an isoleucine‐to‐threonine substitution at codon 73 (p.I73T) inSFTPC, at the same site as in the present case, showed persistently

F I G U R E 2 Chest computed tomography revealing bilateral
diffuse ground‐glass opacities.

elevated TARC/CCL17 level in the bronchoalveolar lavage fluid(BALF). Furthermore, the same study also reported that TARC/CCL17
was specifically released by AT2.3 In ILD caused by SFTPC mutations,

|OTSUBO ET AL.

3

its pathogenesis involves AT2 hyperplasia. The reduction in TARC/editing (supporting). George Imataka: Writing–review and editing

CCL17 level in our patient suggests that either AT2 itself or TARC/(supporting). Shigemi Yoshihara: Writing–review and editing (supporting).

CCL17 produced by AT2 decreased with treatment. In this case, wereport, for the first time, elevated serum TARC/CCL17 level in aACKNOWLEDGME NT S

patient with SFTPC mutation, which decreased with treatment.

The authors would like to thank Editage (www.editage.com) for

Our patient showed no symptoms of atopic dermatitis. Further-English language editing. The authors thank Dr. Goro Koinuma,more, she had neither skin condition nor elevation of IgE and IL‐4

Division of Pulmonology, National Center for Child Health andlevels. In the SFTPC p.I73T mouse model mentioned above, noDevelopment, Tokyo, Japan, for his invaluable expert opinion

significant level of IL‐4 or IL‐13 was detected in BALF. Moreover, noregarding the diagnosis and treatment of the patients.

involvement of the antigen‐specific Th2 response was observed.
This high TARC/CCL17 level was not considered to be a result of theGM‐CSF cascade. TARC/CCL17 is released from macrophages as aCONFLIC TS OF I NTERES T
The authors declare no conflicts of interest.

product of the GM‐CSF cascade.4 GM‐CSF is also known to be produced
by AT2.5 However, in this case, serum GM‐CSF levels were within normal

DATA AVAILABILITY STATEMENT

range, both at the beginning of treatment and after improvement.

The data that support the findings of this study are available from theThe limitation to this case report is that bronchoalveolar lavage

corresponding author upon reasonable request.

was not performed. Therefore, the evaluation was based on serumlevels rather than on local lung findings.
Normal serum values of TARC/CCL17 in children have not been
established yet. Cut‐off values of TARC/CCL17 for the diagnosis of

ORC I D
Yuto Otsubo
Yuji Fujita

https://orcid.org/0000-0001-8184-6873
https://orcid.org/0000-0001-6440-9110

atopic dermatitis have been found to be different among various age
groups. A previous study reported measured serum TARC/CCL17

RE F ER EN CES

values in 45 children with atopic dermatitis and 52 non‐atopic

1.

controls. It showed that serum TARC/CCL17 cutoff values toestablish AD diagnosis were: 1431 pg/ml in the 0–1 year group,2.

803 pg/ml in the 2–5 year group, and 510 pg/ml in the 6‐year andolder group. Within the same literature, they also reported
significantly higher normal TARC/CCL17 values in the 0‐ to 1‐year‐3.

6old group. Compared with the cutoff values in that report, TARC/
CCL17 level was elevated in our present case.

4.

TARC/CCL17 may be associated with ILD and could potentially be used as a biomarker for detecting childhood ILD inpatients with SFTPC mutations. Further elucidation of the chemokine and receptor signaling cascade may lead to targeting somestages for therapy, which may be an important issue for establishing future medical treatment. Therefore, elucidation of this5.
6.

Beers MF, Mulugeta S. Surfactant protein C biosynthesis and its
emerging role in conformational lung disease. Annu Rev Physiol.
2005;67:663‐696.
Sivakumar P, Ammar R, Thompson JR, et al. Integrated plasma
proteomics and lung transcriptomics reveal novel biomarkers in
idiopathic pulmonary fibrosis. Respir Res. 2021;22:273.
Nureki SI, Tomer Y, Venosa A, et al. Expression of mutant Sftpc inmurine alveolar epithelia drives spontaneous lung fibrosis. J ClinInvest. 2018;128:4008‐4024.
Hamilton JA. GM‐CSF‐dependent inflammatory pathways. FrontImmunol. 2019;10:2055.
Woo YD, Jeong D, Chung DH. Development and functions ofalveolar macrophages. Mol Cells. 2021;44:292‐300.
Fujisawa T, Nagao M, Hiraguchi Y, et al. Serum measurement ofthymus and activation‐regulated chemokine/CCL17 in children withatopic dermatitis: elevated normal levels in infancy and age‐specificanalysis in atopic dermatitis. Pediatr Allergy Immunol. 2009;20:633‐641.

pathogenesis is required.
A U T H O R C O N TR I B U T I O N S

How to cite this article: Otsubo Y, Fujita Y, Ando Y, Imataka G,

Yuto Otsubo: Conceptualization (equal); data curation (equal); formal

Yoshihara S. Elevated serum TARC/CCL17 levels associated withanalysis (equal); methodology (equal); visualization (equal); writing–original

childhood interstitial lung disease with SFTPC gene mutation.

draft (equal); writing–review and editing (equal). Yuji Fujita: Writing–

Pediatric Pulmonology. 2022;1‐3. doi:10.1002/ppul.25950

review and editing (supporting). Yusuke Ando: Writing–review and