A high α1-antitrypsin/interleukin-10 ratio predicts bacterial pneumonia in adults with community-acquired pneumonia: a prospective cohort study.

BACKGROUND: Current microbiological tests fail to identify the causative microorganism in more than half of all pneumonia cases. We explored biomarkers that could be used for differentiating between bacterial and viral pneumonia in patients with community-acquired pneumonia (CAP). METHODS: In this prospective cohort study conducted in Japan, data obtained from adult patients with bacterial pneumonia, including bacterial and viral coinfections (bacterial pneumonia [BP] group), and purely viral pneumonia (VP group) at diagnosis were analyzed using multivariate logistic regression analysis to identify predictors of bacterial pneumonia. Furthermore, a decision tree was developed using the predictors. RESULTS: A total of 210 patients were analyzed. The BP and VP groups comprised 108 and 18 patients, respectively. The other 84 patients had no identified causative microorganism. The two groups shared similar characteristics, including disease severity; however, a significant difference (p < 0.05) was observed between the two groups regarding sputum type; sputum volume score; neutrophil counts; and serum levels of interleukin (IL)-8, IL-10, and α1-antitrypsin (AAT). Sputum volume score (p < 0.001), IL-10 (p < 0.001), and AAT (p = 0.008) were ultimately identified as predictors of BP. The area under the curve for these three variables on the receiver operating characteristic (ROC) curve was 0.927 (95% confidence interval [CI]: 0.881-0.974). The ROC curve for sputum volume score and an AAT/IL-10 ratio showed a diagnostic cutoff of 1 + and 65, respectively. Logistic regression analysis using dichotomized variables at the cutoff values showed that the odds ratios for the diagnosis of BP were 10.4 (95% CI: 2.2-50.2) for sputum volume score (absence vs. presence) and 19.8 (95% CI: 4.7-83.2) for AAT/IL-10 ratio (< 65 vs. ≥ 65). CONCLUSIONS: Considering that obtaining a definitive etiologic diagnosis with the current testing methods is difficult and time consuming, a decision tree with two predictors, namely sputum volume and the AAT/IL-10 ratio, can be useful in predicting BP among patients diagnosed with CAP and facilitating the appropriate use of antibiotics. TRIAL REGISTRATION: UMIN000034673 registered on November 29, 2018.

Effect of long-term clarithromycin therapy on prevention of pneumonia in older adults: A randomized, controlled trial.

AIM: Pneumonia in older adults is increasingly recognized as a healthcare issue in countries with an aging population. Long-term macrolide therapy reduces exacerbations of chronic respiratory diseases, but its effects on the prevention of pneumonia have not been determined. METHODS: We carried out a randomized, controlled trial to test the effect of long-term clarithromycin therapy on the prevention of pneumonia among older adults. People aged ≥65 years who had recovered from pneumonia within the previous 3 months were recruited and randomly allocated to a long-term, low-dose clarithromycin (CAM) therapy group (n = 13) or a control group (n = 15). RESULTS: Both groups were followed up until recurrence of pneumonia. The median follow-up period was 251 days (95% CI 171-330) in the CAM group and 132 days (95% CI 67-196) in the control group (P = 0.627). The recurrence rate of pneumonia was two out of 13 (15%) in the CAM group and five out of 15 (33%) in the control group (P = 0.268). The median time to recurrence of pneumonia was 315 days (95% CI 249-382) in the CAM group and 260 days (95% CI 184-335) in the control group (P = 0.260). None of the differences between groups were statistically significant. CONCLUSIONS: No statistically significant suppressive effects of long-term, low-dose macrolide therapy on the development of pneumonia among older people were found in this small sample. A large-scale, randomized, controlled study is required. Geriatr Gerontol Int 2019; 19: 1006-1009.

Radon Therapy Is Very Promising as a Primary or an Adjuvant Treatment for Different Types of Cancers: 4 Case Reports.

We report on the application of radon inhalation therapy to patients with 4 types of cancer: colon, uterine, lung, and liver cell. The radon treatments were given to improve the efficacy of chemotherapy and were potent in all 4 cases. Marker values decreased and disease symptoms were alleviated. We include a lengthy discussion on the mechanism that may be responsible for the observed results. While employing the radon generator to treat the patient with hepatocellular carcinoma, we discovered that a concentration of 6 MBq/m3 was very effective, while 1 MBq/m3 was marginal. This implies different, and rather high, radon concentration thresholds for the treatment of different types of cancer. The evidence from these 4 cases suggests that radon inhalation may be beneficial against various cancer types as an important adjuvant therapy to conventional chemotherapy and for local high-dose radiotherapy, which would address the problem of distant metastasis. A previous case report on 2 patients with advanced breast cancer, who refused chemotherapy or radiotherapy, indicates that radon may be effective as a primary therapy for cancer. Clinical trials should be carried out to determine the best radon concentrations for treatment of other types of cancer, at different stages of progression.

