Multicentre, randomised study found that honey had no pharmacological effect on nocturnal coughs and sleep quality at 1-5 years of age.

AIM: The World Health Organization has listed honey as a potential treatment for coughs, but there is little evidence to support its use for coughs associated with upper respiratory tract infections (URTIs). This study evaluated how effective honey was for treating nocturnal coughs and sleep difficulties. METHODS: This multicentre, randomised, double-blind, placebo-controlled study focused on patients aged 1-5 years with URTIs and coughs for up to 7 days. They were recruited from 13 general paediatric community clinics in Japan. The participants were given acacia honey or a honey-flavoured syrup placebo in the hour before they were put down to sleep on 2 consecutive nights. Their nocturnal cough and sleep difficulties were assessed on both nights using a 7-point Likert scale. RESULTS: The data collection for 161 patients took place between 20 November 2021 and 28 February 2022, with 78 randomly allocated to the honey group and 83 to the syrup placebo group. Both groups showed improvements on both the first and second nights, with no significant differences between the two groups. CONCLUSION: Both groups showed improvements in their nocturnal coughs and sleep difficulties during the 2-night study, but honey was no more effective than the syrup placebo.

Effect of age on the incidence of aseptic meningitis following immunization with monovalent mumps vaccine.

OBJECTIVE: The purpose of this study was to determine the risk of aseptic meningitis after mumps vaccination in younger children compared with older children. METHODS: This prospective cohort study included a total of 21,465 children under 18 years of age who had received the first dose of three of the Japanese mumps monovalent vaccine. We compared the cumulative incidence of aseptic meningitis for 30 days after vaccination among the following age groups: ≤ 1, 2, 3-4, and ≥ 5 years old. We also investigated the cumulative incidence of salivary gland swelling, a fever (≥ 38°C) lasting at least 3 days during the 10 to 25 days following immunization, vomiting of 3 times or more, headache, and seizure. RESULTS: A total of 10 aseptic meningitis, 551 salivary gland swelling, 844 fevers, 669 vomiting, 757 headaches, and 29 seizure cases were identified. The cumulative incidence of aseptic meningitis increased with age (0.016%, 0.021%, 0.066%, and 0.096%, respectively). Statistical significance was observed between children ≥ 3 years old and those < 3 years of age [0.078% vs. 0.018%, RR 4.35 (95% CI 1.05-18.2), p=0.04]. The cumulative incidence of salivary gland swelling also increased with age (1.8%, 3.0%, 3.5%, and 4.5%, respectively). For non-specific adverse events, the cumulative incidence of fever or seizure decreased with age. In contrast, the cumulative incidence of headache increased with age. The cumulative incidence of vomiting was similar among children ≤ 4 years of age; however, that in those children ≥ 5 years old was significantly lower. CONCLUSIONS: The first dose of mumps vaccine that is currently available for use in Japan may be administered in children less than 3 years of age in order to complicate a less aseptic meningitis after immunization.

CD30 ligand is a new therapeutic target for central nervous system autoimmunity.

The CD30 ligand (CD30L)/CD30 axis plays a critical role in Th1 and Th17 cell differentiation. However, the role in the pathogenesis of central nervous system autoimmunity remains unknown. Here we show the resistance for experimental autoimmune encephalomyelitis (EAE) with markedly reduced induction of antigen-specific Th1 and Th17 cells in CD30L knockout mice. Bone marrow chimera experiments indicated that CD30L on bone marrow-derived cells were critical for the development of EAE and that CD30L reverse signaling in CD4 T cells was dispensable for the pathogenic Th17 cell differentiation at the induction phase. Adoptive transfer experiment revealed an additional role for CD30L in the environment at the effector phase. In vivo neutralization of CD30L by soluble murine CD30-Immunoglobulin fusion protein before disease onset or even after disease onset significantly ameliorated the clinical symptoms. These results indicate that CD30L/CD30 signaling is critically involved in antigen-specific CD4 T cell responses at both the induction and effector phase, thus could be a new target molecule for the treatment of central nervous system autoimmunity.

CD30: from basic research to cancer therapy.

