Coronavirus Disease 2019 Outpatients Research Articles

Evaluation of Antibody Response and Reinfection in Improved Hypertensive, Cardiac, and Diabetic Patients with COVID-19 for six Months in Unvaccinated Outpatients

Background: This study presents a unique investigation into the relationship between the persistence of IgG antibody levels and reinfection in recovered coronavirus disease 2019 (COVID-19) patients. By shedding light on this aspect, we aim to address concerns about the risk of reinfection in unvaccinated patients, offering a fresh perspective in the current COVID-19 research landscape. Objectives: This study takes a novel approach by focusing on the antibody response and reinfection in COVID-19 patients who were treated in outpatient settings for six months. This approach distinguishes our research within the broader context of COVID-19 studies. Methods: Our comprehensive and rigorous prospective cohort study included 149 COVID-19 outpatients referred to Imam Ali Clinic in Dezfoul City, Khuzestan province, Iran. Data was meticulously collected from September 2021 to February 2022. All unvaccinated patients underwent RT-PCR testing, and their anti-SARS-CoV-2 IgM/IgG levels were measured at the onset of illness. Serum IgG levels were then measured again after three and six months using ELISA. Results: All COVID-19 patients had their IgG antibody levels tested three times (on days two to four of the illness, at three months, and at six months). Significant differences in IgG antibody levels were observed between the vaccinated and unvaccinated groups during each period (P < 0.05). Additionally, there were substantial differences between the hypertension and non-hypertension groups (P = 0.032). Importantly, our findings reaffirm the impartiality of our research, as no significant differences were found between reinfection rates and various demographic or disease-related factors. Conclusions: The findings of this study suggest that high levels of IgG antibodies in unvaccinated patients could potentially reduce the risk of reinfection. This insight could have important implications for public health strategies and the management of COVID-19 in unvaccinated populations, providing valuable information for decision-makers in the field.

Severe Acute Respiratory Syndrome Coronavirus 2 Plasma Antibody and Nucleocapsid Antigen Status Predict Outcomes in Outpatients With Coronavirus Disease 2019.

Reliable biomarkers of coronavirus disease 2019 (COVID-19) outcomes are critically needed. We evaluated associations of spike antibody (Ab) and plasma nucleocapsid antigen (N Ag) with clinical outcomes in nonhospitalized persons with mild-to-moderate COVID-19. Participants were nonhospitalized adults with mild-to-moderate COVID-19 enrolled in ACTIV-2 between January and July 2021 and randomized to placebo. We used quantitative assays for severe acute respiratory syndrome coronavirus 2 spike Ab and N Ag in blood and determined numbers of hospitalization/death events within 28 days and time to symptom improvement. Of 209 participants, 77 (37%) had quantifiable spike Ab and 139 (67%) quantifiable N Ag. Median age was 50 years; 111 (53%) were female, 182 (87%) White, and 105 (50%) Hispanic/Latino. Higher risk of hospitalization/death was seen with unquantifiable (22/132 [16.7%]) versus quantifiable (1/77 [1.3%]) spike Ab (risk ratio [RR], 12.83 [95% confidence interval {CI}, 1.76-93.34]) and quantifiable (22/139 [15.8%]) vs unquantifiable (1/70 [1.4%]) N Ag (RR, 11.08 [95% CI, 1.52-80.51]). Increasing risk of hospitalizations/deaths was seen with increasing N Ag levels. Time to symptom improvement was longer with unquantifiable versus quantifiable spike Ab (median, 14 [interquartile range {IQR}, 8 to >27] vs 8 [IQR, 4-22] days; adjusted hazard ratio [aHR], 0.66 [95% CI, .45-.96]) and with quantifiable versus unquantifiable N Ag (median, 12 [7 to >27] vs 10 [5-22] days; aHR, 0.79 [95% CI, .52-1.21]). Absence of spike Ab and presence of plasma N Ag predicted hospitalization/death and delayed symptom improvement in COVID-19 outpatients.

Molnupiravir's real-world effectiveness in COVID-19 outpatients at high risk of severe disease: a single-center study.