Radon Therapy for Autoimmune Diseases Pemphigus and Diabetes: 2 Case Reports.

We report on the application of radon therapy to relieve the suffering of 2 patients with autoimmune diseases, one with pemphigus with an old myocardial infarction and diabetes mellitus and the other with type I diabetes. We include a lengthy discussion of the biological mechanisms that we believe produced the observed benefits. During the 6 to 9 months of the treatments, the marker values decreased to the upper limit of their normal ranges and the symptoms of the diseases were alleviated. Disorders of Th1/Th2 balance are implicated in the onset of many diseases, including autoimmune diseases. Our decision to give radon (222Rn) therapy to these patients was based on the results of 2 similar case reports and our earlier mouse experiments, which indicated that low doses of radiation induce regulatory T cells. Regulatory T cells regulate the T helper 1 cell and the T helper 2 cell balance. There are more than 80 different autoimmune diseases that are treated with anti-inflammatory agents or immune-suppressing drugs because the exact causes of these diseases and the cures are unknown. These and other case reports indicate that proper radon therapy is an effective treatment. We urge physicians to consider radon as a standard therapy for refractory autoimmune diseases.

The efficacy and safety of sitafloxacin and garenoxacin for the treatment of pneumonia in elderly patients: A randomized, multicenter, open-label trial.

Oral treatment for elderly outpatients with pneumonia is becoming increasingly important in this super-aged society from the perspective of cost-effectiveness and limited hospital capacities. We evaluated the efficacy and safety of two oral respiratory quinolones, sitafloxacin and garenoxacin, in elderly patients with pneumonia. This randomized, multicenter, open-label trial was conducted among patients aged ≥65 years with clinically and radiographically confirmed pneumonia in Japan. Patients were randomly assigned (1:1) to receive either sitafloxacin (100 mg/day) or garenoxacin (400 mg/day) for 3-10 days. The primary efficacy endpoint was the clinical cure rate at 5-10 days after the end of treatment. From December 2013 to November 2017, we enrolled 120 patients at 11 hospitals and randomly assigned 59 patients to the sitafloxacin group (1 patient withdrew) and 61 patients to the garenoxacin group. These included 30 patients with nursing and healthcare-associated pneumonia (NHCAP) (18 receiving sitafloxacin, 12 receiving garenoxacin) and 37 patients with aspiration pneumonia (16 receiving sitafloxacin, 21 receiving garenoxacin). The clinical cure rates in the sitafloxacin and garenoxacin groups were 88.5% (95% confidence interval: 76.6-95.6) and 88.9% (95% confidence interval: 77.4-95.8), respectively. No significant differences were observed in the incidence rates of drug-related adverse events between the sitafloxacin (20.7%; 12/58 patients) and garenoxacin (27.9%; 17/61 patients) groups. The most common adverse event was hepatic dysfunction, which occurred in seven patients in each group. We conclude that sitafloxacin and garenoxacin are comparably effective and safe for the treatment of pneumonia, including NHCAP and aspiration pneumonia, in elderly patients.

Recovery From Rheumatoid Arthritis Following 15 Months of Therapy With Low Doses of Ionizing Radiation: A Case Report.

Rheumatoid arthritis (RA) is an inflammatory autoimmune disease that occurs commonly in old people. Hot spring radon therapy is widely practiced in Central Europe and Japan for relief from the painful symptoms. The usual duration of a spa treatment is a week or two, and the relief is temporary. This article reports on the near-complete recovery of a patient who had been suffering from RA for 10 years. The patient received 15 months of low-dose radon and γ-radiation therapy in a room that reproduced the conditions of a radon spa. The daily 40-minute exposure in the therapy room was supplemented by ten 6-minute radio-nebulizer treatments. The inflammation markers C-reactive protein and matrix metalloproteinase 3 declined strongly to the normal level of 0.07 mg/dL and the near-normal level of 48.9 ng/mL, respectively. After the patient's return to good health, the frequency of the visits was reduced to twice each month. The patient's protection systems appear to have adapted to stimulated conditions, sufficiently to sustain the recovery from RA. Such a long-term course of treatments and follow-up maintenance could be carried out in any hospital that has these low-dose radiation therapy rooms. The therapy could be scheduled to suit patient availability.

Present and Future Prospects of Radiation Therapy Using α-Emitting Nuclides.

