Effects of remdesivir on SARS-CoV-2 viral dynamics and mortality in viraemic patients hospitalized for COVID-19.

BACKGROUND: Studies on the antiviral effects of remdesivir have shown conflicting results. SARS-CoV-2 viraemia could identify patients in whom antiviral treatment may be particularly beneficial. OBJECTIVES: To investigate antiviral effects and clinical outcomes of remdesivir treatment in viraemic patients. METHODS: Viraemic patients hospitalized for COVID-19 with ratio of arterial oxygen partial pressure to fractional inspired oxygen of ≤300, symptom duration ≤10 days, and estimated glomerular filtration rate ≥30 mL/min were included in a cohort. The rate of serum viral clearance and serum viral load decline, 60 day mortality and in-hospital outcomes were estimated. A subgroup analysis including patients with symptom duration ≤7 days was performed. RESULTS: A total of 318 viraemic patients were included. Thirty-three percent (105/318) received remdesivir. The rate of serum viral clearance [subhazard risk ratio (SHR) 1.4 (95% CI 0.9-2.0), P = 0.11] and serum viral load decline (P = 0.11) were not significantly different between remdesivir-treated patients and controls. However, the rate of serum viral clearance was non-significantly higher [SHR 1.6 (95% CI 1.0-2.7), P = 0.051] and the viral load decline was faster (P = 0.03) in remdesivir-treated patients with symptom duration ≤7 days at admission. The 60 day mortality [HR 1.0 (95% CI 0.6-1.8), P = 0.97] and adverse in-hospital outcomes [OR 1.4 (95% CI 0.8-2.4), P = 0.31] were not significantly different between remdesivir-treated patients and controls. CONCLUSIONS: Remdesivir treatment did not significantly change the duration of SARS-CoV-2 viraemia, decline of serum viral load, 60 day mortality or in-hospital adverse outcomes in patients with ≤10 days of symptoms at admission. Remdesivir appeared to reduce the duration of viraemia in a subgroup of patients with ≤7 days of symptoms at admission.

High-Dose Inhaled Nitric Oxide in Acute Hypoxemic Respiratory Failure Due to COVID-19: A Multicenter Phase II Trial.

Rationale: The effects of high-dose inhaled nitric oxide on hypoxemia in coronavirus disease (COVID-19) acute respiratory failure are unknown. Objectives: The primary outcome was the change in arterial oxygenation (PaO2/FiO2) at 48 hours. The secondary outcomes included: time to reach a PaO2/FiO2.300mmHg for at least 24 hours, the proportion of participants with a PaO2/FiO2.300mmHg at 28 days, and survival at 28 and at 90 days. Methods: Mechanically ventilated adults with COVID-19 pneumonia were enrolled in a phase II, multicenter, single-blind, randomized controlled parallel-arm trial. Participants in the intervention arm received inhaled nitric oxide at 80 ppm for 48 hours, compared with the control group receiving usual care (without placebo). Measurements and Main Results: A total of 193 participants were included in the modified intention-to-treat analysis. The mean change in PaO2/FiO2 ratio at 48 hours was 28.3mmHg in the intervention group and 21.4mmHg in the control group (mean difference, 39.1mmHg; 95% credible interval [CrI], 18.1 to 60.3). The mean time to reach a PaO2/FiO2.300mmHg in the interventional group was 8.7 days, compared with 8.4 days for the control group (mean difference, 0.44; 95% CrI, 23.63 to 4.53). At 28 days, the proportion of participants attaining a PaO2/FiO2.300mmHg was 27.7% in the inhaled nitric oxide group and 17.2% in the control subjects (risk ratio, 2.03; 95% CrI, 1.11 to 3.86). Duration of ventilation and mortality at 28 and 90 days did not differ. No serious adverse events were reported. Conclusions: The use of high-dose inhaled nitric oxide resulted in an improvement of PaO2/FiO2 at 48 hours compared with usual care in adults with acute hypoxemic respiratory failure due to COVID-19.

Correlation of SARS-CoV-2 Nasopharyngeal CT Values With Viremia and Mortality in Adults Hospitalized With COVID-19.

