Exploration of the optimal GS-441524 trough concentration for treating COVID-19.

OBJECTIVES: Remdesivir (RDV) is the cornerstone for treating coronavirus disease 2019 (COVID-19). The active metabolite of RDV, GS-441524 (a nucleoside analogue), has high interindividual variability in plasma concentrations; however, its concentration-response relationship is still unclear. This study investigated the target GS-441524 trough concentration for symptom improvement in COVID-19 pneumonia. METHODS: This single-center, retrospective, observational study included Japanese patients (age ≥15 years) with COVID-19 pneumonia who were administered RDV for ≥3 days from May 2020 to August 2021. To determine the cut-off value of GS-441524 trough concentration on Day 3, achievement of the National Institute of Allergy and Infectious Disease Ordinal Scale (NIAID-OS) ≤3 after RDV administration was evaluated using the cumulative incidence function (CIF) with the Gray test and time-dependent receiver operating characteristic (ROC) analysis. Multivariate logistic regression analysis was performed to determine factors influencing GS-441524 target trough concentrations. RESULTS: The analysis comprised 59 patients. The CIF revealed that GS-441524 trough concentration ≥70 ng/mL was associated with the achievement of NIAID-OS ≤3 (P = 0.047), which was significant based on the time-dependent ROC analysis. Factors influencing GS-441524 trough concentration ≥70 ng/mL included a decrease in estimated glomerular filtration rate (eGFR) [adjusted odds ratio (aOR) = 0.96, 95% confidence interval (CI) 0.92-0.99; P = 0.027] and BMI ≥25 kg/m2 (aOR = 0.26, 95% CI 0.07-0.86; P = 0.031). CONCLUSION: GS-441524 trough concentration ≥70 ng/mL is a predictor of efficacy in COVID-19 pneumonia. The presence of lower eGFR or BMI ≥25 kg/m2 was associated with achieving GS-441524 trough concentration ≥70 ng/mL.

[Primary Lung Cancer Initially Suspected of Pulmonary Extranodal Marginal Zone Lymphoma of Mucosa Associated Lymphoid Tissue(MALT)].

Pulmonary mucosa-associated lymphoid tissue (MALT) lymphoma is associated with pre-existing infections or autoimmune disorders. We report a case of lung cancer initially suspected of MALT lymphoma. The patient was a 73-year-old woman. Complete screening examinations identified a tumor in the right middle lobe. Transbronchial lung biopsy revealed the infiltration of CD20+/CD79a+ lymphocytes invading the structure of the alveolus. MALT lymphoma was suspected, and the middle lobe was resected. The tumor was primarily invasive mucinous carcinoma, and lymphocytic infiltration was observed around the tumor. The monoclonal expansion of B cells and genetic and chromosomal abnormalities which are criteria for the diagnosis of MALT lymphoma were not demonstrated and the lesion was diagnosed as reactive lymphoid infiltrates. Marked lymphocytic infiltration regardless of neoplastic or reactive may suggest the presence of latent lesions.

Mycobacterium shinjukuense sp. nov., a slowly growing, non-chromogenic species isolated from human clinical specimens.

Seven isolates of a slowly growing, non-chromogenic Mycobacterium species were obtained from sputum and bronchial lavage fluid samples from elderly patients in different regions of Japan. These isolates were distinguished from related non-tuberculous species by colony morphology, positive results for Tween hydrolysis, catalase at 68 °C, nitrate reductase and pyrazinamidase and negative results for semi-quantitative catalase, urease and arylsulfatase. The mycolic acid pattern obtained by HPLC revealed a single cluster of late-eluting mycolic acids similar to but different from those of Mycobacterium malmoense ATCC 29571(T). The 16S rRNA gene, 16S-23S internal transcribed spacer (ITS), rpoB and hsp65 sequences were unique in comparison with those of other mycobacteria. Comparison of 16S rRNA gene sequences showed that the isolates were most closely related to Mycobacterium tuberculosis H37Rv(T) (21 base differences in 1508 bp; 98.6 % 16S rRNA gene sequence similarity). A representative strain, GTC 2738(T), showed 91.9 % rpoB sequence similarity with Mycobacterium marinum strain M, 95 % hsp65 sequence similarity with Mycobacterium kansasii CIP 104589(T) and 81.1 % 16S-23S ITS sequence similarity with Mycobacterium gordonae ATCC 14470(T). Phylogenetic analysis of concatenated sequences of the 16S rRNA, rpoB and hsp65 genes showed that strain GTC 2738(T) was located on a distinct clade adjacent to M. tuberculosis, M. ulcerans and M. marinum, with bootstrap values of 81 %. DNA-DNA hybridization demonstrated less than 70 % reassociation with type strains of genetically related species and supported the novel species status of the isolates. On the basis of this evidence, a novel species with the name Mycobacterium shinjukuense sp. nov. is proposed. The type strain, isolated from a sputum sample, is strain GTC 2738(T)( = JCM 14233(T) = CCUG 53584(T)).