Therapy with α-radiation has issues associated with internal exposure; its clinical use has been avoided. However, phase III clinical tests of the α-emitting nuclide 223Ra on patients with cancer have been conducted, and results were reported in 2011 to 2012. Since then, research has being carried out on targeted internal therapy by introducing α-emitting nuclides directly into the cancers. For many decades, nontargeted radon therapy has been carried out and is controversial because its mechanism of action is stimulation. The low-level radiation sends powerful signals to upregulate many biological protection systems, which protect against the effects of radiogenic and nonradiogenic toxins. These vital systems prevent, repair, and remove DNA and other biomolecular damage being produced endogenously at a very high rate by the very abundant reactive oxygen species associated with aerobic metabolism. Stimulation of protection systems results in beneficial effects, including a lower risk of cancer. This article reports the results of treatments on 4 patients with cancer and reviews the clinical use of α-radiation from 223Ra and radon. It discusses the prospect of using the novel 225Ac-prostate-specific membrane antigen ligand-617 ligand as a therapeutic agent for prostate cancer. It presents a new treatment system that we developed, α-Radiorespiro-Rn, which seems to be extremely effective in treating cancer.

Treatment of Cancer and Inflammation With Low-Dose Ionizing Radiation: Three Case Reports.

There is considerable evidence from experimental studies in animals, as well as from clinical reports, that low-dose radiation hormesis is effective for the treatment of cancer and ulcerative colitis. In this study, we present 3 case reports that support the clinical efficacy of low-dose radiation hormesis in patients with these diseases. First, a patient with prostate cancer who had undergone surgical resection showed a subsequent increase in prostate-specific antigen (PSA). His PSA value started decreasing immediately after the start of repeated low-dose X-ray irradiation treatment and remained low thereafter. Second, a patient with prostate cancer with bone metastasis was treated with repeated low-dose X-ray irradiation. His PSA level decreased to nearly normal within 3 months after starting the treatment and remained at the low level after the end of hormesis treatment. His bone metastasis almost completely disappeared. Third, a patient with ulcerative colitis showed a slow initial response to repeated low-dose irradiation treatment using various modalities, including drinking radon-containing water, but within 8 months, his swelling and bleeding had completely disappeared. After 1 year, the number of bowel movements had become normal. Interest in the use of radiation hormesis in clinical practice is increasing, and we hope that these case reports will encourage further clinical investigations.

Studies of non-nucleoside HIV-1 reverse transcriptase inhibitors. Part 2: synthesis and structure-activity relationships of 2-cyano and 2-hydroxy thiazolidenebenzenesulfonamide derivatives.

In a previous study, we described the structure-activity relationships (SARs) for a series of thiazolidenebenzenesulfonamide derivatives. These compounds were found to be highly potent inhibitors of the wild type (WT) and Y181C mutant reverse transcriptases (RTs) and modest inhibitors of K103N RT. These molecules are thus considered to be a novel class of non-nucleoside HIV-1 RT inhibitors (NNRTIs). In this paper, we have examined the effects of substituents on both the thiazolidene and benzenesulfonamide moieties. Introduction of a 2-cyanophenyl ring into these moieties significantly enhanced anti-HIV-1 activity, whereas a 2-hydroxyphenyl group endowed potent activity against RTs, including K103N and Y181C mutants. Among the series of molecules examined, 10l and 18b (YM-228855), combinations of 2-cyanophenyl and 4-methyl-5-isopropylthiazole moieties, showed extremely potent anti-HIV-1 activity. The EC50 values of 101 and 18b were 0.0017 and 0.0018 microM, respectively. These values were lower than that of efavirenz (3). Compound 11g (YM-215389), a combination of 2-hydroxyphenyl and 4-chloro-5-isopropylthiazole moieties, proved to be the most active against both K103N and Y181C RTs with IC50 values of 0.043 and 0.013 microM, respectively.

Studies of nonnucleoside HIV-1 reverse transcriptase inhibitors. Part 1: Design and synthesis of thiazolidenebenzenesulfonamides.

A random high-throughput screening (HTS) program to discover novel nonnucleoside reverse transcriptase inhibitors (NNRTIs) has been carried out with MT-4 cells against a nevirapine-resistant virus, HIV-1(IIIB-R). The primary hit, a thiazolidenebenzenesulfonamide derivative, possessed good activity. A systematic modification program examining various substituents at the 3-, 4-, and 5-positions on the thiazole ring afforded compounds with enhanced anti-HIV-1 and reverse transcriptase (RT) inhibitory activities. These results confirm the important role of the substituents at these positions and the thiazolidenebenzenesulfonamide motif as a valuable lead series for the next generation NNRTIs.

