Weekly Clinical Update August 20, 2021

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Clinical Reports

Public Health Response to a Case of Paralytic Poliomyelitis in an Unvaccinated Person and Detection of Poliovirus in Wastewater — New York, June–August 2022
In June 2022, poliovirus was confirmed in an unvaccinated immunocompetent adult resident of New York hospitalized with flaccid lower limb weakness. Vaccine-derived poliovirus type 2 was isolated from the patient and identified from wastewater samples in two neighboring New York counties. Unvaccinated persons in the United States remain at risk for paralytic poliomyelitis if they are exposed to either wild or vaccine-derived poliovirus; all persons in the United States should stay up to date on recommended poliovirus vaccination.
Evidence of human-to-dog transmission of monkeypox virus
Human-to-human transmission of monkeypox virus usually occurs through close contact with the lesions, body fluids, and respiratory droplets of infected people or animals. The possibility of sexual transmission is being investigated, as the current outbreak appears to be concentrated in men who have sex with men and has been associated with unexpected anal and genital lesions. Whether domesticated cats and dogs could be a vector for monkeypox virus is unknown. Here researchers describe the first case of a dog with confirmed monkeypox virus infection that might have been acquired through human transmission.
What to Do If You Were Exposed to COVID-19 and its Isolation and Precautions for People with COVID-19
If you were exposed to the virus that causes COVID-19 or have been told by a healthcare provider or public health authority that you were exposed, here are the steps that you should take, regardless of your vaccination status or if you have had a previous infection. Learn how COVID-19 spreads and the factors that make risk of spread higher or lower.

