Histologic Characteristics and Clinical Courses of Primary Viral Pneumonia Other than COVID-19.

Objective To clarify both the histologic changes in primary viral pneumonia other than COVID-19 and whether patients with severe lung injury (SLI) on biopsy specimens progress to severe respiratory insufficiency. Methods Patients with primary viral pneumonia other than COVID-19, who underwent lung tissue biopsy, were retrospectively studied. Patients Forty-three patients (41 living patients and 2 autopsied cases) were included in the study. Results Nine patients had SLI, whereas most of patients who recovered from primary viral pneumonia showed a nonspecific epithelial injury pattern. One patient underwent a biopsy under mechanical ventilation. Two of 8 (25.0%) patients on ambient air or low-flow oxygen therapy progressed to a severe respiratory condition and then to death, while only 1 (3.1%) of 32 patients without SLI progressed to a severe respiratory condition and death (p=0.096). The proportion of patients who required O2 treatment for ≥2 weeks was higher in patients with SLI than in those without SLI (p=0.033). The 2 autopsy cases showed a typical pattern of diffuse alveolar damage, with both showing hyaline membranes. Non-specific histologic findings were present in 32 patients without SLI. Conclusion Some patients with SLI progressed to severe respiratory insufficiency, whereas those without SLI rarely progressed to severe respiratory insufficiency or death. The frequency of patients progressing to a severe respiratory condition or death did not differ significantly between those with and without SLI. The proportion of patients who required longer O2 treatment was higher in SLI group than in those without SLI.

[Establishment of a risk model for severe adenovirus pneumonia and prospective study of the timing of intravenous immunoglobulin therapy in children]. / å„¿ç«¥é‡ç—‡è ºç— æ¯’æ€§è‚ºç‚Žé£Žé™©æ¨¡åž‹çš„æž„å»ºåŠé™è„‰æ³¨å°„å ç–«çƒè›‹ç™½æ²»ç–—æ—¶æœºçš„å‰çž»æ€§ç ”ç©¶.

OBJECTIVES: To develop a risk prediction model for severe adenovirus pneumonia (AVP) in children, and to explore the appropriate timing for intravenous immunoglobulin (IVIG) therapy for severe AVP. METHODS: Medical data of 1 046 children with AVP were retrospectively analyzed, and a risk prediction model for severe AVP was established using multivariate logistic regression. The model was validated with 102 children with AVP. Then, 75 children aged ≤14 years who were considered at risk of developing severe AVP by the model were prospectively enrolled and divided into three groups (A, B and C) in order of visit, with 25 children in each group. Group A received symptomatic supportive therapy only. With the exception of symptomatic supportive therapy, group B received IVIG treatment at a dose of 1g/(kg·d) for 2 consecutive days, before progressing to severe AVP. With the exception of symptomatic supportive therapy, group C received IVIG treatment at a dose of 1 g/(kg·d) for 2 consecutive days after progressing to severe AVP. Efficacy and related laboratory indicators were compared among the three groups after treatment. RESULTS: Age<18.5 months, underlying diseases, fever duration >6.5 days, hemoglobin level <84.5 g/L, alanine transaminase level >113.5 U/L, and co-infection with bacteria were the six variables that entered into the risk prediction model for severe AVP. The model had an area under the receiver operating characteristic curve of 0.862, sensitivity of 0.878, and specificity of 0.848. The Hosmer-Lemeshow test showed good consistency between the predicted values and the actual observations (P>0.05). After treatment, group B had the shortest fever duration and hospital stay, the lowest hospitalization costs, the highest effective rate of treatment, the lowest incidence of complications, the lowest white blood cell count and interleukin (IL)-1, IL-2, IL-6, IL-8, IL-10 levels, and the highest level of tumor necrosis factor alpha (P<0.05). CONCLUSIONS: The risk model for severe AVP established in this study has good value in predicting the development of severe AVP. IVIG therapy before progression to severe AVP is more effective in treating AVP in children.

Efficacy of low-intensity pulsed ultrasound for the treatment of viral pneumonia: study protocol for a randomized controlled trial.