The FDA recently approved an agonistic anti-CD30 drug conjugate, Brentuximab vedotin, for the treatment for CD30-positive lymphomas. The potent clinical activity of Brentuximab vedotin in Hodgkin's lymphoma and anaplastic large-cell lymphoma was greeted with great enthusiasm by oncologists as it provided a new treatment modality for these diseases. In this review, we will describe how we obtained the hybridoma by pursuing a basic research experiment unrelated to CD30. I will also review what we know about the normal biological functions of CD30 that were studied primarily in murine models of disease but also in patients. The picture emerging is that one of the primary functions of CD30 is the control of memory cells providing costimulation and trafficking information or inducing apoptosis in a microenvironment and cytokine milieu-dependent manner.

CD30 is required for activation of a unique subset of interleukin-17A-producing γδ T cells in innate immunity against Mycobacterium bovis Bacillus Calmette-Guerin infection.

Interleukin-17A (IL-17A)-producing γδ T cells are known to be activated following Mycobacterium bovis bacillus Calmette-Guérin (BCG) infection. Here, we show that CD30, a member of the tumor necrosis factor (TNF) receptor superfamily, is important for activation of IL-17A-producing γδ T cells after BCG infection. Vγ1(-) Vγ4(-) γδ T cells preferentially expressing Vγ6/Vδ1 genes were identified as the major source of IL-17A in the peritoneal cavity during the early stage of BCG infection. The number of IL-17A-producing Vγ1(-) Vγ4(-) γδ T cells bearing Vγ6 increased in peritoneal exudate cells (PEC) of wild-type (WT) mice but not in those of CD30 knockout (KO) mice in response to BCG infection. Consistently, CD30 ligand (CD30L) or CD30 expression, predominantly by Vγ1(-) Vγ4(-) γδ T cells, was rapidly upregulated after BCG infection. Inhibition of CD30L/CD30 signaling by in vivo administration of a soluble CD30 and immunoglobulin fusion protein (CD30-Ig) severely impaired activation of IL-17A-producing Vγ1(-) Vγ4(-) γδ T cells in WT mice, while stimulating CD30L/CD30 signaling by in vivo administration of agonistic anti-CD30 monoclonal antibody (MAb) restored IL-17A production by Vγ1(-) Vγ4(-) γδ T cells in CD30L KO mice after BCG infection. These results suggest that CD30 signaling plays an important role in the activation of IL-17A-producing Vγ1(-) Vγ4(-) γδ T cells bearing Vγ6 at an early stage of BCG infection.

CD30 ligand/CD30 interaction is involved in pathogenesis of inflammatory bowel disease.

BACKGROUND AND AIMS: Although CD30 has long been recognized as an important marker in many lymphomas of diverse origin, and as an activation molecule on B and T cells, its primary function has remained obscure. Soluble CD30 (sCD30) is released from CD30 on the cell membrane by enzymatic cleavage. This study investigated the role of CD30 ligand (CD30L)/CD30 signals in intestinal mucosal damage. METHODS: Serum sCD30 in patients with ulcerative colitis (UC) and Crohn's disease (CD) and healthy individuals was assessed. A model of enteritis induced by anti-CD3 monoclonal antibody injection was studied in wild-type mice and in CD30L knockout mice. RESULTS: Increased sCD30 was observed in UC and CD patients, and the level was correlated with disease activity in both conditions. In a murine model of enteritis, histological intestinal damage was significantly reduced in CD30L knockout mice with decreased Th1 and Th17 cytokine levels. Moreover, blocking of CD30L/CD30 signals by CD30-immunoglobulin (CD30-Ig) resulted in reduced inflammation. CONCLUSIONS: Increased sCD30 expression correlating with disease activity suggested that CD30L/CD30 signals play an important role in pathogenesis of UC and CD. CD30L/CD30 pathway acts as an accelerator of enteritis in a murine disease model. Successful blockade of enteritis by CD30-Ig suggests a potential tool for future therapy of inflammatory bowel diseases.

Late intravenous immunoglobulin treatment in patients with Kawasaki disease.

