Efficacy and safety of Paxlovid in severe adult patients with SARS-Cov-2 infection: a multicenter randomized controlled study.

Background: Nirmatrelvir plus ritonavir (Paxlovid) reduced the risk of hospitalization or death by 89% in high-risk, ambulatory adults with COVID-19. We aimed at studying the efficacy and safety of Paxlovid in hospitalized adult patients with SARS-Cov-2 (Omicron BA.2.2 variant) infection and severe comorbidities. Methods: We conducted an open-label, multicenter, randomized controlled trial in which hospitalized adult patients with severe comorbidities were eligible and assigned in a 1:1 ratio to receive either 300 mg of nirmatrelvir plus 100 mg of ritonavir every 12 h for 5 days with standard treatment or only standard treatment. All-cause mortality on day 28, the duration of SARS-CoV-2 RNA clearance, and safety were evaluated. Findings: 264 patients (mean age, 70.35 years; 122 [46.21%] female) who met the criteria were enrolled at 5 sites in Shanghai from April 10 to May 19 in 2022. After randomization, a total of 132 patients were assigned to receive Paxlovid treatment plus standard treatment, and 132 patients were assigned to receive only standard treatment. The overall 28-day mortality was 4.92%, 8 patients died in the standard treatment group and 5 died in the Paxlovid plus standard treatment group. There was no significant difference in mortality from any cause at 28 days between the Paxlovid plus standard treatment group and the standard treatment group (absolute risk difference [ARD], 2.27; 95% CI -2.94 to 7.49, P = 0.39). There was no significant difference in the duration of SARS-CoV-2 RNA clearance among the two groups (mean days, 10 in Paxlovid plus standard treatment group and 10.50 in the standard treatment group; ARD, -0.62; 95% CI -2.29 to 1.05, P = 0.42). The incidence of adverse events that occurred during the treatment period was similar in the two groups (any adverse event, 10.61% with Paxlovid plus standard treatment vs. 7.58% with the standard, P = 0.39; serious adverse events, 4.55% vs. 3.788%, P = 0.76). Interpretation: Paxlovid showed no significant reduction in the risk of all-cause mortality on day 28 and the duration of SARS-CoV-2 RNA clearance in hospitalized adult COVID-19 patients with severe comorbidities. Funding: National Natural Science Foundation of China (grant number: 82172152, 81873944).

Efficacy and safety of Paxlovid in severe adult patients with SARS-Cov-2 infection: a multicenter randomized controlled study

Background Nirmatrelvir plus ritonavir (Paxlovid) reduced the risk of hospitalization or death by 89% in high-risk, ambulatory adults with COVID-19. We aimed at studying the efficacy and safety of Paxlovid in hospitalized adult patients with SARS-Cov-2 (Omicron BA.2.2 variant) infection and severe comorbidities. Methods We conducted an open-label, multicenter, randomized controlled trial in which hospitalized adult patients with severe comorbidities were eligible and assigned in a 1:1 ratio to receive either 300 mg of nirmatrelvir plus 100 mg of ritonavir every 12 h for 5 days with standard treatment or only standard treatment. All-cause mortality on day 28, the duration of SARS-CoV-2 RNA clearance, and safety were evaluated. Findings 264 patients (mean age, 70.35 years;122 [46.21%] female) who met the criteria were enrolled at 5 sites in Shanghai from April 10 to May 19 in 2022. After randomization, a total of 132 patients were assigned to receive Paxlovid treatment plus standard treatment, and 132 patients were assigned to receive only standard treatment. The overall 28-day mortality was 4.92%, 8 patients died in the standard treatment group and 5 died in the Paxlovid plus standard treatment group. There was no significant difference in mortality from any cause at 28 days between the Paxlovid plus standard treatment group and the standard treatment group (absolute risk difference [ARD], 2.27;95% CI −2.94 to 7.49, P = 0.39). There was no significant difference in the duration of SARS-CoV-2 RNA clearance among the two groups (mean days, 10 in Paxlovid plus standard treatment group and 10.50 in the standard treatment group;ARD, −0.62;95% CI −2.29 to 1.05, P = 0.42). The incidence of adverse events that occurred during the treatment period was similar in the two groups (any adverse event, 10.61% with Paxlovid plus standard treatment vs. 7.58% with the standard, P = 0.39;serious adverse events, 4.55% vs. 3.788%, P = 0.76). Interpretation Paxlovid showed no significant reduction in the risk of all-cause mortality on day 28 and the duration of SARS–CoV-2 RNA clearance in hospitalized adult COVID-19 patients with severe comorbidities. Funding 10.13039/501100001809National Natural Science Foundation of China (grant number: 82172152, 81873944).