BACKGROUND: Viral pneumonia has always been a problem faced by clinicians because of its insidious onset, strong infectivity, and lack of effective drugs. Patients with advanced age or underlying diseases may experience more severe symptoms and are prone to severe ventilation dysfunction. Reducing pulmonary inflammation and improving clinical symptoms is the focus of current treatment. Low-intensity pulsed ultrasound (LIPUS) can mitigate inflammation and inhibit edema formation. We aimed to investigate the efficacy of therapeutic LIPUS in improving lung inflammation in hospitalized patients with viral pneumonia. METHODS: Sixty eligible participants with clinically confirmed viral pneumonia will be assigned to either (1) intervention group (LIPUS stimulus), (2) control group (null stimulus), or (3) self-control group (LIPUS stimulated areas versus non-stimulated areas). The primary outcome will be the difference in the extent of absorption and dissipation of lung inflammation on computed tomography. Secondary outcomes include changes in lung inflammation on ultrasonography images, pulmonary function, blood gas analysis, fingertip arterial oxygen saturation, serum inflammatory factor levels, the sputum excretion volume, time to the disappearance of pulmonary rales, pneumonia status score, and course of pneumonia. Adverse events will be recorded. DISCUSSION: This study is the first clinical study of the efficacy of therapeutic LIPUS in the treatment of viral pneumonia. Given that the current clinical recovery mainly depends on the body's self-limiting and conventional symptomatic treatment, LIPUS, as a new therapy method, might be a major advance in the treatment of viral pneumonia. TRIAL REGISTRATION: ChiCTR2200059550 Chinese Clinical Trial Registry, May 3, 2022.

In vitro and in vivo evaluation of the main protease inhibitor FB2001 against SARS-CoV-2.

FB2001 is a drug candidate that targets the main protease of SARS-CoV-2 via covalently binding to cysteine 145. In this study, we evaluated the inhibitory activities of FB2001 against several SARS-CoV-2 variants in vitro and in vivo (in mice), and we also evaluated the histopathological analysis and immunostaining of FB2001 on lung and brain which have been rarely reported. The results showed that FB2001 exhibited potent antiviral efficacy against several current SARS-CoV-2 variants in Vero E6 cells, namely, B.1.1.7 (Alpha): EC50 = 0.39 ± 0.01 µM, EC90 = 0.75 ± 0.01 µM; B.1.351 (Beta): EC50 = 0.28 ± 0.11 µM, EC90 = 0.57 ± 0.21 µM; B.1.617.2 (Delta): EC50 = 0.27 ± 0.05 µM, EC90 = 0.81 ± 0.20 µM; B.1.1.529 (Omicron): EC50 = 0.26 ± 0.06 µM and EC50 = 0.042 ± 0.007 µM (in the presence of a P-glycoprotein inhibitor). FB2001 remained potent against SARS-CoV-2 replication in the presence of high concentrations of human serum, which indicating that human serum had no significant effect on the in vitro inhibitory activity. Additionally, this inhibitor exhibited an additive effect against SARS-CoV-2 when combined with Remdesivir. Furthermore, FB2001 significantly reduced the SARS-CoV-2 copy numbers and titers in the lungs and brains in vivo, and alleviated the pathological symptoms. In addition, FB2001 could alleviated local bleeding, erythrocyte overflow, edema, and inflammatory cell infiltration in brain tissue, and inhibitors reducing viral titers and improving inflammation in the brain have been rarely reported. A physiologically based pharmacokinetic model was established and verified to predict the FB2001 concentration in human lungs. When FB2001 was administered at 200 mg twice a day for 5 days, the observed Ctrough ss in plasma and predicted Ctrough ss of lung total concentration were 0.163 and 2.5 µg/mL, which were approximately 9 and 132-fold higher than the EC50 of 0.019 µg/mL (0.042 µM) against Omicron variant. Taken together, our study suggests that FB2001 is a promising therapeutic agent in COVID-19 treatment and can be combined with remdesivir to achieve improved clinical outcomes. Owing to its good safety and tolerability in healthy human (NCT05197179 and NCT04766931), FB2001 has been approved for Phase II/III clinical trial (NCT05445934).

Berberine ameliorates pulmonary inflammation in mice with influenza viral pneumonia by inhibiting NLRP3 inflammasome activation and gasdermin D-mediated pyroptosis.