Additive effect of pneumococcal vaccine and influenza vaccine on acute exacerbation in patients with chronic lung disease.

To determine the clinical efficacy of combined vaccination with 23-valent pneumococcal vaccine (PV) and influenza vaccine (IV) against pneumonia and acute exacerbation of chronic lung diseases (CLD), we conducted an open-label, randomized, controlled study among 167 adults with CLD over a 2-year period. Subjects were randomly assigned to a PV+IV group (n=87) or an IV group (n=80). The number of patients with CLD experiencing infectious acute exacerbation (P=0.022), but not pneumonia (P=0.284), was significantly lower in the PV+IV group compared with the IV group. When these subjects were divided into subgroups, an additive effect of PV with IV in preventing infectious acute exacerbation was significant only in patients with chronic obstructive pulmonary diseases (P=0.037). In patients with CLD, the Kaplan-Meier survival curves demonstrated a significant difference for infectious acute exacerbation (P=0.016) between the two groups. An additive effect of PV with IV on infectious acute exacerbation was found during the first year after vaccination (P=0.019), but not during the second year (P=0.342), and was associated with serotype-specific immune response in sera of these patients who used PV during the same period.

Clinical efficacy of the transdermal tulobuterol patch in patients with chronic obstructive pulmonary disease: a comparison with slow-release theophylline.

BACKGROUND: There is insufficient evidence for the efficacy of a transdermal tulobuterol patch (TP), although combination therapy with bronchodilators is recommended for chronic obstructive pulmonary disease (COPD). OBJECTIVE: A randomized, controlled crossover study was conducted to evaluate the clinical efficacy and safety of the TP in 16 patients with COPD. Slow-release theophylline was used as a control drug. METHODS: Following a 2-week run-in period, patients were randomly allocated to two groups by the envelope method; they then received the TP and theophylline for 4 weeks each by the crossover method. Pulmonary function tests, peripheral blood examination, and electrocardiography were performed before and after each treatment period. Patients recorded in diaries their symptom scores, numbers of administrations of inhaled beta(2) agonists, and presence/absence of adverse reactions. RESULTS: Patients receiving TP exhibited significant improvement in the number and ease of sputum expectoration and in cough frequency score and wheezing severity score compared with baseline (p<0.05); the corresponding improvement in patients receiving theophylline was non-significant. Assessment of quality of life by the St. George's Hospital Respiratory Questionnaire revealed that treatment with TP was associated with significant improvement in symptoms, impact, and total scores compared with baseline (p<0.05); theophylline gave only a non-significant improvement in total score. Neither drug caused significant changes in the results of physiological examinations or in pulse or blood pressure. There was no difference in safety between the treatments. CONCLUSION: Treatment of COPD patients with TP is more effective than with theophylline.

Comparative immune responses of patients with chronic pulmonary diseases during the 2-year period after pneumococcal vaccination.