The coronavirus disease 2019 (COVID-19) pandemic started in March 2020. Since then, there has been an urgent need for effective therapeutic methods to manage the disease. We aimed to assess the effectiveness of molnupiravir in reducing the need for hospitalization in at-risk, non-hospitalized COVID-19 patients. This was a single-center, non-randomized, observational retrospective study of non-hospitalized patients with confirmed COVID-19, treated at the Clinic for Infectious and Tropical Diseases, University Clinical Center in Belgrade, Serbia. The study was conducted between 15 December 2021 and 15 February 2022 and included 320 patients. Of these, 165 (51.6%) received treatment with molnupiravir. The study and control groups were similar in gender and age distribution. The study group had a higher proportion of vaccination (75.2% vs. 51%, p < 0.001). There was no statistically significant difference in presence of comorbidity within the groups. Majority of the patients who received molnupiravir did not require hospitalization; and this was statistically significant in comparison to control group (92.7 vs. 24.5%, p < 0.001). Oxygen supplementation was less frequently required in the study group compared to the control group (0.6% vs. 31%, p < 0.001). During the follow-up period of 12.12 ± 3.5 days, significantly less patients from the study group were admitted to the intensive care unit (p < 0.001). Molnupiravir significantly reduced the risk of hospitalization by 97.9% (HR 0.021; 95% CI 0.005-0.089; p < 0.001). Molnupiravir is an effective therapy in preventing the development of severe forms of COVID-19 and hospitalization.

Outpatient treatment with concomitant vaccine-boosted convalescent plasma for patients with immunosuppression and COVID-19.

Although severe coronavirus disease 2019 (COVID-19) and hospitalization associated with COVID-19 are generally preventable among healthy vaccine recipients, patients with immunosuppression have poor immunogenic responses to COVID-19 vaccines and remain at high risk of infection with SARS-CoV-2 and hospitalization. In addition, monoclonal antibody therapy is limited by the emergence of novel SARS-CoV-2 variants that have serially escaped neutralization. In this context, there is interest in understanding the clinical benefit associated with COVID-19 convalescent plasma collected from persons who have been both naturally infected with SARS-CoV-2 and vaccinated against SARS-CoV-2 ("vax-plasma"). Thus, we report the clinical outcome of 386 immunocompromised outpatients who were diagnosed with COVID-19 and who received contemporary COVID-19-specific therapeutics (standard-of-care group) and a subgroup who also received concomitant treatment with very high titer COVID-19 convalescent plasma (vax-plasma group) with a specific focus on hospitalization rates. The overall hospitalization rate was 2.2% (5 of 225 patients) in the vax-plasma group and 6.2% (10 of 161 patients) in the standard-of-care group, which corresponded to a relative risk reduction of 65% (P = 0.046). Evidence of efficacy in nonvaccinated patients cannot be inferred from these data because 94% (361 of 386 patients) of patients were vaccinated. In vaccinated patients with immunosuppression and COVID-19, the addition of vax-plasma or very high titer COVID-19 convalescent plasma to COVID-19-specific therapies reduced the risk of disease progression leading to hospitalization.IMPORTANCEAs SARS-CoV-2 evolves, new variants of concern (VOCs) have emerged that evade available anti-spike monoclonal antibodies, particularly among immunosuppressed patients. However, high-titer COVID-19 convalescent plasma continues to be effective against VOCs because of its broad-spectrum immunomodulatory properties. Thus, we report clinical outcomes of 386 immunocompromised outpatients who were treated with COVID-19-specific therapeutics and a subgroup also treated with vaccine-boosted convalescent plasma. We found that the administration of vaccine-boosted convalescent plasma was associated with a significantly decreased incidence of hospitalization among immunocompromised COVID-19 outpatients. Our data add to the contemporary data providing evidence to support the clinical utility of high-titer convalescent plasma as antibody replacement therapy in immunocompromised patients.

Nirmatrelvir/ritonavir and remdesivir against symptomatic treatment in high-risk COVID-19 outpatients to prevent hospitalization or death during the Omicron era: a propensity score-matched study.

Even though worldwide death rates from coronavirus disease 2019 (COVID-19) have decreased, the threat of disease progression and death for high-risk groups continues. Few direct comparisons between the available severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antivirals have been made. We aimed to compare two SARS-CoV-2 antivirals (nirmatrelvir/ritonavir and remdesivir) against all-cause hospitalization or death. This is a propensity score-matched cohort study. We included all high-risk outpatients with COVID-19 in a tertiary referral center in Mexico City from 1 January 2022 to 31 July 2023. The primary outcome was all-cause hospitalization or death 28 days after symptom onset. The secondary outcome was COVID-19-associated hospitalization or death 28 days after symptom onset. Logistic regression analysis for characteristics associated with the primary outcome and a multi-group comparison with Kaplan-Meier survival estimates were performed. Of 1566 patients analyzed, 783 did not receive antiviral treatment, 451 received remdesivir, and 332 received nirmatrelvir/ritonavir. The median age was 60 years (interquartile range: 46-72), 62.5% were female and 97.8% had at least one comorbidity. The use of nirmatrelvir/ritonavir was associated with an absolute risk reduction of 8.8% and a relative risk reduction of 90% for all-cause hospitalization or death. The use of remdesivir was associated with an absolute risk reduction of 6.4% and a relative risk reduction of 66% for all-cause hospitalization or death. In multivariable analysis, both antivirals reduced the odds of 28-day all-cause hospitalization or death [nirmatrelvir/ritonavir odds ratio (OR) 0.08 - 95% confidence interval (CI): 0.03-0.19, remdesivir OR 0.29 - 95% CI: 0.18-0.45]. In high-risk COVID-19 outpatients, early antiviral treatment with nirmatrelvir/ritonavir or remdesivir was associated with lower 28-day all-cause hospitalization or death.