OBJECTIVE: To evaluate the effectiveness of intravenous immunoglobulin (IVIG) treatment of Kawasaki disease ≥10 days after illness onset. METHODS: We selected patients initially treated with IVIG on days 11 to 20 in the database of the 20th nationwide survey in Japan. We then selected pair-matched control subjects of the same gender and age, who were initially treated with IVIG on days 4 to 8 with the same dose at the same institutions. We compared the proportions of additional treatments and coronary artery lesions (CALs) between the groups. We also compared fractional changes in various laboratory data before and after IVIG. Fractional change was defined as follows: (Y - X)/X, in which X represents the data before treatment and Y the data after treatment. RESULTS: One hundred fifty patients (75 pairs) were studied. The proportion of patients who received additional treatments among those given initial IVIG after days 10 was slightly lower than those treated earlier (12% vs 16%). The fractional changes in the white blood cell count, % neutrophils, and C-reactive protein were similar. Among all patients, the proportions of CALs during the convalescent phase were significantly higher in the late than in the early group (27% vs 1%). Among patients who had not developed CALs before initial treatment, the proportions with CALs during the acute phase were similar (8% vs 8%). CONCLUSIONS: IVIG treatment ≥10 days after illness onset achieves resolution of inflammation but was found to be insufficient for preventing CALs.

The central role of CD30L/CD30 interactions in allergic rhinitis pathogenesis in mice.

CD30 ligand (CD30L) plays an important role in the amplification and/or activation of effector CD4(+) T cells, irrespective of Th cell subset. To examine the role of CD30L in allergic rhinitis, we evaluated an OVA model of allergic rhinitis in CD30L knock out (KO) mice on a BALB/c background sensitized with OVA. Symptoms of allergic rhinitis such as eosinophil infiltration into the nasal mucosa were drastically diminished in OVA-sensitized CD30L KO mice following intranasal challenge with OVA. The levels of OVA-specific IgE in the sera and the Th2 response in nasopharynx-associated lymphoid tissues and cervical LNs of CD30L KO mice were significantly lower than those of WT mice following intranasal challenge with OVA. Intranasal administration of CD30-Ig during the effector phase with OVA significantly prevented the development of allergic rhinitis in WT mice. These results suggest that CD30L plays an important role in allergic rhinitis and that the inhibition of CD30L/CD30 signaling might be useful as a novel biological therapy for allergic rhinitis.

CD30 ligand is a target for a novel biological therapy against colitis associated with Th17 responses.

We have previously found that CD30 ligand (CD30L; CD153)/CD30 signaling executed by the T-T cell interaction plays a critical role in Th17 cell differentiation, at least partly via downregulation of IL-2 production. In this study, we investigated the role of CD30L in the development of colitis experimentally induced by dextran sulfate sodium (DSS), in which IL-17A is involved in the pathogenesis. CD30L(-/-) mice were resistant to both acute colitis induced by administration of 3 to ∼ 5% DSS and to chronic colitis induced by administration of 1.5% DSS on days 0-5, 10-15, and 20-25 as assessed by weight loss, survival rate, and histopathology. The levels of IFN-γ, IL-17A, and IL-10 were significantly lower but the IL-2 level higher in the lamina propria T lymphocytes of CD30L(-/-) mice than those in lamina propria T lymphocytes of wild-type mice after DSS administration. Soluble murine CD30-Ig fusion protein, which was capable of inhibiting Th17 cell differentiation in vitro, ameliorated both types of DSS-induced colitis in wild-type mice. Modulation of CD30L/CD30 signaling by soluble CD30 could be a novel biological therapy for inflammatory diseases associated with Th17 responses.

CD30 ligand/CD30 plays a critical role in Th17 differentiation in mice.

