Remdesivir and Ledipasvir among the FDA-Approved Antiviral Drugs Have Potential to Inhibit SARS-CoV-2 Replication.

The rapid spread of the virus, the surge in the number of deaths, and the unavailability of specific SARS-CoV-2 drugs thus far necessitate the identification of drugs with anti-COVID-19 activity. SARS-CoV-2 enters the host cell and assembles a multisubunit RNA-dependent RNA polymerase (RdRp) complex of viral nonstructural proteins that plays a substantial role in the transcription and replication of the viral genome. Therefore, RdRp is among the most suitable targets in RNA viruses. Our aim was to investigate the FDA approved antiviral drugs having potential to inhibit the viral replication. The methodology adopted was virtual screening and docking of FDA-approved antiviral drugs into the RdRp protein. Top hits were selected and subjected to molecular dynamics simulations to understand the dynamics of RdRp in complex with these drugs. The antiviral activity of the drugs against SARS-CoV-2 was assessed in Vero E6 cells. Notably, both remdesivir (half-maximal effective concentration (EC50) 6.6 µM, 50% cytotoxicity concentration (CC50) > 100 µM, selectivity index (SI) = 15) and ledipasvir (EC50 34.6 µM, CC50 > 100 µM, SI > 2.9) exerted antiviral action. This study highlights the use of direct-acting antiviral drugs, alone or in combination, for better treatments of COVID-19.

Toll-like receptor 2 downregulation and cytokine dysregulation predict mortality in patients with Staphylococcus aureus bacteremia.

BACKGROUND: Staphylococcus aureus bacteremia (SAB) presents heterogeneously, owing to the differences in underlying host conditions and immune responses. Although Toll-like receptor 2 (TLR2) is important in recognizing S. aureus, its function during S. aureus infection remains controversial. We aimed to examine the association of TLR2 expression and associated cytokine responses with clinical SAB outcomes. METHODS: Patients from a prospective SAB cohort at two tertiary-care medical centers were enrolled. Blood was sampled at several timepoints (≤5 d, 6-9 d, 10-13 d, 14-19 d, and ≥ 20 d) after SAB onset. TLR2 mRNA levels were determined via real-time PCR and serum tumor necrosis factor [TNF]-α, interleukin [IL]-6, and IL-10 levels were analyzed with multiplex-high-sensitivity electrochemiluminescent ELISA. RESULTS: TLR2 levels varied among 59 SAB patients. On days 2-5, TLR2 levels were significantly higher in SAB survivors than in healthy controls (p = 0.040) and slightly but not significantly higher than non-survivors (p = 0.120), and SAB patients dying within 7 d had lower TLR2 levels than survivors (P = 0.077) although statistically insignificant. IL-6 and IL-10 levels were significantly higher in non-survivors than in survivors on days 2-5 post-bacteremia (P = 0.010 and P = 0.021, respectively), and those dying within 7 d of SAB (n = 3) displayed significantly higher IL-10/TNF-α ratios than the survivors did (P = 0.007). CONCLUSION: TLR2 downregulation and IL-6 and IL-10 concentrations suggestive of immune dysregulation during early bacteremia may be associated with mortality from SAB. TLR2 expression levels and associated cytokine reactions during early-phase SAB may be potential prognostic factors in SAB, although larger studies are warranted.

Clinical Progression and Cytokine Profiles of Middle East Respiratory Syndrome Coronavirus Infection.

Clinical progression over time and cytokine profiles have not been well defined in patients with Middle East respiratory syndrome coronavirus (MERS-CoV) infection. We included 17 patients with laboratory-confirmed MERS-CoV during the 2015 outbreak in Korea. Clinical and laboratory parameters were collected prospectively. Serum cytokine and chemokine levels in serial serum samples were measured using enzyme-linked immunosorbent assay. All patients presented with fever. The median time to defervescence was 18 days. Nine patients required oxygen supplementation and classified into severe group. In the severe group, chest infiltrates suddenly began to worsen around day 7 of illness, and dyspnea developed at the end of the first week and became apparent in the second week. Median time from symptom onset to oxygen supplementation was 8 days. The severe group had higher neutrophil counts during week 1 than the mild group (4,500 vs. 2,200/µL, P = 0.026). In the second week of illness, the severe group had higher serum levels of IL-6 (54 vs. 4 pg/mL, P = 0.006) and CXCL-10 (2,642 vs. 382 pg/mL, P < 0.001). IFN-α response was not observed in mild cases. Our data shows that clinical condition may suddenly deteriorate around 7 days of illness and the serum levels of IL-6 and CXCL-10 was significantly elevated in MERS-CoV patients who developed severe diseases.

Cancer-specific incidence rates of tuberculosis: A 5-year nationwide population-based study in a country with an intermediate tuberculosis burden.