Symptoms, Viral Loads, and Rebound Among COVID-19 Outpatients Treated With Nirmatrelvir/Ritonavir Compared With Propensity Score-Matched Untreated Individuals.

Nirmatrelvir/ritonavir (N/R) reduces severe outcomes from coronavirus disease 2019 (COVID-19); however, rebound after treatment has been reported. We compared symptom and viral dynamics in individuals with COVID-19 who completed N/R treatment and similar untreated individuals. We identified symptomatic participants who tested severe acute respiratory syndrome coronavirus 2-positive and were N/R eligible from a COVID-19 household transmission study. Index cases from ambulatory settings and their households contacts were enrolled. We collected daily symptoms, medication use, and respiratory specimens for quantitative polymerase chain reaction for 10 days during March 2022-May 2023. Participants who completed N/R treatment (treated) were propensity score matched to untreated participants. We compared symptom rebound, viral load (VL) rebound, average daily symptoms, and average daily VL by treatment status measured after N/R treatment completion or 7 days after symptom onset if untreated. Treated (n = 130) and untreated participants (n = 241) had similar baseline characteristics. After treatment completion, treated participants had greater occurrence of symptom rebound (32% vs 20%; P = .009) and VL rebound (27% vs 7%; P < .001). Average daily symptoms were lower among treated participants without symptom rebound (1.0 vs 1.6; P < .01) but not statistically lower with symptom rebound (3.0 vs 3.4; P = .5). Treated participants had lower average daily VLs without VL rebound (0.9 vs 2.6; P < .01) but not statistically lower with VL rebound (4.8 vs 5.1; P = .7). Individuals who completed N/R treatment experienced fewer symptoms and lower VL but rebound occured more often compared with untreated individuals. Providers should prescribe N/R, when indicated, and communicate rebound risk to patients.

SARS-CoV-2 infection and increasing autoimmune disorders among ICU-hospitalized COVID-19 patients.

In acute conditions, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes multi-organ damage due to the induction of inappropriate immune responses, particularly lung tissue fibrosis. To evaluate the consequence of the deterioration of the immune system, autoimmune markers were assessed. In a case-control study, 108 patients with coronavirus disease 2019 (COVID-19) were admitted to the intensive care unit (ICU), and 158 outpatients with mild clinical symptoms, with SARS-CoV-2 reverse transcription quantitative polymerase chain reaction (RT-qPCR) positive tests, were included for comparison. The demographic and hematologic variables and presence of the main autoantibodies in sera of 40 eligible ICU-hospitalized COVID-19 patients and 40 COVID-19 outpatients were assessed. Out of 108 COVID-19 ICU-hospitalized patients, 40 were selected as the control group (40/158) who had no underlying diseases before hospitalization, according to their self-declaration and clinical records at the time of admission. The results demonstrated that the main complete blood count indices, such as red blood cells and platelets, decreased dramatically in ICU-hospitalized patients. Furthermore, the autoantibody profiles were positive in 45% and 15% of ICU-admitted patients for antinuclear antibodies and antineutrophilic cytoplasmic autoantibodies, respectively. In ICU patients, anti-PM/Scl 100 or AMA-M2 was 33%. Anti SS-A, anti-SS-B, anti-Ro-52, and anti-Jo-1 in 11.5% for each one were reactive. Other autoantibodies of the ICU group were as follows: CENP (5.6%), Rib-protein (5.6%), and nucleosome (5.6%). However, only two individuals in the control group had positive results for SS-A and SS-B (5%). Induction of such particular autoantibodies by the virus can justify the multi-organ involvement and severity of the disease in ICU patients, which may also cause other organ involvement in the long term.

Evaluation of Possible Association between Serum Levels of Aldosterone and Cortisol with Clinical Symptoms Progression in COVID-19 Suspicious Outpatients Tested for SARS-CoV2 RT-PCR: An Analytical Cross-Sectional Study.