Viral pneumonia is a common complication caused by Influenza A virus infection and is characterized by severe pulmonary inflammation. A previous study showed that berberine (BBR) significantly ameliorated the pulmonary inflammation in mice with influenza viral pneumonia but its underlying mechanism is not entirely understood. In this study, we reproduced the mouse model of influenza viral pneumonia through intranasal infection of A/Puerto Rico/8/34 (H1N1), to further investigate the anti-inflammatory mechanism of BBR based on nucleotide-binding oligomerization domain-like receptor protein (NLRP) 3 inflammasome activation and Gasdermin D (GSDMD)-mediated pyroptosis. Consistent with MCC950 (10 mg/kg, a specific NLRP3 inflammasome inhibitor), BBR (10 mg/kg) obviously improved the weight loss and survival rate of infected mice, alleviated their pulmonary inflammation, and suppressed the accumulation of tumor necrosis factor and interleukin (IL)-6 in lungs without obvious inhibition on viral multiplication (hemagglutinin titer and nucleoprotein messenger RNA). Moreover, BBR (10 mg/kg) reduced the expressions of NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC), and cysteinyl aspartate-specific proteinase (Caspase)1 (Caspase1 precursor [Pro-caspase1] + Caspase1p20 subunit) and the ratio of Caspase1p20 subunit to Caspase1, thus inhibiting the NLRP3 inflammasome activation and resulting in the decreased contents of mature IL-1ß and IL-18 in lungs. The GSDMD expression (GSDMD precursor [Pro-GSDMD] + GSDMD-N terminal [NT]) and the ratio of GSDMD-NT to GSDMD were also declined by BBR (10 mg/kg). These evidence indicate that BBR may ameliorate pulmonary inflammation in mice with influenza viral pneumonia through inhibiting NLRP3 inflammasome activation, as well as depressing GSDMD-mediated pyroptosis via declining GSDMD expression and restraining NLRP3 inflammasome-mediated GSDMD activation.

Nirmatrelvir-remdesivir association for non-hospitalized adults with COVID-19, point of view.

The efforts of the scientific world directed to identifying new antiviral drugs and therapies effective against SARS-CoV-2 continue. New oral antivirals against SARS-CoV-2 such as paxlovid have recently authorized. Evidence shows that these antivirals have good efficacy in reducing the risk of hospitalization in COVID-19 positive patients. Remdesivir is an authorized antiviral for the treatment of SARS-CoV-2 infection. To date, there are still few data in the literature on the safety profile and the risk of generating antiviral-resistant SARS-CoV-2 drug variants. In this manuscript we describe the evidence in the literature on the monotherapy use of paxlovid and monotherapy use of remdesivir, and the scientific hypothesis of using nirmatrelvir and remdesivir in association with the aim of increasing treatment efficacy, reducing the risk of adverse reactions and generating antiviral drug-resistant variants.

Targeting ectromelia virus and TNF/NF-κB or STAT3 signaling for effective treatment of viral pneumonia.

Viral causes of pneumonia pose constant threats to global public health, but there are no specific treatments currently available for the condition. Antivirals are ineffective when administered late after the onset of symptoms. Pneumonia is caused by an exaggerated inflammatory cytokine response to infection, but tissue necrosis and damage caused by virus also contribute to lung pathology. We hypothesized that viral pneumonia can be treated effectively if both virus and inflammation are simultaneously targeted. Combined treatment with the antiviral drug cidofovir and etanercept, which targets tumor necrosis factor (TNF), down-regulated nuclear factor kappa B-signaling and effectively reduced morbidity and mortality during respiratory ectromelia virus (ECTV) infection in mice even when treatment was initiated after onset of clinical signs. Treatment with cidofovir alone reduced viral load, but animals died from severe lung pathology. Treatment with etanercept had no effect on viral load but diminished levels of inflammatory cytokines and chemokines including TNF, IL-6, IL-1ß, IL-12p40, TGF-ß, and CCL5 and dampened activation of the STAT3 cytokine-signaling pathway, which transduces signals from multiple cytokines implicated in lung pathology. Consequently, combined treatment with a STAT3 inhibitor and cidofovir was effective in improving clinical disease and lung pathology in ECTV-infected mice. Thus, the simultaneous targeting of virus and a specific inflammatory cytokine or cytokine-signaling pathway is effective in the treatment of pneumonia. This approach might be applicable to pneumonia caused by emerging and re-emerging viruses, like seasonal and pandemic influenza A virus strains and severe acute respiratory syndrome coronavirus 2.