Nirmatrelvir-ritonavir therapy and COVID-19 vaccination improve clinical outcomes of SARS-CoV-2 Omicron variant infection.

To evaluate the effect of Nirmatrelvir-ritonavir therapy and coronavirus disease 2019 (COVID-19) vaccination on clinical outcomes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron infection, we retrospectively analyzed the clinical data of 762 adult patients with confirmed Omicron BA2.2 variant infection, of them 488 patients received standard therapy and 274 patients received Nirmatrelvir-ritonavir therapy. Subjects were matched by propensity score matching using R language, the baseline factors were balanced by the nearest-neighbor matching method and were compared, together with the factors including progression to severe/critical disease, viral clearance time, length of hospital stay, and virological rebound of SARS-CoV-2 infection. Nirmatrelvir-ritonavir therapy significantly accelerated viral clearance at Days 14 and  28 during hospitalization, but it had no impact on disease progression, length of hospital stay, or infection rebound. In contrast, COVID-19 vaccination before admission was positively correlated with the viral clearance rate and negatively correlated with disease progression in a dose-dependent way. COVID-19 vaccination reduced the probability of infection rebound. Other factors such as the number of comorbidities, pneumonia on-admission, and high D2 levels were positively correlated with disease progression. Our study strongly recommended booster COVID-19 vaccination for the elderly population, particularly patients with comorbidities to prevent critical disease.

Utility of urine lipoarabinomannan (LAM) in diagnosing mycobacteria infection among hospitalized HIV-positive patients.

OBJECTIVES: Cross-reactivity with nontuberculous mycobacteria (NTM) species might limit the use of urine lipoarabinomannan (LAM) test to diagnose tuberculosis (TB) in people living with HIV (PLWH). This study aimed to investigate the utility of the LAM test among hospitalized HIV-positive patients. METHODS: This prospective study enrolled HIV-positive inpatients with any TB symptom or seriously ill patients with advanced immunodeficiency. Urine samples were tested using the Alere Determine LAM Ag, and participants were categorized as confirmed TB, confirmed NTM infection, unclassified mycobacteria infection, and no mycobacteria infection based on microbiologic reference standards. RESULTS: A total of 382 participants were included. The prevalence of confirmed TB and NTM infection was 5.24% (20 of 382) and 4.45% (17 of 382), respectively. The sensitivity and specificity of the urine LAM for TB diagnosis were 65.00% (95% confidence interval [CI] 40.78-84.61) and 89.36% (95% CI 85.68-92.36), respectively. The LAM test for NTM yielded a sensitivity of 58.82% (95% CI 32.92-81.56) and specificity of 88.61% (95% CI 84.87-91.70). Notably, the negative predictive values of the urine LAM for TB and NTM were 97.85% (95% CI 95.63-99.13) and 97.85% (95% CI 95.63-99.13), respectively. CONCLUSIONS: Cross-reactivity with NTM cause high false-positive LAM for TB diagnosis in PLWH. The correct identification of mycobacteria species is crucial for deciding treatment strategies.

Therapeutic Monitoring of Plasma Digoxin for COVID-19 Patients Using a Simple UPLC-MS/MS Method

Background: Cardiovascular diseases (CVD) have been reported in 8%-16% of patients with 2019 coronavirus disease (COVID-19). Digoxin is one of the main drugs to treat CVD. Objective: The clinician conducted therapeutic drug monitoring (TDM) of digoxin according to the drug usage on patients to monitor the concentration of digoxin, so as to avoid its toxic and side effects, and provide a theoretical reference for clinical usage of digoxin in patients with COVID-19. Methods: A method for quantifying digoxin concentration in plasma with ultra-performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) was developed. After simple protein precipitation of plasma with methanol, digoxin and its internal standard (digoxin-d3) were detected in the positive ion mode using multiple reaction monitoring. Results: Plasma digoxin in the range of 0.2 - 10 ng/mL had good linearity. The UPLC-MS/MS method was validated with inter-run accuracies ranging from 91.3% to 107.4% and precision less than 13%. Nine plasma samples (5 at valley concentration and 4 at follow-up after stopping dosing) from three patients with COVID-19 were tested. The mean plasma digoxin concentration was 0.73 ng/mL (ranged from 0 to 1.31 ng/mL). Digoxin was detected at the concentration of 0.93 ng/mL after stopping drug administration for 14 days. Conclusion: In this study, we established a simple UPLC-MS/MS method using protein-precipitation to perform TDM of digoxin in patients with COVID-19, and found that about 56% of digoxin plasma concentration was within the treatment window (0.8 - 2.0 ng/mL). Digoxin can be remained in the body for nearly 14 days in severe patients with COVID-19 after stopping dosing.