Aldosterone is a key component of Renin-Angiotensin-Aldosterone System (RAAS). The RAAS could play a substantial role in the pathophysiology of coronavirus disease 2019 (COVID-19). Moreover, the dynamics of the Hypothalamic-Pituitary-Adrenal (HPA) axis may have changed in COVID-19. Cortisol, as an important factor in assessing immune system activity, is an important part of this axis. The present study compared the serum levels of aldosterone and cortisol in COVID-19 outpatients with those of potentially non-infected participants. It was also aimed to assess the possible association between serum levels of aldosterone and cortisol with clinical symptoms progression in COVID-19 outpatients. Demographic characteristics (i.e., gender and age) and clinical data (i.e., oxygen saturation [SPO2], respiratory rate [RR], and heart rate) were collected. Serum cortisol and aldosterone measurements were conducted using the ELISA technique. Clinical symptoms of the positive polymerase chain reaction (PCR) group were followed up on for 28 days in weekly intervals. SPO2 was significantly lower in the positive PCR group; however, the RR was significantly higher (P=0.03 and P=0.001, respectively). Significantly higher levels of aldosterone were found in males of the negative PCR group, compared to females (P=0.05). Cortisol (OR=0.937, P=0.033) and aldosterone (OR=1.005, P=0.020) levels had a decreasing and increasing effect on the chances of respiratory symptoms occurring over time, respectively. Furthermore, over time, women were twice as likely as men to develop neurologic symptoms (OR=0.530, P=0.015). According to the findings of this study, cortisol and aldosterone are associated with the chance of respiratory symptoms occurring over time. However, the levels of these two markers do not seem to be related to the progression of clinical symptoms of lower grades of COVID-19.

NLRP3 inflammasome and interleukin-1 contributions to COVID-19-associated coagulopathy and immunothrombosis.

Immunothrombosis-immune-mediated activation of coagulation-is protective against pathogens, but excessive immunothrombosis can result in pathological thrombosis and multiorgan damage, as in severe coronavirus disease 2019 (COVID-19). The NACHT-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome produces major proinflammatory cytokines of the interleukin (IL)-1 family, IL-1β and IL-18, and induces pyroptotic cell death. Activation of the NLRP3 inflammasome pathway also promotes immunothrombotic programs including release of neutrophil extracellular traps and tissue factor by leukocytes, and prothrombotic responses by platelets and the vascular endothelium. NLRP3 inflammasome activation occurs in patients with COVID-19 pneumonia. In preclinical models, NLRP3 inflammasome pathway blockade restrains COVID-19-like hyperinflammation and pathology. Anakinra, recombinant human IL-1 receptor antagonist, showed safety and efficacy and is approved for the treatment of hypoxaemic COVID-19 patients with early signs of hyperinflammation. The non-selective NLRP3 inhibitor colchicine reduced hospitalization and death in a subgroup of COVID-19 outpatients but is not approved for the treatment of COVID-19. Additional COVID-19 trials testing NLRP3 inflammasome pathway blockers are inconclusive or ongoing. We herein outline the contribution of immunothrombosis to COVID-19-associated coagulopathy, and review preclinical and clinical evidence suggesting an engagement of the NLRP3 inflammasome pathway in the immunothrombotic pathogenesis of COVID-19. We also summarize current efforts to target the NLRP3 inflammasome pathway in COVID-19, and discuss challenges, unmet gaps, and the therapeutic potential that inflammasome-targeted strategies may provide for inflammation-driven thrombotic disorders including COVID-19.

Efficacy and safety of molnupiravir for the treatment of SARS-CoV-2 infection: a systematic review and meta-analysis.

The role of molnupiravir for coronavirus disease 2019 (COVID-19) treatment is unclear. We conducted a systematic review until 1 November 2022 searching for randomized controlled trials (RCTs) involving COVID-19 patients comparing molnupiravir [±standard of care (SoC)] versus SoC and/or placebo. Data were pooled in random-effects meta-analyses. Certainty of evidence was assessed according to the Grading of Recommendations, Assessment, Development and Evaluations approach. Nine RCTs were identified, eight investigated outpatients (29 254 participants) and one inpatients (304 participants). Compared with placebo/SoC, molnupiravir does not reduce mortality [risk ratio (RR) 0.27, 95% CI 0.07-1.02, high-certainty evidence] and probably does not reduce the risk for 'hospitalization or death' (RR 0.81, 95% CI 0.55-1.20, moderate-certainty evidence) by Day 28 in COVID-19 outpatients. We are uncertain whether molnupiravir increases symptom resolution by Day 14 (RR 1.20, 95% CI 1.02-1.41, very-low-certainty evidence) but it may make no difference by Day 28 (RR 1.05, 95% CI 0.92-1.19, low-certainty evidence). In inpatients, molnupiravir may increase mortality by Day 28 compared with placebo (RR 3.78, 95% CI 0.50-28.82, low-certainty evidence). There is little to no difference in serious adverse and adverse events during the study period in COVID-19 inpatients/outpatients treated with molnupiravir compared with placebo/SoC (moderate- to high-certainty evidence). In a predominantly immunized population of COVID-19 outpatients, molnupiravir has no effect on mortality, probably none on 'hospitalization or death' and effects on symptom resolution are uncertain. Molnupiravir was safe during the study period in outpatients although a potential increase in inpatient mortality requires careful monitoring in ongoing clinical research. Our analysis does not support routine use of molnupiravir for COVID-19 treatment in immunocompetent individuals.

