Background: Pediatric asthma remains a critical public health problem, particularly in Japan, where adherence to new treatment guidelines and effective medication use are inconsistent. Therefore, we aimed to evaluate the current management practices for pediatric asthma to identify areas for improvement and enhance future treatment approaches. Methods: We conducted a web-based cross-sectional survey involving caregivers of children and adolescents aged 0–19 years diagnosed with asthma at various medical institutions in Japan. The survey focused primarily on evaluating the control status of asthma in these patients and examining factors such as treatment adherence, environmental exposure, and the presence of allergic diseases. Results: The data showed that 65.9% of the patients received some form of asthma treatment; however, a significant proportion (26.2%) still experienced poor symptom control (n=2000). The most affected group were children aged 0–3 years. The analysis showed that environmental factors and coexisting allergic diseases notably influenced poor asthma control, although direct correlations with treatment adherence were not statistically significant. Conclusion: These findings highlight the substantial gap in the effective management of pediatric asthma, particularly in very young children. Notably, pharmacotherapy is essential; however, there is an urgent need to develop comprehensive treatment plans that address environmental and lifestyle factors. Future strategies should focus on personalized care tailored to each child’s specific need, incorporating medical and non-medical interventions to optimize asthma control and improve overall health outcomes.

Title: Sublingual-swallow immunotherapy was effective and safe in severe cow’s milk protein allergy: A pediatric case　Author: Masaya kato, M.D.; Shigemi Yoshihara, M.D., Ph.DAffiliations: Department of Pediatrics, Dokkyo Medical University, Tochigi 321-0293, JapanCorresponding author: Masaya KatoDepartment of Pediatrics, Dokkyo Medical University880 Kitakobayashi, Mibu, Shimotsuga, Tochigi 321-0293, JapanPhone: +81-282-87-2155, Fax: +81-282-86-7521E-mail: [email protected], figure, and table count: 746 words, 1 figure.Financial support: This research received no external funding.Consent statement: Written informed consent was obtained from the patient’s parent and the patient for publication of this report and images.To the editor: Although an increasing number of patients with food allergy have been able to achieve tolerance and desensitization through oral immunotherapy, many children with severe Cow‘s milk (CM) allergy do not progress to oral immunotherapy and do not reach desensitization. We report a case in which sublingual-swallow immunotherapy was used to safely increase the dose of CM to 25 ml in a 12-year-old male patient who had a threshold of 1.2 ml of CM for induction of allergy symptoms.The patient had a history of five anaphylactic shocks since infancy after consuming less than 3 ml of CM, and had, therefore, eliminated CM completely from his diet. At age 11, the patient participated in a clinical study involving epicutaneous immunotherapy; however, that did not improve his symptom elicitation threshold. At age 12, casein-specific IgE 6.83 UA/ml, casein-specific IgG4 0.59 mgA/L and oral food challenge (OFC) of CM showed urticaria at 1.2 ml. Tingling of oral cavity was observed in OFC of 0.2 ml of CM, but no other symptoms were noted.We started sublingual-swallow immunotherapy, in which the patient held 0.2 ml of CM under his tongue for 2 minutes before consuming it orally, once a day. Initially, the patient complained of tingling in the oral cavity; however this disappeared within one week of therapy. The dose of CM was increased by 0.1 ml every week with no adverse events observed. As the amount increased, it could not be held only under the tongue, so it was held in the oral cavity. The dose was increased by 0.1 ml per day, 2 months after the start of therapy, but no allergic reaction was observed. After 3 months, the patient was able to consume 10 ml, and after 6 months, up to 30 ml of CM. Since he could not hold more than 20 ml, this amount was held in the oral cavity for 2 minutes before swallowing, while the rest was swallowed without holding. We performed OFC using a pancake containing 25 ml of CM, but no allergy-related symptoms were observed. Thereafter, at the patient’s request, he was given dairy products equivalent to 25 ml of milk 2–3 times a week. After a 2-week ban on CM at 14 months, an oral tolerance test (sweet bread equivalent to 25 ml of milk) was conducted, and the patient complained of mild oral discomfort, but consumed the entire amount without major symptoms. Casein-specific IgG4 levels increased, whereas casein-specific IgE levels decreased for the duration of this therapy.　(Figure 1).Keet et al.1 reported that sublingual immunotherapy (SLIT) with CM was inferior to oral immunotherapy (OIT). However, the study compared three milk protein doses during the maintenance phase of immunotherapy: 7 mg in the SLIT group, 1 g in the OIT B group, and 2 g in the OIT A group, suggesting that increasing the SLIT dose may increase efficacy. A French pilot study reported that milk thresholds increased from an average of 39 ml (range 4–106 ml) to 143 ml (range 44–≥200 ml) after 6 months of treatment by holding milk under the tongue for 2 minutes and then spitting it out (starting at 0.1 ml and increasing to 1.0 ml).2 SLIT induces IL-10-producing regulatory T cells,3 promotes antigen-specific IgG4 production, and suppresses IgE production.4 In addition, since the oral mucosa is devoid of inflammatory cells, such as mast cells, basophils, and eosinophils, and rich in antigen-presenting cells, such as dendritic cells, SLIT induces immune tolerance with fewer adverse reactions.5During OFC and OIT for milk allergy, we experience that food such as pancakes require chewing, and are more successful than swallowing milk. This may lead to sublingual immune tolerance. In addition, holding the food in the oral cavity allows the patient to spit it out if symptoms are strong, which is safer than swallowing it. There have been reports of success with the combination of OIT and omalizumab,6.7 but not everyone can afford this treatment due to the high cost of medical care. In this respect, the present method is easy to perform because the dairy product is simply held in the oral cavity for two minutes and then swallowed. In this case, the patient’s oral tingling disappeared after one week of treatment, suggesting that the treatment induced immune tolerance by the sublingual mucosa, and we believe it is worthwhile to try it for severe CM allergy. We plan to perform this therapy on more cases and conduct a comparative study with OIT in future.

