Rebound mortality rate of Legionella pneumonia in Japan.

Legionella pneumonia is a fatal disease caused by Legionella pneumophila, a bacterium belonging to the genus Legionella. The incidence of this disease has been increasing since 2005 and has continued to increase following the COVID-19 pandemic in Japan. Furthermore, Legionella pneumonia mortality rates have increased slightly since the pandemic due to some plausible reasons. The increased proportion of older patients with legionellosis might affect it because advanced age is a major risk factor for disease mortality. Additionally, physicians were focused on COVID-19 while examining febrile patients; therefore, they might have missed the early diagnosis of other respiratory infections, including Legionella pneumonia.

A narrative review on drug development for the management of antimicrobial- resistant infection crisis in Japan: the past, present, and future.

INTRODUCTION: Antimicrobial resistance (AMR) is a major threat to global health requiring continuous development of new antimicrobial agents. Antimicrobial research and development (R&D) should be promoted in the pharmaceutical industry and academia to ensure sustainable patient access to new treatment options and reduce the global AMR burden. AREAS COVERED: This review describes the historical challenges in novel antimicrobial drug development in Japan, current national efforts to promote the development, and proposals to effectively manage future AMR pandemics. Literature searches were performed in the PubMed database (from inception to January 2022). EXPERT OPINION: R&D activities in the antimicrobial space in Japan have been insufficient due to multiple factors, including unfavorable cost-profit balance and differences in regulatory requirements between Japan and Western countries. However, the situation is improving with the implementation of the Japanese AMR action plan, drug R&D programs led by the Japan Agency for Medical Research and Development, and efforts of regulatory agencies in the United States, Europe, and Japan in aligning and expediting the clinical development process. Further actions during the interpandemic period will strengthen antimicrobial R&D, including international and interdisciplinary collaboration, continued funding and investment with the national government's leadership, and fostering of new-generation academic research leaders.PLAINLANGUAGE SUMMARYEvery year, many people suffer and die of antimicrobial-resistant infections worldwide. New treatment options are required to tackle antimicrobial-resistant infections; however, pharmaceutical companies have not been very active in developing antimicrobial agents in the last two decades. This was mainly due to the difficulty in discovering new and effective compounds and insufficient funds being spent on drug discovery. In addition, differences in drug development requirements between the United States (US), Europe, and Japan have made it difficult for Japanese pharmaceutical companies to develop antimicrobial agents that can be used in all regions in a timely manner. In the last decade, several measures have been taken to re-activate antimicrobial research and development in the pharmaceutical industry, as well as in academia, in Japan. These measures include a national action plan to combat antimicrobial-resistant infections and research support programs led by the Japan Agency for Medical Research and Development. Regulatory authorities in the US, Europe, and Japan have initiated efforts to expedite the development of drugs to treat infections. Moreover, pathways for accelerated regulatory review have been established to reduce the time taken for new drugs to be approved, and this has already been applied to several new anti-infective drugs. To combat the coronavirus disease 2019 (COVID-19) pandemic, the development of novel vaccines and antiviral drugs has been accelerated with unprecedented speed. Additional actions, such as international research collaboration programs and investment in new antimicrobial development, may help promote antimicrobial research and development activities in Japan.

Is the information on infection prevention measures against COVID-19 reaching the target audience? A cross-sectional survey among eating and drinking services in Tokyo, Japan.

Objectives: The study aims to evaluate information gathering behaviour (IGB) and its effectiveness in eating and drinking services for infection control during COVID-19. Study design: A cross-sectional survey using anonymous self-administered questionnaires was conducted in October 2021. Participants were asked what IGB they use to obtain infection control measures, to what extent they understand the measures (and, if they do not understand them, what inhibits their comprehension), and which IGBs they do not currently use and why. Methods: The sample included 957 eating and drinking services in Ota City, Tokyo. The response rate was 14.5%. Binomial logistic regression was used to analyse the factors associated with the baseline characteristics using Stata v.17.0. Results: The highest proportion of respondents used television (88.0%); another large proportion (38.9%) used guidelines. Regarding difficulty in understanding the retrieved information, 'difficulty in coming up with specific actions' had the highest ratio for every IGB. Regarding reasons for not currently using IGB, 'it takes too much time to extract the necessary information' showed the highest ratios of all IGBs. Individuals over 60 years had a negative relationship with the use of guidelines and the Internet. Participants also advised that they did not use time-consuming guidelines. Conclusion: Current information dissemination methods for information on COVID-19 infection control may not successfully convey information or reach their target populations. This study indicates the need for specific expressions and layouts to effectively share information on COVID-19. Also, special means of communication must be established to cater to individuals aged 60 and above.