Exploring the Use of Monoclonal Antibodies and Antiviral Therapies for Early Treatment of COVID-19 Outpatients in aReal-World Setting: A Nationwide Study from England and Italy.

Real-world data on early treatment of coronavirus disease 2019 (COVID-19) outpatients with newly approved therapies are sparse. To explore the pattern of use of monoclonal antibodies (mAbs)/antiviral therapies approved for early COVID-19 treatment in non-hospitalized patients from England and Italy from December 2021 to October 2022. Public national dashboards on weekly mAb/antiviral use and/or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection diagnoses from the Italian Medicines Agency, the Italian National Institute of Health, National Health Service in England and the UK Government were explored. Prevalence of antiviral use in outpatients during the entire study period and every two weeks was calculated, as a whole and by class and compounds. An interrupted time-series (ITS) analysis was carried out to assess the impact of predominant SARS-CoV-2 variants over time on the prevalence of use of mAbs/antivirals in England and Italy. Overall, 77,469 and 195,604 doses of mAbs/antivirals were respectively administered to a total of 10,630,903 (7.3 per 1000) and 18,168,365 (10.8 per 1000) patients diagnosed with SARS-CoV-2 infection in England and Italy. Prevalence of use every two weeks increased from 0.07% to 3.1% in England and 0.9% to 2.3% in Italy during the study period. Regarding individual compounds, sotrovimab (prevalence of use, 1.6%) and nirmatrelvir/ritonavir (1.6%) in England, and nirmatrelvir/ritonavir (1.7%) and molnupiravir (0.5%) in Italy, reported the highest prevalence during a 2-week period. In the ITS analysis, the transition from Delta to Omicron variant predominance was associated with a significant increase in the use of sotrovimab, molnupiravir, remdesivir and nirmatrelvir/ritonavir in both England and Italy, with a reduction of other marketed mAbs. The extent of the increase was higher in England than in Italy for all these drugs except for nirmatrelvir/ritonavir. In this dual nationwide study, the prevalence of use of mAbs/antivirals against SARS-CoV-2 for early outpatients' treatment increased slowly up to 2.0-3.0% of all patients diagnosed with SARS-CoV-2 infection in both England and Italy from December 2021 to October 2022. The trend of individual drug use varied in relation to predominant SARS-CoV-2 variants with some differences across countries. In line with scientific societies' guidelines, nirmatrelvir/ritonavir was the most frequently prescribed antiviral in both countries in the most recent period.

Outpatient treatment of COVID-19: an experience with 552 cases in Mexico.

The impact of the coronavirus disease 2019 (COVID-19) pandemic has globally challenged health services, especially because when the pandemic first reached Mexico, in February 2020, there was no known effective and safe treatment. A treatment scheme was offered by the Institute for the Integral Development of Health (IDISA) in Mexico City from March 2020 to August 2021 when there were many patients with COVID-19. This report summarizes the experience managing COVID-19 with this scheme. This is a descriptive, retrolective study. The data was obtained from the case files of the patients who attended the IDISA from March 2020 to August 2021 with COVID-19. All the cases were treated with the scheme consisting of nitazoxanide, azithromycin, and prednisone. Various laboratory blood tests and chest computerized tomography scan were done. When indicated, supplementary oxygen, and another specific treatment were used. A standardized clinical recording was conducted for 20 days based on symptoms and systemic symptoms. Based on the World Health Organization criteria, the patients were classified according to the disease severity: 170 mild, 70 moderate, and 312 severe cases. The outcome was the discharge of 533 patients after their recovery, 16 were excluded from the study, and 6 died. The use of nitazoxanide, azithromycin, and prednisone proved to be effective as it resulted in improvement of symptoms and in successful outcomes for the management of COVID-19 outpatients.