Sales of "COVID kit" drugs and adverse drug reactions reported by the Brazilian Health Regulatory Agency / Vendas de "kit-COVID" e reações adversas a esses medicamentos relatadas pela Agência Nacional de Vigilância Sanitária / Ventas de medicamentos del "kit-COVID" y reacciones adversas a los medicamentos notificadas por la Agencia Nacional de Vigilancia Sanitaria

Off-label use of azithromycin, hydroxychloroquine, and ivermectin (the "COVID kit") has been suggested for COVID-19 treatment in Brazil without clinical or scientific evidence of efficacy. These drugs have known adverse drug reactions (ADR). This study aimed to analyze if the sales of drugs in the "COVID kit" are correlated to the reported number of ADR after the COVID-19 pandemic began. Data was obtained from the Brazilian Health Regulatory Agency (Anvisa) website on reported sales and ADRs for azithromycin, hydroxychloroquine, and ivermectin for all Brazilian states. The period from March 2019 to February 2020 (before the pandemic) was compared to that from March 2020 to February 2021 (during the pandemic). Trend adjustment was performed for time series data and cross-correlation analysis to investigate correlation between sales and ADR within the same month (lag 0) and in the following months (lag 1 and lag 2). Spearman's correlation coefficient was used to assess the magnitude of the correlations. After the pandemic onset, sales of all investigated drugs increased significantly (69.75% for azithromycin, 10,856,481.39% for hydroxychloroquine, and 12,291,129.32% for ivermectin). ADR levels of all medications but azithromycin were zero before the pandemic, but increased after its onset. Cross-correlation analysis was significant in lag 1 for all drugs nationwide. Spearman's correlation was moderate for azithromycin and hydroxychloroquine but absent for ivermectin. Data must be interpreted cautiously since no active search for ADR was performed. Our results show that the increased and indiscriminate use of "COVID kit" during the pandemic correlates to an increased occurrence of ADRs.

No Brasil, o uso off label de azitromicina, hidroxicloroquina e ivermectina (o "kit-COVID") foi sugerido para tratar COVID-19 sem que tivéssemos evidências clínicas ou científicas de sua eficácia. Estas drogas têm causado reações adversas (RA) em quem as tomam. Este estudo almejou analisar se a venda dos medicamentos que compõem o "kit-COVID" correlaciona-se com o número relatado de RAs após o início da pandemia da COVID-19. Os dados sobre vendas e RA associados a azitromicina, hidroxicloroquina e ivermectina foram obtidos no site da Agência Nacional de Vigilância Sanitária (Anvisa) para todos os estados brasileiros. Comparamos o período entre março de 2019 e fevereiro de 2020 (antes da pandemia) ao de março de 2020 a fevereiro de 2021 (durante a pandemia). Ajustamos tendências para os dados de séries temporais e as análises de correlação cruzada para investigar a correlação entre vendas e RA em um mesmo mês (lag 0) e nos seguintes (lag 1 e 2). O coeficiente de correlação de Spearman foi utilizado para avaliar a magnitude das correlações. Após o início da pandemia, as vendas de todos os medicamentos investigados aumentaram significativamente (69,75% para azitromicina, 10.856.481,39% para hidroxicloroquina e 12.291.129,32% para ivermectina). Os níveis de RAs de todos os medicamentos (com exceção de azitromicina) eram zero antes da pandemia mas aumentaram após seu início. A análise de correlação cruzada foi significativa no lag 1 para todas as drogas em todo o país. A correlação de Spearman foi moderada para azitromicina e hidroxicloroquina, mas ausente para ivermectina. Os dados devem ser interpretados com cautela, uma vez que não realizamos uma busca ativa por RA. Nossos resultados mostram que o uso aumentado e indiscriminado do "kit-COVID" durante a pandemia se correlaciona com uma ocorrência aumentada de RAs.

