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J Infect Chemother ; 2022 Nov 13.
Article in English | MEDLINE | ID: covidwho-2105375


Coronavirus disease 2019 (COVID-19)-associated pulmonary aspergillosis (CAPA) is being increasingly recognized as a severe complication that contributes to poor prognoses among patients with COVID-19. However, little is known regarding the clinical course of CAPA with hematological malignancies, especially after allogeneic hematopoietic stem cell transplantation (HSCT). A 29-year-old woman was diagnosed with proven CAPA with an Aspergillus fumigatus identified by cultures of bronchoalveolar lavage and lung biopsy four years after haploidentical HSCT for acute myelogenous leukemia. She had been taking oral prednisolone for bronchiolitis obliterans syndrome that developed after HSCT. Although prolonged RT-PCR positivity for SARS-CoV-2 (133 days after the onset of COVID-19) without shedding of viable virus was observed, the COVID-19 was treated with favipiravir, remdesivir, dexamethasone, and enoxaparin. However, the CAPA did not respond to combination therapy, which included triazole (voriconazole, itraconazole, posaconazole) and echinocandin (caspofungin, micafungin), even though the Aspergillus fumigatus isolate was found to be susceptible to these agents in vitro. Nevertheless, a total of 16 weeks of liposomal amphotericin B (L-AMB) therapy led to a favorable response, and the patient was discharged from the hospital on day 213. This case provided essential experience of CAPA treated with L-AMB in a recipient with chronic respiratory disease after HSCT.

BMC Med ; 20(1): 342, 2022 09 27.
Article in English | MEDLINE | ID: covidwho-2053903


BACKGROUND: In vitro drug screening studies have indicated that camostat mesilate (FOY-305) may prevent SARS-CoV-2 infection into human airway epithelial cells. This study was conducted to investigate whether camostat mesilate is an effective treatment for SARS-CoV-2 infection (COVID-19). METHODS: This was a multicenter, double-blind, randomized, parallel-group, placebo-controlled study. Patients were enrolled if they were admitted to a hospital within 5 days of onset of COVID-19 symptoms or within 5 days of a positive test for asymptomatic patients. Severe cases (e.g., those requiring oxygenation/ventilation) were excluded. Patients were enrolled, randomized, and allocated to each group using an interactive web response system. Randomization was performed using a minimization method with the factors medical institution, age, and underlying diseases (chronic respiratory disease, chronic kidney disease, diabetes mellitus, hypertension, cardiovascular diseases, and obesity). The patients, investigators/subinvestigators, study coordinators, and other study personnel were blinded throughout the study. Patients were administered camostat mesilate (600 mg qid; four to eight times higher than the clinical doses in Japan) or placebo for up to 14 days. The primary efficacy endpoint was the time to the first two consecutive negative tests for SARS-CoV-2. RESULTS: One-hundred fifty-five patients were randomized to receive camostat mesilate (n = 78) or placebo (n = 77). The median time to the first test was 11.0 days (95% confidence interval [CI]: 9.0-12.0) in the camostat mesilate group and 11.0 days (95% CI: 10.0-13.0) in the placebo group. Conversion to negative viral status by day 14 was observed in 45 of 74 patients (60.8%) in the camostat mesilate group and 47 of 74 patients (63.5%) in the placebo group. The primary (Bayesian) and secondary (frequentist) analyses found no significant differences in the primary endpoint between the two groups. No additional safety concerns beyond those already known for camostat mesilate were identified. CONCLUSIONS: Camostat mesilate did not substantially reduce the time to viral clearance, based on upper airway viral loads, compared with placebo for treating patients with mild to moderate SARS-CoV-2 infection with or without symptoms. TRIAL REGISTRATION:, NCT04657497. Japan Registry for Clinical Trials, jRCT2031200198.