Population-based studies of the incidence of tuberculosis in cancer patients according to the type of cancer are limited. We investigated the cancer-specific incidence of tuberculosis in a nationwide population-based cohort in a country with an intermediate burden of tuberculosis.We used mandatory National Health Insurance claims data to construct a cancer cohort of adults (aged 20-99 years) with newly diagnosed malignancies other than lung cancer, from January 2008 to December 2012. Patients who developed tuberculosis in this period were identified in the cancer cohort and the general population. Standardized incidence ratios (SIRs) of tuberculosis in the cancer cohort according to type of cancer and time after cancer diagnosis were calculated by comparing the observed incidence rates with those inferred from the age- and gender-specific incidence rates in the general population.A total of 855,382 cancer patients and 1589,876 person-years (py) were observed. A total of 5745 patients developed tuberculosis; the mean incidence rate was 361.3 per 100,000 py, and the SIR was 2.22 (95% confidence interval [CI], 2.17-2.27). The incidence rate was highest for hematologic malignancy and lowest for thyroid cancer. It was also highest as 650.1 per 100,000 py, with SIR of 3.70 (CI, 3.57-3.83) for the first 6 months after diagnosis of malignancy and then declined. However, it still remained higher than that of the general population after 24 months (SIR = 1.43, CI, 1.36-1.51).The incidence of tuberculosis increases after diagnosis in patients with malignancies. The risk of tuberculosis differs according to the type of cancer and remains elevated even 24 months after cancer diagnosis. Tuberculosis should be considered an important comorbidity in patients with malignancies.

Hemophagocytic lymphohistiocytosis associated with SFTS virus infection: A case report with literature review.

BACKGROUND: Severe fever with thrombocytopenia syndrome (SFTS) is a new emerging zoonosis. Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening syndrome caused by hyperinflammation. Here, we report the case of SFTS-associated HLH. CASE SUMMARY: A 62-year-old man was admitted to local hospital with 8 days of fever and chill. He had leukopenia, thrombocytopenia, and developed seizure. An attending physician examined bone marrow to rule out hematologic malignancy. He was transferred to tertiary referral hospital for suspicious HLH. We decided to confirm its histologic feature for sure. Bone marrow and liver biopsy showed hemophagocyotic histiocytes. Serological tests for other infections were all negative except SFTS virus polymerase chain reactions (PCRs) as positive from serum, bone marrow, bronchoalveolar lavage fluid, and liver biopsy specimen. A definitive diagnosis was SFTS-associated HLH. During 2 weeks of conservative treatment, he succeeded in recovery from multiple organ failure. CONCLUSION: SFTS should be considered one of differential diagnosis of HLH. In certain endemic areas, SFTS infection deserves clinicians' attention because it can be presented hematologic diseases as HLH.

Differences in characteristics between first and breakthrough neutropenic fever after chemotherapy in patients with hematologic disease.

OBJECTIVE: This study was conducted to compare the clinical and microbiological characteristics of first and breakthrough neutropenic fever in hematologic malignancy patients after chemotherapy. METHODS: Breakthrough neutropenic fever was any episode of fever, not present initially, that developed either during antibiotic therapy or within 1 week of discontinuation of therapy. A total of 687 neutropenic fever episodes in 241 patients were observed from April 2003 to March 2014. RESULTS: Blood cultures revealed 210 causative microorganisms: 199 (94.8%) were bacteria and 11 (5.2%) were fungi. Gram-negative bacteria predominated in both types of neutropenic episode (first 75% (120/160) vs. breakthrough 56% (18/32)) and the most common pathogen was Escherichia coli. Antibiotic resistance rates were higher in breakthrough episodes than first episodes (piperacillin/tazobactam 6% vs. 31%, p=0.006; ceftazidime 9% vs. 31%, p=0.025). Inappropriate empirical antibiotic treatment was also more frequent (0% vs. 19%, p=0.001), as was the 30-day mortality rate (4.3% (19/442) vs. 7.9% (19/245), p=0.058), although the latter effect was not statistically significant. CONCLUSION: It is concluded that the epidemiological profile of breakthrough neutropenic fever is different from that of first episode fever. These data reinforce the view that pooled reporting of neutropenic fever may be misleading, and that clinicians should approach breakthrough fever as a distinct entity.

Factors influencing culture positivity in pyogenic vertebral osteomyelitis patients with prior antibiotic exposure.

We conducted a retrospective cohort study to evaluate factors influencing tissue culture positivity in patients with pyogenic vertebral osteomyelitis exposed to antibiotics before diagnosis. Tissue culture was positive in 48.3% (28/58) of the patients, and the median antibiotic-free period was 1.5 days (range, 0.7 to 5.7 days). In a multivariate analysis, a higher C-reactive protein (CRP) level (adjusted odds ratio [aOR], 1.18; 95% confidence interval, 1.07 to 1.29) and open surgical biopsy (aOR, 6.33; 95% confidence interval, 1.12 to 35.86) were associated with tissue culture positivity.