Background: Both severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viremia and nasopharyngeal viral load have been suggested to be predictors of unfavorable outcome in coronavirus disease 2019 (COVID-19). This study aimed to investigate whether nasopharyngeal viral load is correlated with viremia and unfavorable outcome. Methods: The presence of SARS-CoV-2 RNA was determined in paired nasopharyngeal and serum samples collected at admission from patients hospitalized for COVID-19. Standardized cycle threshold values (CT values) were used as an indicator of viral load. An adjusted logistic regression was used to estimate the risk of viremia at different nasopharyngeal CT values. A Cox regression was used to estimate the risk of 60-day mortality. Results: A total of 688 patients were included. Viremia at admission was detected in 63% (146/230), 46% (105/226), and 31% (73/232) of patients with low, intermediate, and high nasopharyngeal CT values. The adjusted odds ratios of being viremic were 4.4 (95% CI, 2.9-6.8) and 2.0 (95% CI, 1.4-3.0) for patients with low and intermediate CT values, compared with high CT values. The 60-day mortality rate was 37% (84/230), 15% (36/226), and 10% (23/232) for patients with low, intermediate, and high nasopharyngeal CT values at admission, respectively. Adjusted hazard ratios were 2.6 (95% CI, 1.6-4.2) and 1.4 (95% CI, 0.8-2.4) for patients with low and intermediate CT values compared with high CT values. Conclusions: There was a dose-dependent correlation between nasopharyngeal CT values and viremia at admission for COVID-19. Moreover, there was an increased risk of 60-day mortality for patients with low, compared with high, nasopharyngeal CT values.

Duration of SARS-CoV-2 viremia and its correlation to mortality and inflammatory parameters in patients hospitalized for COVID-19: a cohort study.

SARS-CoV-2 viremia at admission is associated with high risk for mortality. However, longitudinal data on viremia duration are limited. Viremic patients hospitalized for COVID-19 were included in a cohort. Time to serum viral clearance and the effect of viremia duration on the odds of mortality were calculated. One hundred and twenty-one viremic patients were included. Median age was 62 (IQR 52-71) years and 68% were males. The total in-hospital mortality of the cohort was 33%. Median time from admission to serum viral clearance was 7 (95% CI 6-8) days. Duration of viremia showed a relative risk ratio of 1.40 (95% CI 1.02-1.92) for the odds of mortality in an adjusted multinomial logistic regression. Serum viral clearance coincided with defervescence and decreasing C-reactive protein. Median time to serum viral clearance was 7 days after admission. The odds of mortality increased with 40% for each additional day of viremia.

Severe Acute Respiratory Syndrome Coronavirus 2 RNA in Serum as Predictor of Severe Outcome in Coronavirus Disease 2019: A Retrospective Cohort Study.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19). This study aimed to determine if SARS-CoV-2 RNA in serum at admission correlated with clinical outcome in COVID-19. METHODS: COVID-19 patients admitted to the infectious diseases department of a tertiary level Swedish hospital and sampled for SARS-CoV-2 RNA in serum at admission during 10 April to 30 June 2020 were included. Primary outcomes were day 28 all-cause mortality and progress to critical disease. RESULTS: The cohort (N = 167) consisted of 106 SARS-CoV-2 RNA serum-negative and 61 serum-positive patients. Median sampling time for initial SARS-CoV-2 in serum was 1 day (interquartile range [IQR], 1-2 days) after admission, corresponding to day 10 (IQR, 8-12) after symptom onset. Median age was 53 years (IQR, 44-67 years) and 63 years (IQR, 52-74 years) for the serum-negative and -positive patients, respectively. In the serum-negative and -positive groups, 3 of 106 and 15 of 61 patients died, respectively.The hazard ratios for critical disease and all-cause mortality were 7.2 (95% confidence interval [CI], 3.0-17) and 8.6 (95% CI, 2.4-30), respectively, for patients with serum-positive compared to serum-negative results. CONCLUSIONS: SARS-CoV-2 RNA in serum at hospital admission indicates a high risk of progression to critical disease and death.

Nitric oxide dosed in short bursts at high concentrations may protect against Covid 19.

It has long been suggested that NO may inhibit an early stage in viral replication. Furthermore, in vitro tests have shown that NO inhibits the replication cycle of severe acute respiratory syndrome coronavirus. Despite smoking being listed as a risk factor to contract Covid-19, only a low proportion of the smokers suffered from SARS-corona infection in China 2003, and from Covid-19 in China, Europe and the US. We hypothesize, that the intermittent bursts of high NO concentration in cigarette smoke may be a mechanism in protecting against the virus. Mainstream smoke from cigarettes contains NO at peak concentrations of between about 250 ppm and 1350 ppm in each puff as compared to medicinal use of no more than 80 to a maximum of 160 ppm. The diffusion of NO through the cell wall to reach the virus should be significantly more effective at the very high NO concentration in the smoke, according to classic laws of physics. The only oxide of nitrogen in the mainstream smoke is NO, and the NO2 concentration that is inhaled is very low or undetectable, and methemoglobin levels are lower in smokers than non-smokers, reasonably explained by the breaths of air in between the puffs that wash out the NO. Specialized iNO machines can now be developed to provide the drug intermittently in short bursts at high concentration dose, which would then provide both a preventative drug for those at high risk, as well as an effective treatment, without the health hazards associated with smoking.

Efficacy of Routine Fecal Microbiota Transplantation for Treatment of Recurrent Clostridium difficile Infection: A Retrospective Cohort Study.