COVID-19 , Bayes Theorem , COVID-19/drug therapy , Double-Blind Method , Esters/adverse effects , Esters/therapeutic use , Guanidines/adverse effects , Guanidines/therapeutic use , Humans , SARS-CoV-2 , Treatment Outcome
Vaccine ; 40(38): 5631-5640, 2022 09 09.
Article in English | MEDLINE | ID: covidwho-1984213


BACKGROUND: Although several assays are used to measure anti-receptor-binding domain (RBD) antibodies induced after severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccination, the assays are not fully comparable in practice. This study evaluated the immunogenicity of the BNT162b2 mRNA vaccine in healthy adults using two immunoassays. METHODS: This prospective cohort study included SARS-CoV-2-naïve adults, predominantly healthcare workers, aged 20-64 years, who received two BNT162b2 vaccine doses between March and May 2021. Blood samples were collected before the first vaccination (S0), before the second vaccination (S1), 4 weeks after the second vaccination (S2), and 6 months after the second vaccination (S3). anti-RBD antibodies were measured using the Architect SARS-CoV-2 IgG II Quant (Abbott Laboratory) and Elecsys anti-SARS-CoV-2 S (Roche Diagnostics) assays. RESULTS: Among the 385 participants, the geometric mean antibody titers (GMTs) on the Architect assay (AU/mL) were 7.5, 693, 7007, and 1030 for S0, S1, S2, and S3, respectively. The corresponding GMTs on the Elecsys assay (U/mL) were 0.40, 24, 928, and 659, respectively. The GMT ratio (S3/S2) was 0.15 on the Architect and 0.71 on the Elecsys assay. The correlation between antibody titers measured with the two assays were strong at all time points after vaccination (Spearman's correlation coefficient: 0.74 to 0.86, P < 0.01 for all). GMT was significantly lower in the older age group after vaccination (P < 0.01), with no significant differences according to sex. Seroprotection (≥5458 AU/mL on the Architect assay and ≥ 753 U/mL on the Elecsys) at each time point was 0 %, 1 %, 67 %, and 1 % on the Architect assay and 0 %, 1 %, 62 %, and 43 % on the Elecsys, respectively. CONCLUSIONS: Two BNT162b2 vaccine doses resulted in adequate anti-RBD antibody response, which varied by age. As the two assays showed different kinetics, the results of single immunoassays should be interpreted with caution.

COVID-19 , Viral Vaccines , Adult , Aged , Antibodies, Viral , BNT162 Vaccine , COVID-19/prevention & control , Humans , Immunoassay , Japan , Prospective Studies , SARS-CoV-2 , Vaccination , Vaccines, Synthetic , mRNA Vaccines
J Infect Chemother ; 28(5): 616-622, 2022 May.
Article in English | MEDLINE | ID: covidwho-1649513


INTRODUCTION: Coronavirus disease 2019 (COVID-19) has greatly impacted medical care practices. Although the effects on infectious disease treatment and infection control, such as antimicrobial resistance, have been specified, very few reports exist on the specific effects of COVID-19. METHODS: We investigated the effects of COVID-19 on daily medical practices at a tertiary hospital in Japan by comparing the use of hand sanitizers, the detection of bacteria from blood cultures, and the amount dose of antibacterial drugs used for one year before (April 2019 to March 2020, fiscal year 2019.) and after COVID-19 admissions began (April 2020 to March 2021, fiscal year 2020). RESULTS: The use of hand sanitizers increased by 1.4-3 times during the year after COVID-19 admissions began; the incidence of methicillin-susceptible Staphylococcus aureus and all S. aureus detected in blood cultures reduced in all departments. No decrease was observed in the usage of all antibacterial drugs; rather, the usage of all antibacterial drugs tended to increase in all departments. Therefore, no significant change was observed in the detection of drug-resistant bacteria and the trends of antibacterial drug use based on the acceptance of COVID-19 patients. CONCLUSIONS: The prevalence of drug-resistant bacteria and trends of antibacterial drug use remained unchanged despite the increased use of hand sanitizers due to the admission of patients with COVID-19.

COVID-19 , Communicable Diseases , Methicillin-Resistant Staphylococcus aureus , Staphylococcal Infections , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , COVID-19/drug therapy , COVID-19/epidemiology , Communicable Diseases/drug therapy , Drug Resistance, Bacterial , Humans , Infection Control , Japan/epidemiology , Microbial Sensitivity Tests , Staphylococcal Infections/drug therapy , Staphylococcus aureus , Tertiary Care Centers
Microbiol Spectr ; 9(3): e0096521, 2021 12 22.
Article in English | MEDLINE | ID: covidwho-1596481