Comparing SARS-CoV-2 Testing in Anterior Nasal Vestibular Swabs vs. Oropharyngeal Swabs.

Purpose: To investigate the sensitivity of SARS-CoV-2 testing in specimens collected from the anterior nasal vestibules of COVID-19 patients. Methods: A cross-sectional analysis was performed on 30 patients with a confirmed diagnosis of COVID-19 at the Shanghai Public Health Clinical Center from March 14, 2020 to March 21, 2020. Paired specimens were collected from both the anterior nasal vestibule and the oropharynx from all patients. All specimens were tested for SARS-CoV-2 using reverse transcription-polymerase chain reaction (RT-PCR) assays. Results: Of the 30 patients with confirmed COVID-19, 17 patients (56.7%) tested positive for SARS-CoV-2 when oropharyngeal specimens were used, while 20 patients (66.7%) tested positive when nasal swab specimens were used. There was no statistically significant difference in sensitivity between the two methods. Conclusions: Respiratory swabs collected from the nasal vestibule offer a less invasive alternative to oropharyngeal swabs for specimen collection in the detection of SARS-CoV-2 infection, and have adequate sensitivity.

Thymosin Alpha-1 Has no Beneficial Effect on Restoring CD4+ and CD8+ T Lymphocyte Counts in COVID-19 Patients.

Dysregulation of immune response was observed in COVID-19 patients. Thymosin alpha 1 (Tα1) is used in the management of COVID-19, because it is known to restore the homeostasis of the immune system during infections and cancers. We aim to observe the longitudinal changes in T lymphocyte subsets and to evaluate the efficacy of Tα1 for COVID-19. A retrospective study was conducted in 275 COVID-19 patients admitted to Shanghai public health clinical center. The clinical and laboratory characteristics between patients with different T lymphocyte phenotypes and those who were and were not treated with Tα1 were compared. Among the 275 patients, 137 (49.8%) were males, and the median age was 51 years [interquartile range (IQR): 37-64]. A total of 126 patients received Tα1 therapy and 149 patients did not. There were 158 (57.5%) patients with normal baseline CD4 counts (median:631/µL, IQR: 501~762) and 117 patients (42.5%) with decreased baseline CD4 counts (median:271/µL, IQR: 201~335). In those with decreased baseline CD4 counts, more patients were older (p<0.001), presented as critically ill (p=0.032) and had hypertension (p=0.008) compared with those with normal CD4 counts. There was no statistical difference in the duration of virus shedding in the upper respiratory tract between the two groups (p=0.214). In both the normal (14 vs 11, p=0.028) and the decreased baseline CD4 counts group (15 vs 11, p=0.008), duration of virus clearance in the patients with Tα1 therapy was significantly longer than that in those without Tα1 therapy. There was no significant difference in the increase of CD4+ (286 vs 326, p=0.851) and CD8+ T cell (154 vs 170, p=0.842) counts in the recovery period between the two groups with or without Tα1 therapy. Multivariate linear regression analysis showed that severity of illness (p<0.001) and Tα1 therapy (p=0.001) were associated with virus clearance. In conclusion, reduction of CD4+ T and CD8+ T cell counts were observed in COVID-19 patients. Tα1 may have no benefit on restoring CD4+ and CD8+ T cell counts or on the virus clearance. The use of Tα1 for COVID-19 need to be more fully investigated.

Case report: histopathology and molecular pathology analysis on enteric tissue of a COVID-19 patient.