Performance evaluation of Novaplex SARS-CoV-2 variants assay kit series for SARS-CoV-2 detection using single nucleotide polymorphisms.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants have received increasing attention globally because of their increased transmissibility and potential to escape immunity. Although whole-genome sequencing is the gold standard method for SARS-CoV-2 mutation detection and lineage determination, it is costly and time-consuming. However, SARS-CoV-2 variants can be identified based on select variant-specific single nucleotide polymorphisms (SNPs) in the spike protein-encoding gene (S). This study validated and compared the limit of detection (LOD) of L452R, N501Y, HV69/70 del and E484K as variant-specific SNPs of the S gene and RdRP as a SARS-CoV-2-specific gene, using the Novaplex SARS-CoV-2 variants assay kit series. For three SARS-CoV-2 lineages (B.1.617.2, B.1.1.7 and R.1), one strain per lineage was used. Variant-specific SNPs of the S gene were analysed using the Novaplex SARS-CoV-2 variants I assay and Novaplex SARS-CoV-2 variants II assay kits. Validation confirmed the LODs of the variant kits. The LOD for each target variant-specific SNP and RdRP was five RNA copies per reaction. The Novaplex SARS-CoV-2 variants assay kit series performs well and the LOD for SARS-CoV-2 detection and variant-specific SNP detection are consistent. The kits are suitable for use as routine laboratory tests for SARS-CoV-2 and variant-specific SNP detection in a single step, saving time and labour.

Development of a Fully Automated Desktop Analyzer and Ultrahigh Sensitivity Digital Immunoassay for SARS-CoV-2 Nucleocapsid Antigen Detection.

BACKGROUND: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak has had a significant impact on public health and the global economy. Several diagnostic tools are available for the detection of infectious diseases, with reverse transcription-polymerase chain reaction (RT-PCR) testing specifically recommended for viral RNA detection. However, this diagnostic method is costly, complex, and time-consuming. Although it does not have sufficient sensitivity, antigen detection by an immunoassay is an inexpensive and simpler alternative to RT-PCR. Here, we developed an ultrahigh sensitivity digital immunoassay (d-IA) for detecting SARS-CoV-2 nucleocapsid (N) protein as antigens using a fully automated desktop analyzer based on a digital enzyme-linked immunosorbent assay. METHODS: We developed a fully automated d-IA desktop analyzer and measured the viral N protein as an antigen in nasopharyngeal (NP) swabs from patients with coronavirus disease. We studied nasopharyngeal swabs of 159 and 88 patients who were RT-PCR-negative and RT-PCR-positive, respectively. RESULTS: The limit of detection of SARS-CoV-2 d-IA was 0.0043 pg/mL of N protein. The cutoff value was 0.029 pg/mL, with a negative RT-PCR distribution. The sensitivity of RT-PCR-positive specimens was estimated to be 94.3% (83/88). The assay time was 28 min. CONCLUSIONS: Our d-IA system, which includes a novel fully automated desktop analyzer, enabled detection of the SARS-CoV-2 N-protein with a comparable sensitivity to RT-PCR within 30 min. Thus, d-IA shows potential for SARS-CoV-2 detection across multiple diagnostic centers including small clinics, hospitals, airport quarantines, and clinical laboratories.

Usefulness of the Legionella Score for differentiating from COVID-19 pneumonia to legionella pneumonia.

Legionella pneumophila is a major causative pathogen of community-acquired pneumonia (CAP), but recently the novel coronavirus disease 2019 (COVID-19) became the most common causative pathogen of CAP. Because L. pneumophila CAP is clinically distinct from bacterial CAPs, the Japan Society for Chemotherapy (JSC) developed a simple scoring system, the Legionella Score, using six parameters for the presumptive diagnosis of L. pneumophila pneumonia. We investigated the clinical and laboratory differences of L. pneumophila CAP and COVID-19 CAP and validated the Legionella Score in both CAP groups. We analyzed 102 patients with L. pneumophila CAP and 956 patients with COVID-19 CAP. Dyspnea and psychiatric symptoms were more frequently observed and cough was less frequently observed in patients with L. pneumophila CAP than those with COVID-19 CAP. Loss of taste and anosmia were observed in patients with COVID-19 CAP but not observed in those with L. pneumophila CAP. C-reactive protein and lactate dehydrogenase levels in L. pneumophila CAP group were significantly higher than in the COVID-19 CAP group. In contrast, sodium level in the L. pneumophila CAP group was significantly lower than in the COVID-19 CAP group. The median Legionella Score was significantly higher in the L. pneumophila CAP group than the COVID-19 CAP group (score 4 vs 2, p < 0.001). Our results demonstrated that the JSC Legionella Score had good diagnostic ability during the COVID-19 pandemic. However, physicians should consider COVID-19 CAP when loss of taste and/or anosmia are observed regardless of the Legionella Score.