The prompt rollout of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine is facilitating population immunity, which is becoming more dominant than natural infection-mediated immunity. In the midst of coronavirus disease 2019 (COVID-19) vaccine deployment, understanding the epitope profiles of vaccine-elicited antibodies will be the first step in assessing the functionality of vaccine-induced immunity. In this study, the high-resolution linear epitope profiles of Pfizer-BioNTech COVID-19 mRNA vaccine recipients and COVID-19 patients were delineated by using microarrays mapped with overlapping peptides of the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. The vaccine-induced antibodies targeting the RBD had a broader distribution across the RBD than that induced by the natural infection. Half-maximal neutralization titers were measured in vitro by live virus neutralization assays. As a result, relatively lower neutralizability was observed in vaccine recipient sera, when normalized to a total anti-RBD IgG titer. However, mutation panel assays targeting the SARS-CoV-2 variants of concern have shown that the vaccine-induced epitope variety, rich in breadth, may grant resistance against future viral evolutionary escapes, serving as an advantage of vaccine-induced immunity. IMPORTANCE Establishing vaccine-based population immunity has been the key factor in attaining herd protection. Thanks to expedited worldwide research efforts, the potency of mRNA vaccines against the coronavirus disease 2019 (COVID-19) is now incontestable. The next debate is regarding the coverage of SARS-CoV-2 variants. In the midst of vaccine deployment, it is of importance to describe the similarities and differences between the immune responses of COVID-19 vaccine recipients and naturally infected individuals. In this study, we demonstrated that the antibody profiles of vaccine recipients are richer in variety, targeting a key protein of the invading virus, than those of naturally infected individuals. Vaccine-elicited antibodies included more nonneutralizing antibodies than infection-elicited antibodies, and their breadth in antibody variations suggested possible resilience against future SARS-CoV-2 variants. The antibody profile achieved by vaccinations in naive individuals provides important insight into the first step toward vaccine-based population immunity.

COVID-19 Vaccines/immunology , COVID-19/immunology , Epitope Mapping , Protein Binding , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/chemistry , /immunology , Antibodies, Neutralizing/immunology , Antibodies, Viral/chemistry , COVID-19/prevention & control , COVID-19 Vaccines/chemistry , Humans , Spike Glycoprotein, Coronavirus/immunology , Vaccination , Vaccines, Synthetic/immunology , /chemistry
Intern Med ; 60(23): 3827-3831, 2021.
Article in English | MEDLINE | ID: covidwho-1547076


A 73-year-old man previously treated with rituximab for his mucosa-associated lymphoid tissue lymphoma suffered a suboptimal humoral immune response against an acquired SARS-CoV-2 infection. A detailed serological description revealed discrepant antigen-specific humoral immune responses. The titer of spike-targeting, "viral-neutralizing" antibodies remained below the detection level, in contrast to the anti-nucleocapsid, "binding" antibody response, which was comparable in both magnitude and kinetics. Accordingly, viral neutralizability and clearance was delayed, leading to prolonged RNAemia and persistent pneumonia. The present case highlights the need to closely monitor this unique population of recipients of B-cell-targeted therapies for their neutralizing antibody responses against SARS-CoV-2.

COVID-19 , SARS-CoV-2 , Aged , Antibodies, Viral , Antibody Formation , Humans , Male , Rituximab/therapeutic use , Spike Glycoprotein, Coronavirus
Respir Investig ; 60(1): 154-157, 2022 Jan.
Article in English | MEDLINE | ID: covidwho-1458829


An internet questionnaire survey for investigating empirical antibiotic usage and bacterial superinfections in patients with coronavirus disease-2019 (COVID-19) in Japan was conducted among the chief physicians of respiratory disease departments of 715 Japanese Respiratory Society-certified hospitals using Google Forms between January 28, 2021 and February 28, 2021. Responses to the questionnaire survey were obtained from 198 of 715 hospitals (27.6%). The survey revealed that the complication incidences of community-acquired pneumonia; hospital-acquired pneumonia, including ventilator-associated pneumonia; and sepsis were 2.86, 5.59, and 0.99%, respectively, among patients with moderate/severe and critical COVID-19. Bacterial co-infection and secondary infection rarely affected patients with COVID-19 in Japan, and the isolated pathogens were not specific to these patients. Moreover, the anti-inflammatory effects of macrolides for COVID-19 were not observed in several studies. These results might be useful in clinical practice for COVID-19.