Effect of fluvoxamine on preventing neuropsychiatric symptoms of post COVID syndrome in mild to moderate patients, a randomized placebo-controlled double-blind clinical trial

BackgroundShortly after the Coronavirus disease 2019 (COVID-19) pandemic, a considerable number of recovered patients reported persisting symptoms, especially neuropsychological manifestations, which were later named post-COVID syndrome (PCS). Immune dysregulation was suggested as one of the main mechanisms for PCS. Fluvoxamine, a selective serotonin reuptake inhibitor (SSRI) that is mostly used to treat depression, anxiety disorders, and obsessive–compulsive disorder, has been suggested as an anti-COVID drug due to its anti-inflammatory effects, mainly through the sigma-1 receptor. Therefore, we aimed to evaluate fluvoxamine's effect on PCS neuropsychiatric symptoms.MethodIn this double-blind randomized clinical trial, we included confirmed mild to moderate COVID-19 outpatients using polymerase chain reaction (PCR) by an infectious disease specialist. The presence of severe COVID-19 symptoms was evaluated by the infectious disease specialist and included dyspnea, SpO2 < 94% on room air, PaO2/FiO2 < 300 mm Hg, a respiratory rate > 30 breaths/min, and lung infiltrates > 50%. Then we performed permuted block randomization and assigned patients 1:1 into two groups to either receive fluvoxamine 100 mg tablet or a placebo daily for 10 days. Eligible patients were evaluated after 12 weeks for the presence of fatigue, as the primary, and other PCS symptoms as secondary outcomes.ResultsWe screened a total of 486 patients from March to June 2022. After 12 weeks, 42 patients receiving fluvoxamine and 43 patients receiving Placebo were evaluated for PCS. Patients had a mean age of 38.5 ± 14.1 and 48% of them were women. Fatigue was significantly lower in the fluvoxamine group (p-value 0.026). No significant differences were observed in other symptoms.ConclusionWe concluded that taking fluvoxamine during active COVID-19 can reduce the chance of fatigue but the advantage of fluvoxamine was not observed for other symptoms. Further studies are necessary to confirm these preliminary results.

Hydroxychloroquine for treatment of non-hospitalized adults with COVID-19: A meta-analysis of individual participant data of randomized trials.

Hydroxychloroquine (HCQ) was initially promoted as an oral therapy for early treatment of coronavirus disease 2019 (COVID-19). Conventional meta-analyses cannot fully address the heterogeneity of different designs and outcomes of randomized controlled trials (RCTs) assessing the efficacy of HCQ in outpatients with mild COVID-19. We conducted a pooled analysis of individual participant data from RCTs that evaluated the effect of HCQ on hospitalization and viral load reduction in outpatients with confirmed COVID-19. We evaluated the overall treatment group effect by log-likelihood ratio test (-2LL) from a generalized linear mixed model to accommodate correlated longitudinal binary data. The analysis included data from 11 RCTs. The outcome of virological effect, assessed in 1560 participants (N=795 HCQ, N=765 control), did not differ significantly between the two treatment groups (-2LL=7.66; p=0.18) when adjusting for cohort, duration of symptoms, and comorbidities. The decline in polymerase chain reaction positive tests from day 1 to 7 was 42.0 and 41.6 percentage points in the HCQ and control groups, respectively. Among the 2037 participants evaluable for hospitalization (N=1058 HCQ, N=979 control), we found no significant differences in hospitalization rate between participants receiving HCQ and controls (odds ratio 0.995; 95% confidence interval 0.614-1.610; -2LL=0.0; p=0.98) when adjusting for cohort, duration of symptoms, and comorbidities. This individual participant data meta-analysis of 11 HCQ trials that evaluated severe acute respiratory syndrome-coronavirus 2 viral clearance and COVID-19 hospitalization did not show a clinical benefit of HCQ. Our meta-analysis provides evidence to support the interruption in the use of HCQ in mild COVID-19 outpatients to reduce progression to severe disease.

Mild COVID-19 induces early, quantifiable, persistent troponin I elevations in elder men.