Antibody responses to a 23-valent pneumococcal vaccine for Streptococcus pneumoniae serotypes 6B, 14, 19F, and 23F in 84 patients with chronic pulmonary diseases over a 2-year period after vaccination were examined by using a third-generation enzyme-linked immunosorbent assay. Of these patients, 28 (31%) were low responders who had developed increases of at least twofold in the levels of serotype-specific immunoglobulin G (IgG) in sera for none of the four serotypes at 1 month after vaccination. Although no specific clinical features of low responders were evident, their prevaccination levels of IgG for all serotypes were higher than those of responders. In responders, the levels of IgG specific for serotypes 14 and 23F in sera were greatly increased 1 month after vaccination and those specific for serotypes 6B and 19F were moderately increased. In contrast, no significant increases in the levels of IgG specific for serotypes 6B, 19F, and 23F in the low responders during the same period were found, but the levels of IgG specific for serotype 14 did increase. Although a rapid decline in the levels of IgG for all serotypes in responders between 1 month and 6 months after vaccination was found, the levels of IgG specific for serotypes 14 and 23F in sera remained higher than the prevaccination levels for at least 2 years after vaccination. These data suggest the need for the revaccination of responders but not low responders among patients with chronic pulmonary diseases. Revaccination as early as 3 years postvaccination is recommended for responders to increase the reduced levels of IgG in sera, especially those specific for the weak vaccine antigens.

Prevalence of previously undiagnosed airflow limitation in patients who underwent preoperative pulmonary function test.

Although being a rapidly expanding socioeconomical burden worldwide, chronic obstructive pulmonary disease (COPD) is often overlooked because of its insidious progression. Since spirometry is the primary tool for the diagnosis of COPD, physicians should be aware of the disease in any situation where interpreting spirometry. This study was to estimate the prevalence of undiagnosed COPD among patients who underwent spirometry as a preoperative evaluation for elective surgeries. Patients aged 40 years or older who completed routine spirometry as a preoperative evaluation for elective surgeries between January to December, 2000. Medical records were reviewed for medical history, clinical findings, smoking status, and discharge diagnoses for patients who demonstrated airflow limitation (AL), defined as FEV(1)/FVC<70% on spirometry. Of the 1031 patients who qualified for the study, 263 (26%) presented AL. Sixty-nine of these patients with AL (26%) had underlying conditions that could account for AL, such as asthma and previously diagnosed COPD. The remaining 194 patients with AL (74%) were suspected to have undiagnosed COPD, 90% of which was mild in severity. Only 30 (15%) of these patients appeared to be diagnosed have received a diagnosed as COPD by physician on this occasion. This study testifies that COPD is often unnoticed, and demonstrates that every spirometry, such as in preoperative evaluation, gives a clue to identify affected individuals, for which awareness of the disease is essential.

[Tuberculosis in elderly].

We compared patients with active tuberculosis treated at Kurume University Hospital between cases 65 years and above and below 65. The comparison included immunologic and clinical features. Anergy to tuberculin skin tests with purified protein derivative (PPD) was evident in 7% of patients under 65 and in 14% of those over 65. Older patients had fewer lymphocytes in peripheral blood and lower serum concentrations of interferon (IFN)-gamma than younger patients. Complications were more frequently seen in patients above 65, but the time required for negative conversion of sputum cultures did not differ by age. Adequacy of the regimen of chemotherapy and the sensitivity to anti-mycobacterial drugs were the most important determinants of the time for negative conversion of sputum culture. Major clinical problems of old tuberculosis patients were concurrent diseases, bed ridden states, necessity of nursing care, and poor performance status of patients.

Visualization of pulmonary arteriovenous malformation by three dimensional computed tomography: a case report.

Pulmonary arteriovenous malformation (PAVM) is an anomaly condition characterized by abnormal vascular communications between arteries and veins in the lungs. Hereby we describe a 60-year-old female with PAVM. Although the patient was asymptomatic, an abnormal round opacity was found on a chest X-ray film. Computed tomography (CT) of the lung disclosed nodules connected with enlarged vessels. Because PAVM was suspected, the patient was further evaluated by spiral CT coupled with three dimensional reconstruction of the images (3D-CT). As a result, PAVM was clearly visualized and invasive procedures such as angiography was not performed. The present case illustrates that 3D-CT is a diagnostic procedure of choice when PAVM is suspected.