Clinical evaluation methods for new antimicrobial agents to treat respiratory infections: Report of the Committee for the Respiratory System, Japan Society of Chemotherapy.

The present report constitutes an attempt to improve and modify the existing clinical evaluation method for new antimicrobial agents to treat respiratory infections. One year ago, a general guideline on the clinical evaluation of antimicrobial agents to treat respiratory infections was drafted in Japanese, leaving scope for critical discussion, and this has been translated into English, as there were no major changes. In this report, respiratory infections have been discussed under the headings "acute respiratory tract infection" and pneumonia and acute exacerbation of chronic pulmonary diseases. Standardized criteria were set for the assessment of severity of infection and effectiveness of the antimicrobial agent in question. Severity was evaluated on the basis of a combined assessment of the severity of infection and severity of the clinical condition of the patients. Clinical effectiveness of the antimicrobial agent used was evaluated on the basis of clinical outcome as well as microbiological outcome of the trial. Body temperature, local pain, cough, change in sputum quality, peripheral white blood cell count, C-reactive protein level, and chest radiograph were used as the parameters for the evaluation. To maintain the quality of specimens to be examined, Geckler's classification of specimens was used. This report was constructed based on the analysis of large amounts of material collected over the years, incorporating internal and external factors concerning the present evaluation methods. The newly suggested standardized criteria for clinical evaluation of the new antimicrobial drugs are expected to be practiced properly hereupon and subjected to further improvement if necessary.

Diagnosis of Measles Pneumonia from Bronchoalveolar Lavage Fluid by Reverse-Transcriptase Polymerase Chain Reaction: Case Report.

A 24-year-old male contracted measles during treatment with prednisolone for bronchial asthma and eosinophilic pneumonia. Five days after the appearance of skin eruptions, infiltration shadows were detected in the hilum of the left lung on a chest X-ray and a chest computed tomography revealed diffuse macular and infiltration shadows in both lungs and in the left S6 segment, respectively. Pneumonia complicating measles may be caused by either the measles virus itself or by a secondary bacterial infection. Since this patient had been treated with prednisolone, pneumonia caused by a pathogen other than bacteria, or recurrence of eosinophilic pneumonia were suspected, and bronchoalveolar lavage was performed. Culture of the bronchoalveolar lavage fluid (BALF) was negative for bacteria, acid-fast bacilli, and mycetes, and polymerase chain reaction (PCR) analysis did not detect cytomegalovirus, but reverse transcriptase PCR did detect the measles virus. There were increased lymphocytes in the BALF with a significantly reduced CD4/CD8 ratio. Histological findings revealed alveolitis. Based on conventional diagnostic criteria, pneumonia due to the measles virus was confirmed. Since the criteria of pneumonia due to measles virus includes histological, serological and bacteriological studies which require an extended period of time, RT-PCR using BALF may be useful for the rapid diagnosis of measles pneumonia.

Clinical and Immunological Evaluation of Infection in Patients on Hemodialysis.

Infection is a major complication associated with increased morbidity and mortality in patients on hemodialysis. We analyzed the incidence and type of infection occurring in 4841 patients on hemodialysis between 1986 and 1993 in our hospital and 11 other hemodialysis centers. Infection was noted in 193 patients (4.98 infections/1000 patients/year). Pneumonia (n=71) and bacteremia (n=24) were the 2 most common infections, followed by tuberculosis (n=14), herpes zoster infections (n=12) and infections at the vascular access site (n=12). The most commonly isolated organism in pneumonia, bacteremia and vascular access site infections wasStaphylococcus aureus. Analysis of the prognosis of patients with pneumonia showed a mortality rate of 50% in patients greater than 60 years old, which was significantly higher than that of younger patients (6.7%,P<0.01), whereas the mortality rate in patients with bacteremia was not different between the 2 age groups (60.0% vs. 57.9%, respectively). We also analyzed changes in immunological function and nutritional status in 16 patients on hemodialysis and 21 healthy control subjects. Although the phagocytic and bactericidal activities of neutrophils and monocytes were not different between the groups, superoxide production, the percentage of natural killer cells and the degree of blastoid transformation with phytohemagglutinin stimulation were significantly lower in hemodialysis patients. Low levels of Niderman's index and serum albumin and transferrin indicated poor nutritional status in these patients. Furthermore, the degree of Niderman's index and serum albumin significantly correlated with impairment of immunological function, such as reduced blastoid transformation and the number of lymphocytes. Our results suggest that analysis of the patterns of infection in patients on hemodialysis should provide better management and that improvement of malnutrition may ameliorate impaired immunity in hemodialysis patients.