Elderly patients, especially men, are at risk of increased morbidity from coronavirus disease 2019 (COVID-19). Long-term data on troponin I levels in longitudinal observational studies of outpatients with mild to moderate COVID-19 are scarce. This controlled cohort study aimed to evaluate the course of troponin I concentrations over a long period in convalescent COVID-19 outpatients with mild to moderate symptoms. In this cohort study, individuals with PCR-confirmed, mild to moderate SARS-CoV-2 infection as well as control individuals with confirmed negative PCR and negative SARS-CoV-2 serology were included. Study visits were performed from April 2020 through July 2021 (initialized during the first wave of the corona pandemic in Switzerland). A study visit in patients comprised blood draws every week in the first month and additionally after 8 weeks. This course was repeated in patients observed long-term. This study enrolled 278 individuals from the Canton of St. Gallen, Switzerland, aged 12-92 years (59.5% women), who had mild to moderate COVID-19 symptoms (outpatients only) and a diagnosis confirmed by positive RT-PCR. Fifty-four of the participants with confirmed SARS-CoV-2 infection were followed for 14 months with repeat cycles of the testing protocol. In addition, 115 symptomatic patients that were PCR and serology negative were enrolled in the same time period as a control group. In COVID-19 patients, low-level troponin I concentrations (cTnI) were significantly increased from baseline until week 9 after positive RT-PCR diagnosis in men older than 54 years [ΔcTnI = 5.0 ng/L (median); 95% CI 4.1-6.0; p = 0.02]. The troponin I concentration remained elevated throughout 14 months in men older than 54 years within the cohort with a prolonged observation period. This statistically significant change in troponin I concentration was not dependent on co-morbidities in this group. ALT, Creatinine, BNP, and D-Dimer values after convalescence did not differ in comparison to the control cohort. In this analysis of individuals with confirmed SARS-CoV-2 infection, hs troponin I levels of men aged 54 or older significantly increased after infection. They remained elevated for at least 14 months after diagnosis. This suggests the possibility of an ongoing, long-term, low-grade myocardial injury. Further studies with focus on elderly patients and a prolonged observational period are necessary to elucidate whether the phenomenon observed is associated with detectable structural changes to the heart muscle or is without further clinical consequences.

Evaluation of a new COVID-19 triage algorithm in the emergency department including combined antigen and PCR-testing: A case-control study.

The coronavirus disease 2019 (COVID-19) pandemic is a major challenge for global healthcare systems. Early and safe triage in the emergency department (ED) is crucial for proper therapy. However, differential diagnosis remains challenging. Rapid antigen testing (RAT) may help to improve early triage and patient safety. We performed a retrospective study of 234 consecutive patients with suspected COVID-19 who presented to our ED in November 2020. All underwent SARS-CoV-2-nasopharyngeal swab testing using both RAT and reverse transcription polymerase chain reaction (RT-PCR). The inpatient treatment was established according to an empirically developed triage algorithm. The accuracy of the suggested algorithm was analyzed based on the rate of outpatients returning within 7 days and inpatients staying for less than 48 hours. COVID-19 inpatients and outpatients were compared for symptoms, vital signs, and C-reactive protein levels. Of the 221 included patients with suspected COVID-19 infection, the diagnosis could be confirmed in 120 patients (54.3%) by a positive RT-PCR result, whereas only 72% of those had a positive antigen test. Of the 56 COVID-19 outpatients, three returned within 7 days with the need for hospital treatment due to clinical deterioration. Among the 64 COVID-19 inpatients, 4 were discharged within 48 hours, whereas 60 stayed longer (mean duration 10.2 days). The suggested triage algorithm was safe and efficient in the first 234 consecutive patients. RAT can confirm a diagnosis in 72% of PCR proven COVID-19 patients and allows early cohort isolation as an important way to save hospital capacity.

Evaluation of Bebtelovimab for Treatment of Covid-19 During the SARS-CoV-2 Omicron Variant Era.

Monoclonal antibody (mAb) treatment is associated with decreased risk of hospitalization and death in high-risk outpatients with mild to moderate coronavirus disease 2019 (COVID-19) caused by early severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants. Bebtelovimab exhibits in vitro activity against the Omicron variant and its sublineages; however, clinical data are lacking. A retrospective cohort study was conducted comparing bebtelovimab-treated patients with propensity score-adjusted and matched nontreated control groups. Participants included high-risk outpatients eligible for bebtelovimab treatment under Emergency Use Authorization with a positive SARS-CoV-2 test from March 30 to May 28, 2022. Treated patients received single-dose intravenous treatment with bebtelovimab. The primary outcome was hospitalization or death over 28 days. Before matching/statistical adjustment, mAb-treated patients were, on average, 10 years older than nontreated patients (61.6 vs 51.3 years) and had higher prevalence of obstructive sleep apnea, hypertension, chronic kidney disease, cancer, organ or cell transplant, and immunocompromised status (standardized mean differences ≥0.20). The adjusted odds ratio (OR) of hospitalization or death comparing 1006 treated with 2023 nontreated patients was 0.50 (95% CI, 0.31-0.80). Among 930 treated and 930 propensity score-matched nontreated patients, the incidence of hospitalization or death was 3.1% vs 5.5%, respectively (conditional OR, 0.53; 95% CI, 0.32-0.86). The lower odds ratio of hospitalization or death associated with bebtelovimab treatment was most evident in older patients, those with immunocompromised status, and fully vaccinated patients. Monoclonal antibody treatment with bebtelovimab among COVID-19 outpatients is associated with lower odds of hospitalization or death, particularly among immunocompromised and older patients.

Clinical Impact of Monoclonal Antibodies in the Treatment of High-Risk Patients with SARS-CoV-2 Breakthrough Infections: The ORCHESTRA Prospective Cohort Study.