Choice of SARS-CoV-2 diagnostic test: challenges and key considerations for the future.

A plethora of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) diagnostic tests are available, each with different performance specifications, detection methods, and targets. This narrative review aims to summarize the diagnostic technologies available and how they are best selected to tackle SARS-CoV-2 infection as the pandemic evolves. Seven key settings have been identified where diagnostic tests are being deployed: symptomatic individuals presenting for diagnostic testing and/or treatment of COVID-19 symptoms; asymptomatic individuals accessing healthcare for planned non-COVID-19-related reasons; patients needing to access emergency care (symptom status unknown); patients being discharged from healthcare following hospitalization for COVID-19; healthy individuals in both single event settings (e.g. airports, restaurants, hotels, concerts, and sporting events) and repeat access settings (e.g. workplaces, schools, and universities); and vaccinated individuals. While molecular diagnostics remain central to SARS-CoV-2 testing strategies, we have offered some discussion on the considerations for when other tools and technologies may be useful, when centralized/point-of-care testing is appropriate, and how the various additional diagnostics can be deployed in differently resourced settings. As the pandemic evolves, molecular testing remains important for definitive diagnosis, but increasingly widespread point-of-care testing is essential to the re-opening of society.

IgG Antibodies, SARS-CoV-2 Load, and Prognostic Indicators in Patients with Severe and Mild COVID-19 in Japan.

We assessed the association of severity of coronavirus disease 2019 (COVID-19) with acute respiratory syndrome coronavirus 2 (SARS-CoV-2) load, IgG antibody level, and prognostic indicators.Twenty-one patients hospitalized with COVID-19 were classified as having severe or mild disease on the basis of average respiratory rate during hospitalization (severe: ≥22 breaths/min; mild: <22 breaths/min). Viral load in nasopharyngeal samples, blood levels of C-reactive protein (CRP), lymphocytes, and D-dimer on admission and plasma immunoglobulin G (IgG) index on Day 7±2 after symptom onset were compared in relation to disease severity. Seven patients had severe disease and 14 had mild disease. Those with severe disease had a significantly higher IgG index (median: 3.75 vs 0.56, p=0.01) and CRP (median: 8.6 vs 1.0 mg/dL, p<0.001) and D-dimer levels (median: 1.65 vs 0.75 µg/mL; p=0.002) and a significantly lower lymphocyte count (median: 1,176 vs 666 cells/µL, p=0.005) and viral load (median: 8.7×106 vs 2.3×104 copies/mL, p=0.005). Furthermore, time from symptom onset to virus disappearance was significantly longer in severe patients (median: 24 vs 17 days, p=0.03). A high IgG index in the early phase of the disease was associated with severe disease and might serve as a prognostic indicator.

Proactive Engagement of the Expert Meeting in Managing the Early Phase of the COVID-19 Epidemic, Japan, February-June 2020.

To deal with the risk of emerging diseases with many unknowns, close and timely collaboration and communication between science experts and policymakers are crucial to developing and implementing an effective science-based intervention strategy. The Expert Meeting, an ad hoc medical advisory body, was established in February 2020 to advise Japan's COVID-19 Response Headquarters. The group played an important role in the policymaking process, promoting timely situation awareness and developing science-based proposals on interventions that were promptly reflected in government actions. However, this expert group may have been overly proactive in taking on the government's role in crisis management. For the next stage of managing the coronavirus disease pandemic and future pandemics, the respective roles of the government and its advisory bodies need to be clearly defined. Leadership and strategic risk communication by the government are key.

Combination of a SARS-CoV-2 IgG Assay and RT-PCR for Improved COVID-19 Diagnosis.