BACKGROUND: Patients with recurrent Clostridium difficile infections (CDIs) constitute an increasing treatment problem. Fecal microbiota transplantation (FMT) has shown promising results of treating recurrent CDI, where treatment with antibiotics fails repeatedly. Our study describes retrospective cohort treated with FMT at two major hospitals in Stockholm. METHODS: Medical records of all patients with recurrent CDI treated with FMT during the period 2013-2017 were reviewed. We evaluated cure of CDI-related diarrhea without relapse 10 weeks after FMT. RESULTS: 47 patients were included. One treatment cured 25 patients (53%), and more than one treatment cured 32 patients (68%). Treatment outcome did not vary significantly with treatment with fresh donor feces or frozen fecal culture, days of use of antibiotics or days of hospitalization prior to CDI, and renal function or time from the first CDI to therapy. Treatment failure was associated with a significantly lower Karnofsky performance status score (70 points vs 90, p=0.02). CONCLUSION: Fecal instillation, for the treatment of relapsing CDI, is a promising approach, with 68% success rate reported in this study. The success rate of FMT is high, regardless of multiple comorbidities, extended use of antibiotics, or long time hospitalization. Although generally FMT is performed with fresh donor feces, our data show that the usage of frozen fecal culture could be an effective treatment alternative in recurrent CDI.

Diabetes and Cirrhosis Are Risk Factors for Hepatocellular Carcinoma After Successful Treatment of Chronic Hepatitis C.

BACKGROUND: Successful treatment of hepatitis C virus (HCV) infection reduces the risk for hepatocellular carcinoma (HCC), but a risk remains. Current guidelines recommend continued HCC surveillance after sustained virologic response (SVR) has been achieved. This study aimed to investigate risk factors and incidence rates for HCC after SVR in HCV patients with pretreatment advanced liver disease (Metavir stage F3/F4). METHODS: All patients with advanced liver disease successfully treated for HCV at Karolinska University Hospital during 1992-2013 (n = 399) were followed up for a median of 7.8 years. Data from national registries were used to minimize loss to follow-up. Incidence rates and hazard ratios (HRs) for development of HCC were calculated by Cox regression analysis. RESULTS: Seventeen patients developed HCC during 3366 person-years (PY) of follow-up. The HCC incidence rate was 0.95 (95% confidence interval [CI], .57-1.6) and 0.15 (95% CI, .05-.49) per 100 PY for patients with pretreatment F4 and F3, respectively. Patients with pretreatment cirrhosis and diabetes had a HR to develop HCC of 6.3, and an incidence rate of 7.9 per 100 PY (95% CI, 3.3-19) during the first 2 years of follow-up. The risk for HCC decreased significantly 2 years after SVR had been achieved. CONCLUSIONS: Diabetes mellitus and cirrhosis are strong risk factors for HCC development after SVR has been achieved. The risk to develop HCC diminishes significantly 2 years after SVR. Patients without cirrhosis have a low risk to develop HCC after SVR, and the benefit of HCC surveillance for this group is questionable.

A risk for hepatocellular carcinoma persists long-term after sustained virologic response in patients with hepatitis C-associated liver cirrhosis.

BACKGROUND: The long-term effect of sustained virologic response (SVR) to antiviral therapy on the risk of developing hepatocellular carcinoma (HCC), liver complications, liver-related death, and overall death in hepatitis C virus (HCV)-infected patients with liver cirrhosis is not fully known. METHODS: These risks were evaluated during long-term follow-up in 351 patients with HCV-related cirrhosis. One hundred ten patients with SVR, 193 with non-SVR, and 48 who were untreated were included in a multicenter cohort that was initiated in 2001 and prospectively followed up for a mean of 5.3 (SD, 2.8) years. Complementary follow-up data from national registries were used to minimize the loss of patients during follow-up. RESULTS: Six patients with SVR developed HCC at 0.04, 0.64, 2.4, 7.4, 7.4, and 7.6 years, respectively, after achieving SVR. The incidences of HCC, any liver complication, liver-related death, and overall death per 100 person-years were significantly lower in SVR time with 1.0, 0.9, 0.7, and 1.9, compared to 2.3, 3.2, 3.0, and 4.1 in non-SVR and 4.0, 4.9, 4.5, and 5.1 in untreated time. The long-term consequences did not decline significantly after >3 years versus during the first 3 years of follow-up. CONCLUSIONS: The risk for HCC, liver decompensation, and death in patients with liver cirrhosis related to HCV was markedly reduced after SVR, but a long-term risk of developing HCC remains for up to 8 years. Cirrhotic patients with HCV who achieve SVR should therefore maintain long-term surveillance for HCC. Future studies aimed to better identify those with remaining long-term risk for HCC are needed.