A CD30 ligand (CD30L; CD153) and its receptor, CD30, is a membrane-associated glycoprotein belonging to the TNF superfamily and TNFR superfamily. These were expressed preferentially by activated CD4(+)T cells. In this paper, we show that CD44(low)CD62(hi)CD4(+) T cells from CD30L(-/-) or CD30(-/-) mice exhibited impaired differentiation into Th17 cells but an increased ability to produce IL-2 after in vitro culture under Th17-polarizing conditions. Neutralization with IL-2 by anti-IL-2 mAb partly restored the ability of Th17 differentiation in CD30L(-/-) or CD30(-/-) T cells. Stimulation via CD30L by immobilized anti-CD30L mAb suppressed IL-2 production by CD30(-/-)CD4(+) T cells, indicating that the reverse signal to CD30L is responsible for downregulation of IL-2 production. In vivo Th17 differentiation of CD30L(-/-)CD4(+)CD45RB(high) T cells was also impaired after transfer into SCID mice, whereas CD30L(+/+)CD4(+)CD45RB(high) T cells normally differentiated into Th17 cells in CD30L(-/-) SCID mice. The results of these studies demonstrate that CD30L/CD30 signaling executed by the T-T cell interaction plays a critical role in Th17 cell differentiation, at least partly via downregulation of IL-2 production.

Percutaneous coronary intervention versus coronary artery bypass grafting for stenotic lesions after Kawasaki disease.

OBJECTIVE: To compare the long-term efficacy of percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) for stenotic lesions after Kawasaki disease. STUDY DESIGN: Questionnaires were sent to pediatricians in Japan in hospitals with 100 or more beds. A total of 1637 questionnaires were sent, and 1347 (82%) were returned. The primary endpoints of the study were the composite of deaths from any cause and the Q-wave myocardial infarction. The secondary endpoints were the repeat-revascularization for the target vessel. RESULTS: A total of 67 patients underwent PCI and 81 patients underwent CABG. Although the rates of the primary endpoints did not differ between the groups (hazard ratio 1.35 [95% confidence interval 0.29 to 6.32], P=.7), the rate of the secondary endpoints in the PCI group was significantly higher than that in the CABG group (hazard ratio 2.23 [95% confidence interval 1.04 to 4.76], P=.04). The benefit with CABG for the secondary endpoints was notable in patients younger than 12 years old, and who had ischemic change. CONCLUSIONS: PCI after Kawasaki disease resulted in a lower efficacy in comparison to CABG because of increased repeat-revascularization procedures.

Health-related quality of life in adolescents and young adults with a history of Kawasaki disease.

OBJECTIVE: To investigate the health-related quality of life (HRQOL) in adolescents and young adults with Kawasaki disease (KD). STUDY DESIGN: We conducted a cross-sectional observational study. Patients were eligible for this study when they were > or =16 years of age and had received a diagnosis of KD > or =5 years before the start of this study. The patients were divided in 3 groups according to their coronary status: normal, aneurysms, and giant aneurysms/ischemia. A self-administered questionnaire (Medical Outcome Study Short Form 36) was mailed to the patients to evaluate the HRQOL. RESULTS: Of 624 total questionnaires mailed, 377 were delivered, and 250 were returned. The response rates of the normal, aneurysm, and giant aneurysms/ischemia groups were 33%, 62%, and 72% of all eligible patients, respectively. All subscale scoress of HRQOL, except vitality and role-emotional (limitations in the usual role activities because of emotional problems) in patients with KD were significantly higher than scores from the national norms. CONCLUSIONS: The HRQOL of adolescents and young adults with a history of KD is favorable. However, long-term follow-up is necessary, because the general health perceptions of older patients tended to be lower.

Susceptibility of human T-cell leukemia virus type I-infected cells to humanized anti-CD30 monoclonal antibodies in vitro and in vivo.

Adult T-cell leukemia (ATL) is an aggressive malignancy of activated CD4(+) T cells associated with human T-cell leukemia virus type I (HTLV-I) infection. No conventional chemotherapy regimen has appeared successful in patients with ATL, thus establishing effective therapy is urgently required. In some cases, ATL tumor cells express CD30 on the cell surface, therefore, a therapy with mAb against CD30 would be beneficial. To investigate the effect of CD30-mediated therapy on ATL, we assessed SGN-30, a chimeric anti-CD30 mAb, and SGN-35, a monomethyl auristatin E-conjugated anti-CD30 mAb, in vitro and in vivo. Three HTLV-I-infected cell lines were co-cultured with SGN-30 or SGN-35, and the growth-inhibitory effects on the HTLV-I-infected cells were evaluated using an in vitro cell proliferation assay and cell cycle analysis. SGN-30 and SGN-35 showed growth-inhibitory activity against the HTLV-I-infected cell lines by apoptosis and/or cell growth arrest in vitro. To further investigate the effects of SGN-30 and SGN-35 on HTLV-I-infected cells in vivo, we used NOD/SCID mice subcutaneously engrafted with HTLV-I-infected cells. Both mAbs significantly inhibited the growth of HTLV-I-infected cell tumors in the NOD/SCID murine xenograft models. These data suggest that CD30-mediated therapy with SGN-30 or SGN-35 would be useful for patients with ATL.