Pediatric Pulmonology , LetterElevated serum TARC/CCL17 levels are associated with childhood interstitial lung disease in patients with SFTPC gene mutationYuto Otsubo MD1; Yuji Fujita MD1; Yusuke Ando MD, PhD1; George Imataka MD, PhD1; Shigemi Yoshihara MD, PhD11Department of Pediatrics, Dokkyo Medical University, 880, Kitakobayashi, Mibu, Shimotsuga, Tochigi, 321-0207, JapanCorresponding author:Yuto OtsuboDepartment of Pediatrics, Dokkyo Medical University, 880, Kitakobayashi, Mibu, Shimotsuga, Tochigi, 321-0293, JapanTel: +81-0282-86-1111Fax: +81-0282-86-7152E-mail: [email protected]:Childhood interstitial lung disease; TARC/CCL17; SFTPCRunning head:Childhood ILD and increased TARC/CCL17 levelTo the Editor,Childhood interstitial lung disease (ILD) is a serious and often life-threatening disease that causes interstitial lung lesion formation during childhood. Several causative genes of childhood ILD, such asSFTPC , SFTPB , and ABCA3 , have been identified in some children. The pathogenesis of ILD caused by SFTPC mutations may include the accumulation of surfactant protein C (SP-C) in vesicles, inhibition of pulmonary surfactant reuptake, and decreased secretion of SP-C, but this remains to be confirmed.1Thymus and activation-regulated chemokine/C-C motif chemokine ligand 17 (TARC/CCL17) is a known disease marker of atopic dermatitis. Recently, an association between idiopathic pulmonary fibrosis, a representative disease with pulmonary interstitial lesions, and TARC/CCL17 has been reported,2 but none between childhood ILD and TARC/CCL17.Here we report our experience of a case of childhood ILD in which the patient had an SFTPC mutation and an elevated TARC/CCL17 level at disease onset that decreased as the patient improved with treatment. TARC/CCL17 may be involved in the pathogenesis of ILD in children withSFTPC mutation, which is different from the pathogenesis of atopic dermatitis.An otherwise healthy 15-month-old girl was admitted to our hospital with fever, difficulty breathing, and poor oral intake. Nine days prior to the visit, nasal discharge and cough appeared and gradually worsened; subsequently, poor oral intake appeared. No fine crackles were noted. The patient required supplemental oxygen and was admitted to the hospital. She had no history of respiratory impairment at birth, but she had a family history of ILD in her maternal grandmother. Informed consent was obtained from the patient’s guardians for the publication of this case report.Laboratory tests showed a white blood cell count of 941 × 109/L, neutrophil count of 58%, C-reactive protein level of 0.01 mg/dL, lactate dehydrogenase level of 929 IU/L, Krebs von den Lungen-6 (KL-6) level of 909 U/mL (normal range < 500 U/mL), surfactant protein A level of 2770 ng/mL (normal <43.8 ng/mL), and surfactant protein D level of 319 ng/mL (normal <43 ng/mL), which were suspicious findings for ILD (Table 1). ß-D-glucan level was 7.9 pg/mL (normal <20 pg/mL) and cytomegalovirus antibodies were negative for both IgG and IgM. Chest radiography showed bilateral frosted shadows (Fig. 1), and a chest computed tomography scan showed bilateral diffuse frosted shadows (Fig. 2), leading to ILD diagnosis.Although prednisolone was started on the 2nd day of admission, the patient’s respiratory status did not sufficiently improve, and oxygen supplementation was required. Therefore, methylprednisolone (30 mg/kg/day) was administered twice for 3 consecutive days on days 13-15 and 19-21; however, the respiratory status remained poor. Hydroxychloroquine (10 mg/kg/day) was then started on day 21, and azithromycin (10 mg/kg/day) three times a week was started on day 56, following which the respiratory status gradually improved. On drinking cold water, the patient often coughed and sometimes vomited. When the water was warmed from 4°C to approximately 20°C, coughing and cough-induced vomiting drastically decreased. On day 66 of hospitalization, the patient was discharged with home-based oxygen. Respiratory status, oxygenation, and laboratory data for ILD markers such as KL-6 gradually improved (Table 1).Genetic analysis of SFTPB , SFTPC , ABCA3 ,CSF2RA , and CSF2RB showed SFTPC mutation and p.I73T (c.218T>C), and the ILD was determined to be