Antiviral Therapeutics and Vaccines

Tecovirimat and the Treatment of Monkeypox — Past, Present, and Future Considerations
Tecovirimat is an antiviral drug that was approved for the treatment of smallpox disease under a regulation known as the “Animal Rule.” This pathway allows for approval of drugs for serious or life-threatening conditions when it is not ethical to conduct efficacy studies in humans and not feasible to conduct field trials to study the effectiveness of a drug or biologic product. Under the Animal Rule, efficacy is established on the basis of adequate and well-controlled studies in animal models of the human disease or condition of interest; safety must be adequately evaluated in people. Researchers recognize that monkeypox can cause severe disease and that tecovirimat has been shown to have efficacy in animal models of monkeypox and an acceptable safety profile in healthy people. Therefore, while RCTs are under development, the Centers for Disease Control and Prevention (CDC) and the FDA have worked together to streamline the expanded-access process by reducing paperwork and data collection,⁵and we will continue to fine-tune these mechanisms with input from health care providers using this process. In parallel, we believe that it remains critical to conduct RCTs in the United States to determine whether tecovirimat is a safe and effective treatment for monkeypox disease, especially given the disease’s clinical presentation in the current outbreak. As was the case with antiretrovirals for HIV in the 1980s, without data from RCTs, researchers will not know whether tecovirimat would benefit, harm, or have no effect on people with monkeypox disease. The CDC, the FDA, and the NIH will continue to work together to provide access to tecovirimat for compassionate use while appropriately evaluating its safety and efficacy in RCTs.
Pfizer Reports Additional Data on PAXLOVID™ Supporting Upcoming New Drug Application Submission to U.S. FDA
In the EPIC-SR study of PAXLOVID™(nirmatrelvir [PF-07321332] tablets and ritonavir tablets), the novel primary endpoint of self-reported, sustained alleviation of all symptoms for four consecutive days was not met, as previously reported Data from standard-risk patients, both vaccinated and unvaccinated, while not all statistically significant, are supportive of efficacy data observed in EPIC-HR study and will be included in upcoming NDA submission to U.S. FDA for high-risk patients. Pre-specified secondary endpoint resulted in a nominally significant 62% decrease in COVID-19-related medical visits per day across all patients, relative to placebo. In a sub-group analysis, non-significant 57% reduction in hospitalizations and death observed in PAXLOVID-treated vaccinated patients with at least one risk factor for severe COVID-19. Pfizer to cease enrollment into the EPIC-SR trial due to low rate of hospitalization or death in the standard-risk population; will continue to evaluate treatment in populations with high unmet need.
Hospitalization and Emergency Department Encounters for COVID-19 After Paxlovid Treatment
Recurrence of COVID-19 symptoms and positive SARS-CoV-2 test results have been reported after completion of Paxlovid oral antiviral treatment for COVID-19, but real-world evidence of severe illness following Paxlovid is lacking. COVID-19–related hospital admissions and emergency department (ED) encounters occurring 5–15 days after Paxlovid treatment were described using data from a large integrated health care system. Reports of such hospitalizations or ED encounters occurred infrequently, representing <1% of Paxlovid-treated patients over the study period. When administered as an early-stage treatment, Paxlovid might prevent COVID-19–related hospitalization among persons with mild-to-moderate COVID-19 who are at risk for progression to severe disease.
Effectiveness of Paxlovid in Reducing Severe COVID-19 and Mortality in High Risk Patients
Paxlovid was granted emergency use authorization for the treatment of mild to moderate COVID-19, based on the interim analysis of EPIC-HR trial. Paxlovid effectiveness needs to be assessed in a noncontrolled setting. In this study researchers used population-based real world data to evaluate the effectiveness of Paxlovid. The database of the largest healthcare provider in Israel was used to identify all adults aged 18 years or older with first ever positive test for SARS-CoV-2 between January and February 2022, who were at high risk for severe COVID-19 and had no contraindications for Paxlovid use. Patients were included irrespective of their COVID-19 vaccination status. Cox hazard regression was used to estimate the 28 day HR for severe COVID-19 or mortality with Paxlovid examined as time-dependent variable. Overall, 180,351 eligible were included, of them only 4,737 (2.6%) were treated with Paxlovid, and 135,482 (75.1%) had adequate COVID-19 vaccination status. Both Paxlovid and adequate COVID-19 vaccination status were associated with significant decrease in the rate of severe COVID-19 or mortality with adjusted HR 0.54 (95% CI, 0.39-0.75) and 0.20 (95% CI, 0.17-0.22), respectively. Paxlovid appears to be more effective in older patients, immunosuppressed patients, and patients with underlying neurological or cardiovascular disease (interaction p-value <0.05 for all). No significant interaction was detected between Paxlovid treatment and COVID-19 vaccination status. This study suggests that in the era of omicron and in real life setting Paxlovid is highly effective in reducing the risk of severe COVID-19 or mortality.
Randomized Trial of Metformin, Ivermectin,and Fluvoxamine for Covid-19
In this phase 3, double-blind, randomized, placebo-controlled trial, we used a 2-by-3 factorial design to test the effectiveness of three repurposed drugs — metformin, ivermectin, and fluvoxamine — in preventing serious SARS-CoV-2 infection in nonhospitalized adults who had been enrolled within 3 days after a confirmed diagnosis of infection and less than 7 days after the onset of symptoms. The patients were between the ages of 30 and 85 years, and all had either overweight or obesity. The primary composite end point was hypoxemia (≤93% oxygen saturation on home oximetry), emergency department visit, hospitalization, or death. All analyses used controls who had undergone concurrent randomization and were adjusted for SARS-CoV-2 vaccination and receipt of other trial medications. A total of 1431 patients underwent randomization; of these patients, 1323 were included in the primary analysis. The median age of the patients was 46 years; 56% were female (6% of whom were pregnant), and 52% had been vaccinated. The adjusted odds ratio for a primary event was 0.84 (95% confidence interval [CI], 0.66 to 1.09; P=0.19) with metformin, 1.05 (95% CI, 0.76 to 1.45; P=0.78) with ivermectin, and 0.94 (95% CI, 0.66 to 1.36; P=0.75) with fluvoxamine. In prespecified secondary analyses, the adjusted odds ratio for emergency department visit, hospitalization, or death was 0.58 (95% CI, 0.35 to 0.94) with metformin, 1.39 (95% CI, 0.72 to 2.69) with ivermectin, and 1.17 (95% CI, 0.57 to 2.40) with fluvoxamine. The adjusted odds ratio for hospitalization or death was 0.47 (95% CI, 0.20 to 1.11) with metformin, 0.73 (95% CI, 0.19 to 2.77) with ivermectin, and 1.11 (95% CI, 0.33 to 3.76) with fluvoxamine. None of the three medications that were evaluated prevented the occurrence of hypoxemia, an emergency department visit, hospitalization, or death associated with Covid-19.