A novel role of CD30L/CD30 signaling by T-T cell interaction in Th1 response against mycobacterial infection.

A CD30 ligand (CD30L, CD153) is a type II membrane-associated glycoprotein belonging to the TNF family. To illustrate the potential role of CD30L in CD4(+) Th1 cell responses, we investigated the fate of Ag-specific CD4(+) T cells in CD30L-deficient (CD30L(-/-)) mice after Mycobacterium bovis bacillus Calmette-Guérin (BCG) infection. The number of bacteria was significantly higher in organs of CD30L(-/-) mice than in wild-type (WT) mice 4 wk postinfection. The numbers of purified protein derivative- or Ag85B-specific-IFN-gamma-producing-CD4(+) T cells in spleen, lung, or peritoneal exudate cells were significantly fewer in CD30L(-/-) mice than in WT mice. During the infection, CD30L was expressed mainly by CD44(+)CD3(+)CD4(+) T cells but not by CD3(+)CD8(+) T cells, B cells, dendritic cells, or macrophages. Costimulation with agonistic anti-CD30 mAb or coculturing with CD30L-transfected P815 cells restored IFN-gamma production by CD4(+) T cells from BCG-infected CD30L(-/-) mice. Coculturing with CD30L(+/+)CD4(+) T cells from BCG-infected WT mice also restored the number of IFN-gamma(+)CD30L(-/-)CD4(+) T cells. When transferred into the CD30L(+/+) mice, Ag-specific donor CD30L(-/-) CD4(+) T cells capable of producing IFN-gamma were restored to the compared level seen in CD30L(+/+) CD4(+) T cells on day 10 after BCG infection. When naive CD30L(+/+) T cells were transferred into CD30L(-/-) mice, IFN-gamma-producing-CD4(+) Th1 cells of donor origin were normally generated following BCG infection, and IFN-gamma-producing-CD30L(-/-)CD4(+) Th1 cells of host origin were partly restored. These results suggest that CD30L/CD30 signaling executed by CD30(+) T-CD30L(+) T cell interaction partly play a critical role in augmentation of Th1 response capable of producing IFN-gamma against BCG infection.

A critical role of CD30 ligand/CD30 in controlling inflammatory bowel diseases in mice.

BACKGROUND & AIMS: A CD30-ligand (CD30L) is a 40-kilodalton, type II membrane-associated glycoprotein belonging to the tumor necrosis factor family. Serum levels of soluble CD30 increased in inflammatory bowel diseases (IBD), suggesting that CD30L/CD30 signaling is involved in the pathogenesis of IBD. In this study, we investigated the role of CD30L in oxazolone (OXA)- and trinitrobenzene sulfonic acid (TNBS)-induced colitis in CD30L knockout (KO) mice. METHODS: Colitis was induced by OXA or TNBS in CD30LKO mice with BALB/c or C57BL/6 background, respectively, and diverse clinical signs of the disease were evaluated. Cytokine production from lamina propria T cells of the colon was assessed by enzyme-linked immunosorbent assay. Anti-interleukin (IL)-4 monoclonal antibody (mAb) or agonistic anti-CD30 mAb was inoculated in mice with colitis induced by OXA or TNBS. RESULTS: CD30LKO mice were susceptible to OXA-induced colitis but resistant to TNBS-induced acute colitis. The levels of T helper cell 2 type cytokines such as IL-4 and IL-13 in the LP T cells were significantly higher, but the levels of interferon gamma were lower in OXA- or TNBS-treated CD30LKO mice than in wild-type mice. In vivo administration of agonistic anti-CD30 mAb ameliorated OXA-induced colitis but aggravated TNBS-induced colitis in CD30LKO mice. CONCLUSIONS: These results suggest that CD30L/CD30 signaling is involved in development of both OXA- and TNBS-induced colitis. Modulation of CD30L/CD30 signaling by mAb could be a novel biologic therapy for IBD.