AIMS: Patients with COVID-19 can also have enteric symptoms. Here we analyzed the histopathology of intestinal detachment tissue from a patient with COVID-19. METHODS: The enteric tissue was examined by hematoxylin & eosin stain, PAS (Periodic acid-Schiff) staining, Gram staining, Ziehl-Neelsen stain and Grocott's Methenamine Silver (GMS) Stain. The distribution of CD3, CD4, CK20 and CD68, cytomegalovirus (CMV) and Herpes Simplex Virus (HSV) antigen were determined by immunohistochemistry. In situ hybridization (ISH) of SARS-CoV-2 and Epstein-Barr virus-encoded small RNA (EBER) were also performed. RESULTS: We observed mucosal epithelium shedding, intestinal mucosal erosion, focal inflammatory necrosis with hemorrhage, massive neutrophil infiltration, macrophage proliferation accompanied by minor lymphocyte infiltration. Fungal spores and gram positive cocci but not mycobacteria tuberculosis were identified. Immunohistochemistry staining showed abundant CD68+ macrophages but few lymphocytes infiltration. HSV, CMV and EBV were negative. ISH of SARS-CoV-2 RNA showed positive signal which mostly overlapped with CD68 positivity. CONCLUSIONS: The in situ detection of SARS-CoV-2 RNA in intestinal macrophages implicates a possible route for gastrointestinal infection. Further study is needed to further characterize the susceptibility of enteric cells to SARS-CoV-2 infection.

Detection of SARS-CoV-2 in the ocular surface in different phases of COVID-19 patients in Shanghai, China.

BACKGROUND: To investigate the temporal pattern of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presence on ocular surfaces using conjunctival swabs in coronavirus disease 2019 (COVID-19) patients. METHODS: This study included 59 patients (32 newly admitted and 27 hospitalized for ≥2 weeks) with a COVID-19-confirmed diagnosis at the Shanghai Public Health Clinical Center from March 3, 2020, to March 21, 2020. Conjunctival swab samples were collected from both eyes of all the 59 patients and were tested by reverse transcription polymerase chain reaction (RT-PCR) assay. The range of sampling time lies widely between 1 and 50 days since symptom onset. RESULTS: Among the 32 newly admitted patients, positive RT-PCR results for SARS-CoV-2 in conjunctival swab samples were reported in 2 patients (one eye for each) without ocular discomfort, but 1 positive case had conjunctival congestion. The positive results were detected on Day 5 for 1 patient and Day 7 for the other, but repeated tests after 1 week were negative for both patients. All 27 patients who had been hospitalized for ≥2 weeks had negative test results. The mean time from symptom onset to sampling of 2 positive cases was significantly less than that of 57 negative cases (P<0.001). CONCLUSIONS: SARS-CoV-2 on the ocular surface can be detected in the early phase of COVID-19. The risk of ocular transmission remains and might be higher in the early phase.

Clinical progression of patients with COVID-19 in Shanghai, China.

BACKGROUND: Studies on the 2019 novel coronavirus disease (COVID-19) have generally been limited to the description of the epidemiology and initial clinical characteristics. We investigated the temporal progression in patients with COVID-19. METHODS: In this retrospective, single-center study, we included confirmed cases of COVID-19 from Jan 20 to Feb 6, 2020 in Shanghai. Final date of follow-up was February 25, 2020. RESULTS: Of the 249 patients enrolled, the median age was 51 years old, and 126 (50.6%) were male. The duration from onset of symptoms to hospitalization was 4(2-7) days in symptomatic patients. Fever was occurred in 235(94.3%) patients. A total of 215 (86.3%) patients had been discharged after 16(12-20) days hospitalization. The estimated median duration of fever in all the patients with fever was 10 days (95 confidential intervals [CIs]: 8-11 days) after onset of symptoms. Patients who were transferred to intensive care units (ICU) had significantly longer duration of fever as compared to those not in ICU (31 days v.s. 9 days after onset of symptoms, respectively, P <0.0001). Radiological aggravation of initial image was observed in 163 (65.7%) patients on day 7 after onset of symptoms. 154(94.5%) of these patients showed radiological improvement on day 14. The median duration to negative reverse-transcriptase PCR tests of upper respiratory tract samples was 11 days (95 CIs: 10-12 days). Viral clearance was more likely to be delayed in patients in ICU than those not in ICU (P <0.0001). In multivariate logistical analysis, age (Odds ratio [OR] = 1.06) and CD4 T cell count (OR = 0.55 per 100 cells/ul increase) were independently associated with ICU admission. CONCLUSIONS: The majority of COVID-19 cases are mild. The clinical progression pattern suggests that early control of viral replication and application of host-directed therapy in later stage is essential to improve the prognosis of CVOID-19.