Se ha sugerido el uso fuera de lo establecido de azitromicina, hidroxicloroquina e ivermectina (el "kit-COVID") para el tratamiento de la COVID-19 en Brasil sin evidencia clínica o científica de su eficacia. Estos medicamentos tienen reacciones adversas (RAM) conocidas. Este estudio pretendía analizar si las ventas de medicamentos del "kit-COVID" están correlacionadas con el número de reacciones adversas notificadas tras el inicio de la pandemia de COVID-19. Los datos se obtuvieron del sitio web de la Agencia Nacional de Vigilancia Sanitaria (Anvisa) sobre las ventas y las RAM notificadas para la azitromicina, la hidroxicloroquina y la ivermectina para todos los estados brasileños. Se comparó el periodo de marzo de 2019 a febrero de 2020 (antes de la pandemia) con el de marzo de 2020 a febrero de 2021 (durante la pandemia). Se realizó un ajuste de tendencia para los datos de las series de tiempo y un análisis de correlación cruzada para investigar la correlación entre las ventas y la RAM dentro del mismo mes (lag 0) y en los meses siguientes (lag 1 y lag 2). Se utilizó el coeficiente de correlación de Spearman para evaluar la magnitud de las correlaciones. Tras el inicio de la pandemia, las ventas de todos los medicamentos investigados aumentaron significativamente (69,75% para la azitromicina, 10.856.481,39% para la hidroxicloroquina y 12.291.129,32% para la ivermectina). Los niveles de RAM de todos los medicamentos, excepto la azitromicina, eran nulos antes de la pandemia, pero aumentaron tras su inicio. El análisis de correlación cruzada fue significativo en el lag 1 para todos los medicamentos a nivel nacional. La correlación de Spearman fue moderada para la azitromicina y la hidroxicloroquina, pero no para la ivermectina. Los datos deben interpretarse con cautela, ya que no se realizó una búsqueda activa de RAM. Nuestros resultados muestran que el uso creciente e indiscriminado del "kit-COVID" durante la pandemia se correlaciona con una mayor aparición de las RAM.

New insights and antimicrobial stewardship opportunities in viral pneumonia: five lung ultrasound cases.

BACKGROUND: Antimicrobial stewardship is crucial to avoid antimicrobial resistance in microbes and adverse drug effects in patients. In respiratory infections, however, viral pneumonia is difficult to distinguish from bacterial pneumonia, which explains the overuse of antibiotic therapy in this indication. CASES: Five cases of lung consolidation are presented. Lung ultrasound, in conjunction with procalcitonin levels, were used to exclude or corroborate bacterial pneumonia. CONCLUSION: Lung ultrasound is easy to learn and perform and is helpful in guiding diagnosis in unclear cases of pneumonia and may also offer new insights into the spectrum of certain virus diseases. The use of lung ultrasound can raise awareness in clinicians of the need for antimicrobial stewardship and may help to avoid the unnecessary use of antibiotics.

SARS-CoV-2 Infection in an Adolescent With X-linked Agammaglobulinemia.

We present a case of a 17-year-old boy with X-linked agammaglobulinemia who had mild disease when initially infected with SARS-CoV-2 but after recovering from acute infection developed fevers and a raised erythrocyte sedimentation rate that persisted for several weeks without any ongoing respiratory symptoms. Multiple nasopharyngeal swabs were found to be negative for SARS-CoV-2 during the febrile period, but typical changes of COVID-19 on high resolution CT chest scan led to the detection of SARS-CoV-2 on RT-PCR in a sample from a bronchoalveolar lavage. His fevers completely resolved after a 5-day course of remdesivir.

A Novel Bifunctional Fusion Protein, Vunakizumab-IL22, for Protection Against Pulmonary Immune Injury Caused by Influenza Virus.