Epidemiology

Retrospective detection of asymptomatic monkeypox virus infections among male sexual health clinic attendees in Belgium
The magnitude of the 2022 multi-country monkeypox virus outbreak has surpassed any preceding outbreak. It is unclear whether asymptomatic or otherwise undiagnosed infections are fueling this epidemic. Researchers aimed to assess whether undiagnosed infections occurred among men attending a Belgian sexual health clinic in May 2022. Researchers retrospectively screened 224 samples collected for gonorrhea and chlamydia testing using a monkeypox virus (MPXV) PCR assay, and identified MPXV DNA-positive samples from four men. At the time of sampling, one man had a painful rash, and three men had reported no symptoms. Upon clinical examination 21 to 37 days later, these three men were free of clinical signs and they reported not having experienced any symptoms. Serology confirmed MPXV exposure in all three men, and MPXV was cultured from two cases. These findings show that certain cases of monkeypox remain undiagnosed, and suggest that testing and quarantining of individuals reporting symptoms may not suffice to contain the outbreak.
Risk of SARS-CoV-2 Acquisition in Health Care Workers According to Cumulative Patient Exposure and Preferred Mask Type
In this study, SARS-CoV-2 positivity in HCWs was associated with cumulative COVID-19 patient exposure. The odds of being SARS-CoV-2–positive were reduced by more than 40% in individuals using respirators irrespective of cumulative exposure, even after adjusting for multiple work- and nonwork-related covariables. These data suggest a dose-response association between COVID-19-patient exposure and risk of SARS-CoV-2 infection in HCWs. The presumable protection conferred by respirator use is in line with previous data.¹^,⁴Self-reporting of preferred mask type and residual confounding are potential study limitations. Consequent use of respirators and SARS-CoV-2 vaccination might substantially decrease the work-related risk for HCWs exposed to patients with COVID-19. Whether these results are applicable to newer viral variants, which are more contagious and less neutralized by most vaccines,⁶ remains to be seen.
Effectiveness of HEPA Filters at Removing Infectious SARS-CoV-2 from the Air
Coronavirus disease 2019 (COVID-19) spreads by airborne transmission; therefore, the development and functional evaluation of air-cleaning technologies are essential for infection control. Air filtration using high-efficiency particulate air (HEPA) filters may be effective; however, no quantitative assessment of the effectiveness of these filters in the removal of infectious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from the air has been reported. To evaluate the removal effect of HEPA filtration on airborne SARS-CoV-2, here, researchers disseminated infectious SARS-CoV-2 aerosols in a test chamber in a biosafety level 3 facility and filtered the air with a HEPA-filtered air cleaner in the chamber. The air cleaner with the HEPA filter continuously removed the infectious SARS-CoV-2 from the air in a running-time-dependent manner, and the virus capture ratios were 85.38%, 96.03%, and >99.97% at 1, 2, and 7.1 ventilation volumes, respectively. The air-cleaning performance of a HEPA filter coated with an antiviral agent consisting mainly of a monovalent copper compound was also evaluated, and the capture ratio was found to be comparable to that of the conventional HEPA filter. This study provides insights into the proper use and performance of HEPA-filtered air cleaners to prevent the spread of COVID-19.
Readmissions, post-discharge mortality and sustained recovery among patients admitted to hospital with COVID-19
Many interventional in-patient COVID-19 trials assess primary outcomes through day 28 post-randomization. Since a proportion of patients experience protracted disease or relapse, such follow-up period may not fully capture the course of the disease, even when randomization occurs a few days after hospitalization. Among adults hospitalized with COVID-19 in Eastern Denmark from March 18, 2020 - January 12, 2021 researchers assessed: all-cause mortality, recovery and sustained recovery 90 days after admission, and readmission and all-cause mortality 90 days after discharge. Recovery was defined as hospital discharge and sustained recovery as recovery and alive without readmissions for 14 consecutive days. Among 3,386 patients included in the study 2,796 (82.6%) reached recovery and 2,600 (77.0%) achieved sustained recovery. Of those discharged from hospital, 556 (19.9%) were readmitted, and 289 (10.3%) died. Overall, the median time to recovery was 6 days (Interquartile range (IQR), 3-10), and 19 days (IQR, 11-33) among patients in intensive care in the first two days of admission. Post-discharge readmission and mortality rates were substantial. Therefore, sustained recovery should be favored to recovery outcomes in clinical COVID-19 trials. A 28-day follow-up period may be too short the critically ill.