COVID-19 , Superinfection , Anti-Bacterial Agents/therapeutic use , Humans , Japan/epidemiology , SARS-CoV-2 , Superinfection/drug therapy , Surveys and Questionnaires
J Infect Public Health ; 14(9): 1263-1267, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1392421


BACKGROUND: Healthcare workers (HCWs) who manage patients with the novel coronavirus disease 2019 (COVID-19) are at an increased risk and fear of contracting the infection themselves. Hospitals must reduce both the physical and mental burden of HCWs on the front lines and ensure their safety. No prospective study has focused on the physical health complaints among HCWs engaged in the care of critically ill COVID-19 patients. This study aimed to evaluate the prevalence of various physical symptoms experienced by HCWs following their exposure to COVID-19 patients and investigate the association between occupation and the manifestation of physical symptoms among HCWs at a tertiary hospital in Japan during the current ongoing COVID-19 pandemic. METHODS: A twice-weekly questionnaire targeting HCWs who care for COVID-19 patients was performed at Osaka City University Hospital from April 30 to May 31, 2020. The demographic characteristics of the participants, frequency of exposure to at-risk care, and physical complaints were evaluated. RESULTS: Seventy-six HCWs participated in this study, of whom 24 (31.6%) were doctors, 43 (56.6%) were nurses, and 9 (11.8%) were technicians. The frequency of experiencing any physical symptom was 25.0% among HCWs. Exposure to at-risk care was significantly higher among nurses than among doctors (p < 0.001). Notably, the frequency of physical symptoms among the nurses was very high at 39.5% and obviously higher than that of physical symptoms among the doctors (p < 0.01). CONCLUSIONS: Our results indicate that hospital occupational health care must be provided to HCWs who are engaged in the care of COVID-19 patients and are thus highly exposed to at-risk care.

COVID-19 , Pandemics , Critical Illness , Health Personnel , Humans , Japan/epidemiology , Prospective Studies , SARS-CoV-2 , Tertiary Care Centers
J Infect Chemother ; 27(6): 911-914, 2021 Jun.
Article in English | MEDLINE | ID: covidwho-1101366


CAPA (COVID-19 associated pulmonary aspergillosis) is an important complication of COVID-19. It has been reported that the incidence of CAPA is as high as 19%-33% worldwide. However, its onset has not been reported in Japan. A 72-year-old Japanese man was diagnosed with COVID-19 and was transferred to our hospital due to deterioration of respiratory condition. Treatment with remdesivir, dexamethasone (DEXA), and antibiotics was performed under mechanical ventilation. Although the condition improved temporarily, a new shadow appeared in the lung, and Aspergillus fumigatus was cultured from sputum. The patient was clinically diagnosed with CAPA and treated with voriconazole. However, his progress deteriorated and he died. High-risk COVID-19 patients should be tested for Aspergillus to ensure early diagnosis of CAPA.

COVID-19 , Pulmonary Aspergillosis , Aged , Antifungal Agents/therapeutic use , COVID-19/complications , Fatal Outcome , Humans , Japan , Male , Pulmonary Aspergillosis/diagnosis , Pulmonary Aspergillosis/drug therapy , Respiration, Artificial
JPRN; 25/09/2020; TrialID: JPRN-jRCTs051200060
Clinical Trial Register | ICTRP | ID: ictrp-JPRN-jRCTs051200060



COVID-19 infection
COVID-19 infection


One or two tables of hydroxychloroquine sulfate 200mg once in a day, after meal, oral, for 7 days

Primary outcome:

Serious adverse events during the drug administration period


Inclusion criteria: 1) Male or female with age 18 or greater at the time of consent
(2) Is able to administrate the drug orally
(3) Is able to follow the schedule for medical exam defined in the research protocol
(4) Has provided written consent for participation

*The participants from age 18 to 20 have to provide written consents from both the subject and a legal guardian
*The participants are not limited to the workers who involve in infection control zone

Exclusion criteria: (1) History of COVID-19
(2) History of allergy for hydroxychroloquine
(3) weight less than 31kg
(4) Under medication with the drugs which are listed as contraindications for coadministration with HCQ
(5) History of retinopathy or macular degeneration
(6) Pregnant or planning pregnancy
(7) Breastfeeding
(8) Performance status of 2 or greater
(9) Advanced liver function abnormalities classified as grade C by the Child-Pugh criteria
(10) Renal disease classified CKD stage more than 4
(11) Allergy for quinine
(12) G-6-PD dificiency
(13) Porphyria
(14) scabies
(15) Under medication with gastrointestinal/neural/hematologic disorders
(16) Risk for ophthalmopathy
(17) Ventricular arrhythmia
(18) History of long QTc
(19) Deemed ineligible as determined by the principal investigator or a co-investigator