Influenza A virus infection is usually associated with acute lung injury, which is typically characterized by tracheal mucosal barrier damage and an interleukin 17A (IL-17A)-mediated inflammatory response in lung tissues. Although targeting IL-17A has been proven to be beneficial for attenuating inflammation around lung cells, it still has a limited effect on pulmonary tissue recovery after influenza A virus infection. In this research, interleukin 22 (IL-22), a cytokine involved in the repair of the pulmonary mucosal barrier, was fused to the C-terminus of the anti-IL-17A antibody vunakizumab to endow the antibody with a tissue recovery function. The vunakizumab-IL22 (vmab-IL-22) fusion protein exhibits favorable stability and retains the biological activities of both the anti-IL-17A antibody and IL-22 in vitro. Mice infected with lethal H1N1 influenza A virus and treated with vmab-mIL22 showed attenuation of lung index scores and edema when compared to those of mice treated with saline or vmab or mIL22 alone. Our results also illustrate that vmab-mIL22 triggers the upregulation of MUC2 and ZO1, as well as the modulation of cytokines such as IL-1ß, HMGB1 and IL-10, indicating the recovery of pulmonary goblet cells and the suppression of excessive inflammation in mice after influenza A virus infection. Moreover, transcriptome profiling analysis suggest the downregulation of fibrosis-related genes and signaling pathways, including genes related to focal adhesion, the inflammatory response pathway, the TGF-ß signaling pathway and lung fibrosis upon vmab-mIL22 treatment, which indicates that the probable mechanism of vmab-mIL22 in ameliorating H1N1 influenza A-induced lung injury. Our results reveal that the bifunctional fusion protein vmab-mIL22 can trigger potent therapeutic effects in H1N1-infected mice by enhancing lung tissue recovery and inhibiting pulmonary inflammation, which highlights a potential approach for treating influenza A virus infection by targeting IL-17A and IL-22 simultaneously.

Association of antihypertensives during hospitalisation with acute respiratory failure in patients with viral pneumonia: A population-based case-control study.

BACKGROUND: We aimed to identify associations between the risk of acute respiratory failure (ARF) and types of antihypertensive agents in patients with viral pneumonia. METHODS: In this case-control study, data extracted from the Taiwan National Health Insurance Research Database were analysed. The base population comprised patients with viral pneumonia treated from 2000 to 2013. The case group comprised patients with ARF and the control group comprised participants without ARF. Adjusted odds ratios (ORs) were calculated using a multivariable logistic regression model. RESULTS: In total, 4427 viral pneumonia patients with ARF and 4427 matched control participants without ARF were recruited. Patients with diabetes, alcohol-related disease, asthma, chronic kidney disease or end-stage renal disease, chronic obstructive pulmonary disease, cancer, congestive heart failure, stroke, acute pulmonary oedema and shock had increased odds of developing ARF, especially shock (adjusted OR = 49.3; 95% CI = 27.4, 88.7), cancer (12.6; 8.67, 18.2) and stroke (7.51; 5.32, 10.6). Increasing odds of developing ARF were noted in patients using potassium-sparing diuretics (2.95; 1.54, 5.64), loop diuretics (68.2; 48.1, 96.6), calcium channel blockers (1.64; 1.26, 2.13) and angiotensin-converting enzyme inhibitors (1.70; 1.15, 2.53). Patients with prescriptions of α-blockers (0.44; 0.26, 0.74), ß-blockers (0.37; 0.26, 0.52), thiazides (0.38; 0.25, 0.59) and angiotensin receptor blockers (0.65; 0.51, 0.83) had lower odds of having ARF. CONCLUSION: Patients with viral pneumonia who received α-blockers, ß-blockers, thiazides or angiotensin receptor blockers during hospitalisation had a lower risk of developing ARF.

Inhibition of Autophagy Suppresses SARS-CoV-2 Replication and Ameliorates Pneumonia in hACE2 Transgenic Mice and Xenografted Human Lung Tissues.