BACKGROUND: Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is generally diagnosed by reverse transcription (RT)-PCR or serological assays. The SARS-CoV-2 viral load decreases a few days after symptom onset. Thus, the RT-PCR sensitivity peaks at three days after symptom onset (approximately 80%). We evaluated the performance of the ARCHITECT® SARS-CoV-2 IgG assay (henceforth termed IgG assay; Abbott Laboratories, Lake County, IL, USA), and the combination of RT-PCR and the IgG assay for COVID-19 diagnosis. METHODS: In this retrospective study, 206 samples from 70 COVID-19 cases at two hospitals in Tokyo that were positive using RT-PCR were used to analyze the diagnostic sensitivity. RT-PCR-negative (N=166), COVID-19-unrelated (N=418), and Japanese Red Cross Society (N=100) samples were used to evaluate specificity. RESULTS: Sensitivity increased daily after symptom onset and exceeded 84.4% after 10 days. Specificity ranged from 98.2% to 100% for samples from the three case groups. Seroconversion was confirmed from 9 to 20 days after symptom onset in 18 out of 32 COVID-19 cases with multiple samples and from another case with a positive result in the IgG assay for the first available sample. CONCLUSIONS: The combination of RT-PCR and IgG assay improves the robustness of laboratory diagnostics by compensating for the limitations of each method.

Elective lung resection after treatment for COVID-19 pneumonia.

A 65-year-old man with coronavirus disease 2019 (COVID-19) was admitted to our hospital. Computed tomography detected bilateral pneumonia with a lung nodule suspicious for lung cancer. Lobectomy was performed 3 months after the treatment for COVID-19 without any complications. The surgical specimen revealed fibrosis below the pleura with a small collection of lymphocytes and intravascular hemorrhagic thrombosis, and no residual RNA was detected. This is the first report describing a surgical specimen after recovery from COVID-19 pneumonia, and suggests that elective thoracic surgery can be performed safely, depending on the patient's respiratory function, without infectious risk.

Early Anti-SARS-CoV-2 Immunoglobulin G Response May Be Associated with Disease Severity in Patients with COVID-19.

Most coronavirus disease 2019 (COVID-19) cases are mild or asymptomatic, and a substantial minority of patients have severe or critical diseases. There are several reports on the potential risk factors of severe disease, but few reports have reported a relationship between antibody titer and severity in Japan. Antibody-dependent enhancement affects disease progression. We evaluated the IgG responses in COVID-19 patients at our tertiary hospital. The IgG index was the measure of interest. We assigned 1.4 as the cutoff value for a positive result based on the specifications by the manufacturer and observed that patients could be categorized into two groups: the early elevation of IgG and late elevation of IgG (IgG elevated in the first 7 days ± 2 days or more than 10 days after symptom onset) groups. The former comprised early IgG responders (n = 7) and the latter comprised late IgG responders (n = 14), and they were compared. The C-reactive protein and D-dimer concentrations were significantly higher in the early IgG responders on admission (HD 0). The respiratory rate was also higher. The lymphocytes were significantly fewer on day 7 of hospitalization (HD 7). These results suggest that early production of anti-severe acute respiratory syndrome coronavirus 2 IgG may be associated with clinical indicators of severity.

Immunochromatography and chemiluminescent enzyme immunoassay for COVID-19 diagnosis.

INTRODUCTION: The rapid and accurate detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is required to prevent the spread of COVID-19. This study evaluated the utility of two SARS-CoV-2 antigen detection methods. METHODS: We evaluated two types of antigen detection methods using immunochromatography (Espline) and quantitative chemiluminescent enzyme immunoassay (Lumipulse). RT-PCR was performed as a standard procedure for COVID-19 diagnosis. Lumipulse and RT-PCR were performed for all 486 nasopharyngeal swabs and 136 saliva samples, and the Espline test was performed for 271 nasopharyngeal swabs and 93 saliva samples. RESULTS: The sensitivity and specificity of the Espline test were 10/11 and 260/260 (100%), respectively for the nasopharyngeal swabs and 3/9 and 84/84 (100%), respectively for the saliva samples. High sensitivities for both saliva (8/9) and nasopharyngeal swabs (22/24) were observed in the Lumipulse test. The specificities of the Lumipulse test for nasopharyngeal swabs and saliva samples were 460/462 (99.6%) and 123/127 (96.9%), respectively. CONCLUSION: The Espline test is not effective for saliva samples but is useful for simple and rapid COVID-19 tests using nasopharyngeal swabs because it does not require special devices. The Lumipulse test is a powerful high-throughput tool for COVID-19 diagnosis because it has high detection performance for nasopharyngeal swabs and saliva samples.

Immunochromatographic test for the detection of SARS-CoV-2 in saliva.

We evaluated the rapid immunochromatographic test for severe acute respiratory coronavirus 2 (SARS-CoV-2) antigen detection using 16 saliva specimens collected from 6 COVID-19 hospitalized patients, and detected N-antigen in 4 of 7 RT-PCR positive specimens. This POCT detected SARS-CoV-2 antigen in saliva and would be useful for COVID-19 diagnosis.