Warfarin therapy for giant aneurysm prevents myocardial infarction in Kawasaki disease.

We retrospectively investigated the effect of warfarin therapy in improving the clinical outcome of Kawasaki disease (KD) patients with giant coronary aneurysms (GAs). We followed 2350 KD patients from 1973 to 2004. The GAs (> or =8 mm in diameter) were diagnosed by coronary angiography. Sixty-eight patients (54 males and 14 females) were retrospectively studied. Patients were divided into two groups. One group consisted of 19 patients with 33 branches treated with a combination of low-dose aspirin and warfarin (target international normalized ratio: 1.5 - 2.5 IU). The second group consisted of 49 patients with 102 branches treated with low-dose aspirin without warfarin. The incidence of myocardial infarction was significantly less in the combination therapy group than in patients treated with aspirin without warfarin (1 patient vs. 16 patients, p < 0.05). Sudden death occurred in seven patients taking aspirin without warfarin, but none of the patients receiving warfarin died. No major bleeding events occurred in either group. Combination therapy of warfarin with aspirin is associated with a decreased risk of myocardial infarction in KD patients with GAs.

Effect of revision of Japanese diagnostic criterion for fever in Kawasaki disease on treatment and cardiovascular outcome.

BACKGROUND: The aim of this study was to investigate the effect of a revision of the fever criterion for initial intravenous immunoglobulin (IVIG) treatment, and cardiovascular sequelae, in the new Japanese diagnostic criteria for Kawasaki disease. METHODS AND RESULTS: Patients who were reported in the 16th and 18th nationwide surveys in Japan were analyzed. New criteria group comprised patients who received the diagnosis of Kawasaki disease in the 18th nationwide survey (n=18,789). Old criteria group was comprised patients who received their diagnosis in the 16(th) nationwide survey (n=15,017). The difference between the new and old criteria for complete cases was only 1%. The proportion of patients who were treated with IVIG within 4 days of illness onset in the new criteria group was significantly lower than in the old criteria group (27.7% vs 30.7%). Multivariate logistic regression analysis identified criteria sex, age, recurrence, diagnosis, last day of initial IVIG and additional IVIG treatment as significant independent factors for cardiovascular sequelae. CONCLUSIONS: The guideline revision improves diagnostic sensitivity somewhat, but reflects the clinical reality of the disease that approximately 30% of patients are treated with IVIG within 4 days of illness onset.

Gastric emptying in diabetic patients by the (13)C-octanoic acid breath test: role of insulin in gastric motility.

BACKGROUND: Impairment of gastric emptying is well recognized in patients with diabetes mellitus (DM), especially long-standing insulin-dependent diabetes mellitus (IDDM). The aim of this study was to evaluate the cause of delayed gastric emptying in DM patients. METHODS: In 16 controls, 16 non-insulin-dependent diabetes mellitus (NIDDM) patients and 23 IDDM patients, gastric emptying was studied using the (13)C octanoic acid breath test. Breath samples were taken before a test meal labeled with 100 mg of (13)C octanoic acid, and at 15-min intervals over a 300-min period postprandially. RESULTS: In all DM patients, the gastric emptying coefficient was lower than that in the controls (P < 0.05), and lag time and half-emptying time were significantly longer (P < 0.05). Both NIDDM and IDDM patients showed delayed (13)CO(2) excretion compared with the controls, but IDDM patients showed more delayed gastric emptying than NIDDM patients (P < 0.05). There were no significant differences in sex, HbA1c level, or the rate of neuropathy between the two groups. CONCLUSIONS: IDDM patients showed delayed gastric emptying compared with NIDDM patients, and the (13)C octanoic acid breath test is useful for evaluating DM patients with delayed gastric emptying.