Autophagy is thought to be involved in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, how SARS-CoV-2 interferes with the autophagic pathway and whether autophagy contributes to virus infection in vivo is unclear. In this study, we identified SARS-CoV-2-triggered autophagy in animal models, including the long-tailed or crab-eating macaque (Macaca fascicularis), human angiotensin-converting enzyme 2 (hACE2) transgenic mice, and xenografted human lung tissues. In Vero E6 and Huh-7 cells, SARS-CoV-2 induces autophagosome formation, accompanied by consistent autophagic events, including inhibition of the Akt-mTOR pathway and activation of the ULK-1-Atg13 and VPS34-VPS15-Beclin1 complexes, but it blocks autophagosome-lysosome fusion. Modulation of autophagic elements, including the VPS34 complex and Atg14, but not Atg5, inhibits SARS-CoV-2 replication. Moreover, this study represents the first to demonstrate that the mouse bearing xenografted human lung tissue is a suitable model for SARS-CoV-2 infection and that autophagy inhibition suppresses SARS-CoV-2 replication and ameliorates virus-associated pneumonia in human lung tissues. We also observed a critical role of autophagy in SARS-CoV-2 infection in an hACE2 transgenic mouse model. This study, therefore, gives insights into the mechanisms by which SARS-CoV-2 manipulates autophagosome formation, and we suggest that autophagy-inhibiting agents might be useful as therapeutic agents against SARS-CoV-2 infection. IMPORTANCE Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a global pandemic with limited therapeutics. Insights into the virus-host interactions contribute substantially to the development of anti-SARS-CoV-2 therapeutics. The novelty of this study is the use of a new animal model: mice xenografted with human lung tissues. Using a combination of in vitro and in vivo studies, we have obtained experimental evidence that induction of autophagy contributes to SARS-CoV-2 infection and improves our understanding of potential therapeutic targets for SARS-CoV-2.

Early use of tocilizumab in patients with severe pneumonia secondary to severe acute respiratory syndrome coronavirus 2 infection and poor prognostic criteria: Impact on mortality rate and intensive care unit admission.

ABSTRACT: The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2, keeps spreading globally. Evidence suggests that a subgroup of patients with severe symptomatology might have cytokine storms, which increases mortality. The use of interleukin-6 (IL-6) inhibitors may help in controlling the pathological immune response to the virus. Tocilizumab, a monoclonal antibody against IL-6, stands as an optional treatment for COVID-19 patients presenting this inflammatory hyper-response.We conducted a retrospective, observational, cohort study including 50 patients affected by COVID-19 with severe pneumonia and poor prognosis criteria, who have also undergone standard treatment; 36 of these patients additionally received tocilizumab in an early stage. The need for intensive care unit (ICU) admission, mortality, recovery of respiratory function, and improvement of biochemical and hematological parameters were compared between cohorts.Most patients were men, non-smokers and the most frequently reported comorbidities were hypertension and diabetes. Recurrent symptoms were fever, cough, and dyspnoea. 54.8% of patients from the tocilizumab group needed intubation, while in the control group 85.7% needed it. Treatment with tocilizumab significatively increased IL-6 levels, (554.45; CI 95% 186.69, 1032.93; P < .05) while C-reactive protein mean levels were reduced (-108.19; CI 95% -140.15, -75.33; P < .05), but no significant difference was found between cohorts. In comparison with the controls, tocilizumab reduced mortality (25.0% vs 42.9%, P = .021) and the number of ICU admissions (63.9% vs 100.0%, P = .021). 44.1% of patients treated with tocilizumab showed favorable radiological evolution, when compared with 15.4% of patients from the control group.Tocilizumab may improve clinical symptoms and mitigate deterioration observed in severe COVID-19 patients, and could be considered as an effective therapeutic option in subjects experiencing a significant inflammatory response to the disease.

Complicated pulmonary human coronavirus-NL63 infection after a second allogeneic hematopoietic stem cell transplantation for acute B-lymphocytic leukemia: A case report.

RATIONALE: Viruses are the most common pathogens that can cause infection-related non-recurrent death after transplantation, occurring mostly from the early stages of hematopoietic stem cell transplantation (HSCT) to within 1 year after transplantation. Human coronavirus (HCoV)-NL63 is a coronavirus that could cause mortality among patients with underlying disease complications. Serological tests are of limited diagnostic value in immunocompromised hosts and cases of latent infection reactivation. In contrast, macro-genomic high-throughput (DNA and RNA) sequencing allows for rapid and accurate diagnosis of infecting pathogens for targeted treatment. PATIENT CONCERNS: In this report, we describe a patient who exhibited acute B-lymphocytic leukemia and developed complicated pulmonary HCoV-NL63 infection after a second allogeneic HSCT (allo-HSCT). Six months after the second allo-HSCT, he developed sudden-onset hyperthermia and cough with decreased oxygen saturation. Chest computed tomography (CT) suggested bilateral multiple rounded ground-glass opacities with the pulmonary lobules as units. DIAGNOSES: HCoV-NL63 was detected by metagenomic next-generation sequencing (NGS), and HCoV-NL63 viral pneumonia was diagnosed. INTERVENTIONS: The treatment was mainly based on the use of antiviral therapy, hormone administration, and gamma-globulin. OUTCOMES: After the therapy, the body temperature returned to normal, the chest CT findings had improved on review, and the viral copy number eventually became negative. LESSONS: The latest NGS is an effective method for early infection diagnosis. The HCoV-NL63 virus can cause inflammatory factor storm and alter the neutrophil-to-lymphocyte ratio (NLR). This case suggests that the patient's NLR and cytokine levels could be monitored during the clinical treatment to assess the disease and its treatment outcome in a timely manner.

