Case Report: Kampo Medicine for Non-tuberculous Mycobacterium Pulmonary Disease.

Background: While the number of pulmonary tuberculosis cases has decreased, increase in non-tuberculous mycobacterium pulmonary disease (NTM-PD) is a global problem. Guideline-based therapy for NTM-PD sometimes causes complications that prevent treatment completion, and there are many cases of relapse even if the treatment can be completed. In addition to antibacterial treatment, care of host risk factors, such as aging, lean physique and immunosuppressive state, is also very important for the management of NTM-PD. In Japan, Kampo medicine, a traditional Japanese herbal formulation, used alone or in combination with standard multidrug therapy for NTM-PD, has been found to be effective for such cases. Case Presentation: A 77-year-old lean woman had been diagnosed with Mycobacterium intracellulare pulmonary infection 6 years earlier, and had received the standard multidrug treatment 5 years later at a former hospital due to worsening of her symptoms of cough, breathlessness and hemoptysis. However, the treatment was discontinued within a year due to the development of adverse events. She refused the guideline-based antibacterial treatment, and asked for Kampo medicine instead. Bukuryoshigyakuto was subsequently prescribed, which led to cough and sputum, especially hemosputum, being well controlled. With 3 years of Kampo medicine treatment, she gained weight and her hemosputum disappeared. High-resolution computed tomography images showed improvement in her lung condition, and her sputum smear culture was negative for acid-fast bacillus. Conclusion: Various kinds of Kampo medicines have been used empirically for NTM-PD in Japan. A literature review from 1992 to 2020 showed that hozais, in particular, seem to be key drugs for the treatment of host NTM-PD risk factors. Kampo medicines can contribute to comprehensive treatment for NTM-PD management that does not rely solely on antibacterial drugs.

[ANALYSIS OF BACKGROUNDS AND LEVEL OF UNDERSTANDING OF TREATMENT OF POOR ADHERENCE AND DROPOUT CASES ON SUBLINGUAL IMMUNOTHERAPY FOR JAPANESE CEDAR POLLINOSIS IN THE FIRST FOLLOW-UP YEAR].

BACKGROUND: We considered the factors of poor adherence to and dropout from sublingual immunotherapy (SLIT) by verifying patient backgrounds 1 year after start of treatment. METHODS: We recruited 38 patients who began SLIT between November 2014 and September 2015. We analyzed their attributes and level of understanding of the treatment, and conducted a self-reported survey on factors behind dropout cases and poor adherence cases. RESULTS: Four patients dropped out 1 year after start of treatment. Three left for reasons related to anxiety about side effects. There were five cases of poor adherence. There was no significant difference between good adherence, poor adherence, and dropout regarding level of understanding of the treatment (p=0.59). In the comparison between good and poor adherence groups, except four dropout patients, the adherence tended to be poor in patients with short duration of disease, smoking patients, and young patients. Continuous rate of SLIT achieved about 90%, suggesting relatively high level of adherence. CONCLUSION: It appears possible that anxiety related to side effects could be a factor affecting dropout from SLIT. There was no significant difference regarding level of understanding of the treatment. The adherence tended to be poor in patients with short duration of disease, smoking patients, and young patients.

Human eosinophils recognize endogenous danger signal crystalline uric acid and produce proinflammatory cytokines mediated by autocrine ATP.

Eosinophils are multifunctional leukocytes involved in various inflammatory processes, as well as tissue remodeling and immunoregulation. During inflammation and infection, injured cells and damaged tissues release uric acid and monosodium urate (MSU) crystals as important endogenous danger signals. Uric acid is also implicated in the immunogenic effects of an authentic Th2 adjuvant, aluminum hydroxide. Eosinophils often localize at sites of Th2-type chronic inflammation; therefore, we hypothesized that eosinophils may react to endogenous danger signals. We found that human eosinophils migrate toward soluble uric acid and MSU crystals in a gradient-dependent manner. Eosinophils incubated with MSU crystals, but not those incubated with uric acid solution, produced elevated levels of IL-6 and IL-8/CXCL8. Other cytokines and chemokines, including IL-1beta, IL-10, IL-17, IFN-gamma, CCL2, CCL3, CCL4, TNF-alpha, G-CSF, GM-CSF, fibroblast growth factor, vascular endothelial growth factor, and TGF-beta, were also produced by eosinophils incubated with MSU crystals. Eosinophils exposed to MSU crystals rapidly (i.e., within 1 min of exposure) released ATP into the extracellular milieu. Importantly, this autocrine ATP was necessary for eosinophils to produce cytokines in response to MSU crystals, and P2 nucleotide receptors, in particular P2Y(2), are likely involved in this positive feedback loop. Finally, at higher concentrations, MSU crystals promoted P2R-dependent release of a granule protein (eosinophil-derived neurotoxin) and cell death. Thus, human eosinophils may respond to particulate damage-associated endogenous danger signals. These responses by eosinophils to tissue damage may explain the self-perpetuating nature of chronic inflammation in certain human diseases, such as asthma.

Theophylline attenuates the neutrophil-dependent augmentation of eosinophil trans-basement membrane migration.

BACKGROUND: Recent evidence suggests that both neutrophilic and eosinophilic inflammation persist in the airways of patients with severe asthma. Neutrophils can secrete a variety of mediators which may augment the migration of eosinophils. We have reported that activated neutrophils augment the trans-basement membrane migration (TBM) of eosinophils in vitro. Theophylline has been shown to modulate some functions of both neutrophils and eosinophils. The objective of this study was to evaluate whether theophylline modulates the neutrophil-dependent augmentation of eosinophil TBM. METHODS: Eosinophils and neutrophils were isolated from peripheral blood collected from healthy donors and were then preincubated with either 0.1 mM theophylline or the medium control. The TBM of eosinophils in response to IL-8 was evaluated in the presence or absence of neutrophils by using the chambers with a Matrigel-coated Transwell insert. The generation of O(2)(-) was evaluated by the cytochrome c reduction assay. RESULTS: As previously reported, IL-8-stimulated neutrophils significantly augmented the TBM of eosinophils. Theophylline significantly attenuated the neutrophil-dependent augmentation of eosinophil TBM (p < 0.001) and did not directly modify the TBM of neutrophils in response to IL-8 or LTB4. Similarly, the LTB4-induced TBM of eosinophils was not modified by theophylline. Finally, theophylline attenuated the superoxide anion generation from IL-8-stimulated neutrophils on the Matrigel-coated plates. CONCLUSIONS: Our results show that theophylline can attenuate the neutrophil-dependent augmentation of eosinophil TBM. This effect is possibly attributable to the suppression of neutrophil activation provoked by the combination of basement membrane and IL-8.