Co-administration of Favipiravir and the Remdesivir Metabolite GS-441524 Effectively Reduces SARS-CoV-2 Replication in the Lungs of the Syrian Hamster Model.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide since December 2019, causing coronavirus disease 2019 (COVID-19). Although vaccines for this virus have been developed rapidly, repurposing drugs approved to treat other diseases remains an invaluable treatment strategy. Here, we evaluated the inhibitory effects of drugs on SARS-CoV-2 replication in a hamster infection model and in in vitro assays. Favipiravir significantly suppressed virus replication in hamster lungs. Remdesivir inhibited virus replication in vitro, but was not effective in the hamster model. However, GS-441524, a metabolite of remdesivir, effectively suppressed virus replication in hamsters. Co-administration of favipiravir and GS-441524 more efficiently reduced virus load in hamster lungs than did single administration of either drug for both the prophylactic and therapeutic regimens; prophylactic co-administration also efficiently inhibited lung inflammation in the infected animals. Furthermore, pretreatment of hamsters with favipiravir and GS-441524 effectively protected them from virus transmission via respiratory droplets upon exposure to infected hamsters. Repurposing and co-administration of antiviral drugs may help combat COVID-19. IMPORTANCE During a pandemic, repurposing drugs that are approved for other diseases is a quick and realistic treatment option. In this study, we found that co-administration of favipiravir and the remdesivir metabolite GS-441524 more effectively blocked SARS-CoV-2 replication in the lungs of Syrian hamsters than either favipiravir or GS-441524 alone as part of a prophylactic or therapeutic regimen. Prophylactic co-administration also reduced the severity of lung inflammation. Moreover, co-administration of these drugs to naive hamsters efficiently protected them from airborne transmission of the virus from infected animals. Since both drugs are nucleotide analogs that interfere with the RNA-dependent RNA polymerases of many RNA viruses, these findings may also help encourage co-administration of antivirals to combat future pandemics.

SARS-CoV-2 is localized in cardiomyocytes: a postmortem biopsy case.

A 72-year-old patient was admitted to the intensive care unit due to acute respiratory distress syndrome caused by COVID-19. On day 20, the patient experienced shock. The electrocardiogram showed ST segment elevation in leads V3-V6 and severe left ventricular dysfunction with an ejection fraction of 35%-40%. The left ventricle showed basal hypokinesis and apical akinesis, while the creatine kinase level was normal, indicating Takotsubo cardiomyopathy. On day 24, the patient died of multiple organ failure. In post-mortem biopsy, SARS-CoV-2 antigen was detected in cardiomyocytes by immunostaining. Moreover, SARS-CoV-2 RNA was detected in heart tissue. We need to further analyse the direct link between SARS-CoV-2 and cardiomyocytes.

Intranasal vaccination induced cross-protective secretory IgA antibodies against SARS-CoV-2 variants with reducing the potential risk of lung eosinophilic immunopathology.

To control the coronavirus disease 2019 (COVID-19) pandemic, there is a need to develop vaccines to prevent infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants. One candidate is a nasal vaccine capable of inducing secretory IgA antibodies in the mucosa of the upper respiratory tract, the initial site of infection. However, regarding the development of COVID-19 vaccines, there is concern about the potential risk of inducing lung eosinophilic immunopathology as a vaccine-associated enhanced respiratory disease as a result of the T helper 2 (Th2)-dominant adaptive immune response. In this study, we investigated the protective effect against virus infection induced by intranasal vaccination of recombinant trimeric spike protein derived from SARS-CoV-2 adjuvanted with CpG oligonucleotides, ODN2006, in mouse model. The intranasal vaccine combined with ODN2006 successfully induced not only systemic spike-specific IgG antibodies, but also secretory IgA antibodies in the nasal mucosa. Secretory IgA antibodies showed high protective ability against SARS-CoV-2 variants (Alpha, Beta and Gamma variants) compared to IgG antibodies in the serum. The nasal vaccine of this formulation induced a high number of IFN-γ-secreting cells in the draining cervical lymph nodes and a lower spike-specific IgG1/IgG2a ratio compared to that of subcutaneous vaccination with alum as a typical Th2 adjuvant. These features are consistent with the induction of the Th1 adaptive immune response. In addition, mice intranasally vaccinated with ODN2006 showed less lung eosinophilic immunopathology after viral challenge than mice subcutaneously vaccinated with alum adjuvant. Our findings indicate that intranasal vaccine adjuvanted with ODN2006 could be a candidate that can prevent the infection of antigenically different variant viruses, reducing the risk of vaccine-associated enhanced respiratory disease.