Evaluation of clinical utility of novel coronavirus antigen detection reagent, Espline® SARS-CoV-2.

BACKGROUND: To prevent the novel coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), it is necessary to perform early identification and isolation of people shedding the infectious virus in biological materials with high viral loads several days prior to symptom onset. Rapid antigen tests for infectious diseases are useful to prevent the pandemic spread in clinical settings. METHODS: We evaluated a SARS-CoV-2 antigen test, Espline® SARS-CoV-2 reagent, with reverse transcription polymerase chain reaction (RT-PCR) as reference test, using 129 nasopharyngeal swab specimens collected from COVID-19 hospitalized patients or from patients suspected having COVID-19-like symptoms. Out of these, 63 RT-PCR positive and 66 RT-PCR negative specimens were identified. RESULTS: Among 63 RT-PCR positive specimens, 25 were positive in the Espline test. Test sensitivity was estimated based on the 532.4 copies/reaction of SARS-CoV-2 RNA obtained through receiver operating characteristic analysis. When the specimens were classified based on time since symptom onset, Espline test sensitivity were 73.3% and 29.2% in specimens collected before day 9 and after day 10, respectively. CONCLUSION: Although the overall sensitivity of the Espline® SARS-CoV-2 reagent compared with RT-PCR is less, this antigen test can be useful in identifying people with high risk of virus transmission with high viral loads in order to prevent the pandemic and is useful for diagnosing COVID-19 within 30 min.

Clinical validation of quantitative SARS-CoV-2 antigen assays to estimate SARS-CoV-2 viral loads in nasopharyngeal swabs.

BACKGROUND: Expansion of the testing capacity for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an important issue to mitigate the pandemic of coronavirus disease-2019 (COVID-19) caused by this virus. Recently, a sensitive quantitative antigen test (SQT), Lumipulse® SARS-CoV-2 Ag, was developed. It is a fully automated chemiluminescent enzyme immunoassay system for SARS-CoV-2. METHODS: In this study, the analytical performance of SQT was examined using clinical specimens from nasopharyngeal swabs using reverse transcription polymerase chain reaction (RT-PCR) as a control. RESULTS: Receiver operating characteristic analysis of 24 SARS-CoV-2-positive and 524 -negative patients showed an area under the curve of 0.957 ± 0.063. Using a cut-off value of 1.34 pg/ml, the sensitivity was 91.7%, the specificity was 98.5%, and the overall rate of agreement was 98.2%. In the distribution of negative cases, the 99.5 percentile value was 1.03 pg/ml. There was a high correlation between the viral load calculated using the cycle threshold value of RT-PCR and the concentration of antigen. The tendency for the antigen concentration to decrease with time after disease onset correlated with that of the viral load. CONCLUSIONS: Presented results indicate that SQT is highly concordant with RT-PCR and should be useful for the diagnosis of COVID-19 in any clinical setting. Therefore, this fully automated kit will contribute to the expansion of the testing capability for SARS-CoV-2.

A systematic review of corticosteroid treatment for noncritically ill patients with COVID-19.

The World Health Organization (WHO) has published guidance recommending systemic corticosteroids for the treatment of patients with severe or critical COVID-19 and no corticosteroids for those with nonsevere COVID-19. Although their recommendations for critical cases were based on the results from seven randomized controlled trials (RCTs), those for noncritical cases were based on the results from only one RCT, the Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial. In search of additional evidence of corticosteroids' effect on COVID-19, we systematically reviewed controlled observational studies, besides RCTs, that assessed the impact of corticosteroid treatment on any type of mortality and/or other outcomes in noncritical patients. Of the 4037 titles and abstracts screened, we ultimately included the RECOVERY trial and five controlled observational studies using propensity score matching, (accessed on September 8, 2020). Two of the controlled observational studies assessed the association between corticosteroid treatment and in-hospital mortality, without finding statistical significance. Four of the controlled observational studies assessed corticosteroids' effect on other outcomes, demonstrating that they were associated with reduced risk of intubation in patients requiring oxygen and with longer hospitalization and viral shedding in mild or moderate cases. These results support the WHO recommendations not to use corticosteroids for nonsevere COVID-19.

[XI. Testing and diagnosis]

Genetic testing is undoubtedly the most important factor in the diagnosis of coronavirus disease 2019 (COVID-19), but recently, a simple and highly sensitive antigen test has been developed and made available. In addition to nasopharyngeal wipes, saliva and nasal cavity (nasal entrance) specimens have also been approved. Rapid and accurate diagnosis is essential in controlling infectious diseases, and COVID-19 is required to establish a system for rapid implementation of appropriate testing.