caused by theSFTPC mutation.Additional examination revealed elevated TARC/CCL17 level at 10,270 pg/mL (normal <998 pg/mL), but IgE (24.2 IU/mL; normal <173 IU/mL) and IL-4 (2.7 pg/mL; normal <6 pg/mL) levels were not elevated in the early stages of treatment. TARC/CCL17 level decreased to 2,122 pg/mL on day 131 after the admission. Granulocyte-macrophage colony-stimulating factor (GM-CSF) level was measured twice on days 11 and 83, and on both, the GM-CSF level was under 5 pg/mL without significant elevation. Anti-GM-CSF antibody (0.3 U/mL; normal <1.7 U/mL) was negative.It has been hypothesized that many of these effector cell populations are recruited by TARC/CCL17 and act profibrogenically, but the details remain largely unknown.3) SFTPC mutations increase the number of abnormal alveolar type 2 epithelial cells (AT2) due to impaired metabolism of SP-C. A knock-in mouse model capable of regulating the expression of an isoleucine-to-threonine substitution at codon 73 (p.I73T) in SFTPC, at the same site as in the present case, showed persistently elevated TARC/CCL17 level in the bronchoalveolar lavage fluid (BALF). Furthermore, the same study also reported that TARC/CCL17 is specifically released by AT2.3 In ILD caused by SFTPC mutations, its pathogenesis involves AT2 hyperplasia. The decrease in TARC/CCL17 level in our patient suggests that either AT2 itself or TARC/CCL17 production from AT2 itself decreased with treatment. In this case, we report, for the first time, elevated serum TARC/CCL17 level in a patient with SFTPC mutation, which decreased with treatment.Our patient showed no symptoms of atopic dermatitis, and she had no skin condition, and no elevation of IgE and IL-4 levels. In the SFTPC p.I73T mouse model mentioned above, no significant level of IL-4 or IL-13 was detected in BALF, and no involvement of the Th2 response was observed.This high TARC/CCL17 level was not considered to be a result of the GM-CSF cascade. TARC/CCL17 is released from macrophages as a 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 normal and not elevated, both at the beginning of treatment and after improvement.The limitation of this case is that bronchoalveolar lavage was not performed; therefore, the evaluation was based on serum level rather than local lung findings.This case suggests that TARC/CCL17 is involved in ILD pathogenesis. Further elucidation of the chemokine and receptor signaling cascade may lead to the targeting of some stages for therapy, which may be an important issue for future medical treatment. Therefore, elucidation of this pathogenesis is desirable.References1) Beers MF, Mulugeta S. Surfactant protein C biosynthesis and its emerging role in conformational lung disease. Annu Rev Physiol 2005;67:663-696.2) Sivakumar P, Ammar R, Thompson JR, Luo Y, Streltsov D, Porteous M, McCoubrey C, Ill EC, Beers MF, Jarai G, et al. Integrated plasma proteomics and lung transcriptomics reveal novel biomarkers in idiopathic pulmonary fibrosis. Respir Res 2021;22;273:1-13.3) Nureki SI, Tomer Y, Venosa A, Katzen J, Russo SJ, Jamil S, Barrett M, Nguyen V, Kopp M, Mulugeta S, et al. Expression of mutant Sftpc in murine alveolar epithelia drives spontaneous lung fibrosis. J Clin Invest 2018;128:4008-4024.4) Hamilton JA. GM-CSF-dependent inflammatory pathways. Front Immunol 2019;10;2055:1-8.5) Woo YD, Jeong D, Chung DH. Development and functions of alveolar macrophages. Mol Cells 2021;44:292-300.Conflicts of interest:The authors disclose no conflicts.Contributors:YO cared for the patient, conceived the concept of the case report, and drafted the initial manuscript. YF, YA, GI, and SY critically reviewed the manuscript for intellectual content. All authors approved the final manuscript as submitted and agreed to be accountable for all aspects of the work. All authors have read and approved the final manuscript.Acknowledgment:We would like to thank Editage (www.editage.com) for English language editing.We thank Dr. Goro Koinuma, Division of Pulmonology, National Center for Child Health and Development, Tokyo, Japan, for his invaluable expert opinion regarding the diagnosis and treatment of the patients.Sources of funding:No funding was obtained for this study.

Clinical Letters to the Editor