SARS-CoV-2 Interference of Influenza Virus Replication in Syrian Hamsters.

In hamsters, SARS-CoV-2 infection at the same time as or before H3N2 influenza virus infection resulted in significantly reduced influenza virus titers in the lungs and nasal turbinates. This interference may be correlated with SARS-CoV-2-induced expression of MX1.

A Kidney Transplant Patient Who Died of COVID-19-associated Severe Acute Respiratory Distress Syndrome.

We herein report a 67-year-old kidney transplant patient who died of COVID-19. He was treated with hydroxychloroquine and azithromycin and received mechanical ventilation that temporarily improved his respiratory status. Despite our efforts, however, he later developed respiratory failure and died 43 days after the disease onset. The autopsy revealed prominent organization of alveoli and alveolar ducts, with a massive accumulation of macrophages in the lungs. A few severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigen-positive cells were detected in the lung, suggesting delayed virus clearance owing to his long-term immunosuppressed state, leading to constant lung damage and ultimately respiratory failure.

Near-Complete Genome Sequence of GI-17 Lineage Infectious Bronchitis Virus, Circulating in Iowa.

Avian infectious bronchitis virus (AvIBV) is the causative agent of a highly contagious respiratory disease in chickens which results in significant economic losses in the poultry industry. Here, we report a near-complete genome sequence of the strain, designated IA1162/2020, identified in tracheal swabs from chickens in Iowa in 2020.

Pitfalls in chest CT findings of COVID-19 patients infected during hospitalisation.

OBJECTIVE: This study evaluated the differences in the appearance of COVID-19 pneumonia on chest computed tomography (CT) images of outpatient and cases that developed during hospitalisation. METHOD: Chest CT images of 66 patients (median age, 76 years; range, 29-94 years) who underwent the severe acute respiratory syndrome coronavirus-2 reverse-transcription polymerase chain reaction (RT-PCR) test were included in this retrospective study. The chest CT appearance was categorised as "typical," "indeterminate," "atypical," or "negative" in accordance with the recommendations of the Radiological Society of North America for COVID-19 pneumonia and compared among the following four subgroups: PCR-positive outpatient (n = 14); PCR-positive hospitalised (n = 7); PCR-negative outpatient (n = 9); and PCR-negative hospitalised (n = 36). FINDINGS: The frequency of "typical" findings in the PCR-positive outpatient cases (13/14, 92.9%) was significantly higher than that of those in the PCR-positive hospitalised cases (2/7, 28.6%, P = 0.022). There was no significant difference between the frequency of the "typical" appearance in PCR-positive hospitalised cases and that of those in the PCR-negative hospitalised cases (1/36, 2.8%, P = 0.192). CONCLUSIONS: When COVID-19 patients acquire infections while hospitalised, their chest CT images are less likely to show typical findings than those of outpatient cases. Comprehensive and careful assessments of CT findings and consideration of the possibility of concomitant infections with other pathogens and clinical information, such as underlying diseases, background lung structure, and time course of the infection, are required for the management of such cases.

Lung Pathology of Mutually Exclusive Co-infection with SARS-CoV-2 and Streptococcus pneumoniae.

Postmortem lung pathology of a patient in Japan with severe acute respiratory syndrome coronavirus 2 infection showed diffuse alveolar damage as well as bronchopneumonia caused by Streptococcus pneumoniae infection. The distribution of each pathogen and the accompanying histopathology suggested the infections progressed in a mutually exclusive manner within the lung, resulting in fatal respiratory failure.

[Imaging findings of COVID-19 pneumonia, focusing on CT]

At the time of writing (end of July 2020), the number of infected or suspected cases of novel coronavirus infection (COVID-19) has been increasing in various medical institutions as the second wave of infection approaches. In the "Diagnostic Imaging Surveillance of Viral Pneumonia" conducted by the Japanese Society of Radiology since March 2020, the number of suspected cases of viral pneumonia by chest computed tomography (CT) has been increasing since July of this year, almost in parallel with the increasing trend in the number of newly infected patients nationwide. While limitations in the sensitivity of PCR and antigen tests have been pointed out, there is a growing consensus in clinical practice that diagnostic imaging, especially chest CT, is useful for the adjunctive diagnosis of COVID-19 pneumonia and for follow-up during the course of treatment. In this article, we summarize the significance of chest CT in the diagnosis and management of COVID-19 pneumonia and introduce the findings of typical images.