A case report of COVID-19 in refractory myasthenia: Outcome with remdesivir and dexamethasone.

RATIONALE: Myasthenia gravis (MG) patients are at increased risk of COVID-19 infection and its complications due to chronic immunosuppression. COVID-19 infection can also increase the risk of myasthenia exacerbation. PATIENT CONCERNS: The patient presented with respiratory distress, fever and chills and was diagnosed with COVID-19 pneumonia. His past medical history includes seropositive generalized MG diagnosed in 2019, hypertension, atrial fibrillation and congestive heart failure with reduced ejection failure. DIAGNOSES: Refractory seropositive generalized MG having COVID-19 pneumonia and respiratory failure (needing mechanical ventilation) with sepsis. INTERVENTION: Use of intravenous remdesivir and dexamethasone and patient's myasthenic exacerbation (due to COVID-19 and its complications) was successfully treated with plasmapheresis. OUTCOMES: Patient was successfully weaned off ventilator to trach collar and was discharged to inpatient rehabiliation. He was followed up 1 month post hospital discharge and was on trach collar. LESSONS: This case report illustrates early use of the combination therapy might be beneficial in refractory myasthenia gravis cases even with chronic immunosuppression and severe COVID-19 infection.

Off-label tocilizumab and adjuvant iron chelator effectiveness in a group of severe COVID-19 pneumonia patients: A single center experience.

ABSTRACT: Tocilizumab (TCZ), a monoclonal recombinant antibody against IL-6 receptor, is currently used in managing the cytokine release syndrome (CRS) that occurred in coronavirus disease 2019 (COVID-19) selected cases. The primary objective of our study was to establish the effectiveness of TCZ in patients with severe or critical severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pneumonia.We retrospectively analyzed 25 consecutive patients, admitted in the Academic Emergency Hospital Sibiu, Romania from April 1, 2020 until May 25, 2020, all with confirmed SARS-CoV-2 infection and severe pneumonia. All patients were treated off-label with TCZ, beside their standard care. Adjuvant iron chelator was associated in 11 patients.Six female and 19 male patients admitted in our hospital all with confirmed SARS-CoV-2 infection and severe pneumonia as defined by Chinese Centers for Disease Control and Prevention were enrolled in this study. Seventeen of the 25 enrolled patients (68%) were seriously ill requiring noninvasive ventilation or oxygen mask, and 8 cases (32%) were critically ill requiring invasive mechanical ventilation. All patients received TCZ, and also received hydroxychloroquine, and lopinavir/ritonavir 200/50 mg for 10 days. Adjuvant iron chelator (deferasirox - marketed as Exjade) was associated in 11 patients who had ferritin serum levels above 1000 ng/mL. No side effects were encountered during infusions or after TCZ. We observed a rapid increase in arterial oxygen saturation for 20 of the 25 cases (80%) with a favorable evolution toward healing. Survivors were younger than 60 years old (80%), had less comorbidities (10% no comorbidities, 70% with 1 or 2 comorbidities), lower serum ferritin levels (30% under 1000 ng/mL), and 50% had no serum glucose elevation. Our patients with CRS had no response to corticosteroid therapy. Five out of the 25 patients had an unfavorable evolution to death. The off-label use of TCZ in patients with severe or critically ill form of SARS-CoV-2 infection had good results in our study.Off-label use of TCZ in severe and critical cases of COVID-19 pneumonia is effective in managing the "cytokine storm." Better outcomes were noted in younger patients. Associated adjuvant iron chelators may contribute to a good outcome and needs to be confirmed in larger studies.