The clinical impact of anti-spike monoclonal antibodies (mAb) in Coronavirus Disease 2019 (COVID-19) breakthrough infections is unclear. We present the results of an observational prospective cohort study assessing and comparing COVID-19 progression in high-risk outpatients receiving mAb according to primary or breakthrough infection. Clinical, serological and virological predictors associated with 28-day COVID-19-related hospitalization were identified using multivariate logistic regression and summarized with odds ratio (aOR) and 95% confidence interval (CI). A total of 847 COVID-19 outpatients were included: 414 with primary and 433 with breakthrough infection. Hospitalization was observed in 42/414 (10.1%) patients with primary and 8/433 (1.8%) patients with breakthrough infection (p < 0.001). aOR for hospitalization was significantly lower for breakthrough infection (aOR 0.12, 95%CI: 0.05–0.27, p < 0.001) and higher for immunocompromised status (aOR:2.35, 95%CI:1.08–5.08, p = 0.003), advanced age (aOR:1.06, 95%CI: 1.03–1.08, p < 0.001), and male gender (aOR:1.97, 95%CI: 1.04–3.73, p = 0.037). Among the breakthrough infection group, the median SARS-CoV-2 anti-spike IgGs was lower (p < 0.001) in immunocompromised and elderly patients >75 years compared with that in the immunocompetent patients. Our findings suggest that, among mAb patients, those with breakthrough infection have significantly lower hospitalization risk compared with patients with primary infection. Prognostic algorithms combining clinical and immune-virological characteristics are needed to ensure appropriate and up-to-date clinical protocols targeting high-risk categories.

The MedConnect Program: Symptomatology, Return Visits, and Hospitalization of COVID-19 Outpatients Following Discharge From the Emergency Department.

Background and objectiveAlthough hospitalization is required for only a minority of those infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the high rates of morbidity and mortality among these patients have led researchers to focus on the predictors of admission and adverse outcomes in the inpatient population. However, there is scarce data on the clinical trajectory of individuals symptomatic enough to present for emergency care, but not sick enough to be admitted. In light of this, we aimed to examine the symptomatology, emergency department (ED) revisits, and hospitalization of coronavirus disease 2019 (COVID-19) outpatients after discharge from the ED.MethodsAdult patients with COVID-19 infection were prospectively enrolled after discharge from the ED between May and December 2020. Patients were followed up longitudinally for 14 days via phone interviews designed to provide support and information and to track symptomatology, ED revisits, and hospitalization.ResultsA volunteer, medical student-run program enrolled 199 COVID-19 patients discharged from the ED during the first nine months of the pandemic. Of the 176 patients (88.4%) who completed the 14-day protocol, 29 (16.5%) had a second ED visit and 17 (9.6%) were admitted, 16 (9%) for worsening COVID-19 symptoms. Age, male sex, comorbid illnesses, and self-reported dyspnea, diarrhea, chills, and fever were associated with hospital admission for patients with a subsequent ED visit. For those who did not require admission, symptoms generally improved following ED discharge. Age >65 years and a history of cardiovascular disease (CVD) were associated with a longer duration of cough, but generally, patient characteristics and comorbidities did not significantly affect the overall number or duration of symptoms.ConclusionsNearly one in five patients discharged from the ED with COVID-19 infection had a second ED evaluation during a 14-day follow-up period, despite regular phone interactions aimed at providing support and information. More than half of them required admission for worsening COVID-19 symptoms. Established risk factors for severe disease and self-reported persistence of certain symptoms were associated with hospital admission, while those who did not require hospitalization had a steady improvement in symptoms over the 14-day period.

Cost-Effectiveness Analysis of Molnupiravir Versus Best Supportive Care for the Treatment of Outpatient COVID-19 in Adults in the US.

Background and aimsCoronavirus disease 2019 (COVID-19) imposes a substantial and ongoing burden on the US healthcare system and society. Molnupiravir is a new oral antiviral for treating COVID-19 in outpatient settings. This study evaluated the cost-effectiveness profile of molnupiravir versus best supportive care in the treatment of adult patients with mild-to-moderate COVID-19 at risk of progression to severe disease, from a US payer’s perspective.MethodsThe model was developed using a decision tree for the short-term acute phase of COVID-19 and a Markov state transition model for the long-term post-acute phase. This model compared molnupiravir with best supportive care as consistent with the MOVe-OUT trial. Costs were reported in 2021 US dollars. Transition probabilities were derived from the phase III MOVe-OUT trial and the TriNetX real-world electronic health records database. Costs were derived from the TriNetX database and utility values from a de novo, vignette-based utility study. Deterministic and probabilistic sensitivity analyses (DSA/PSA) were conducted. Primary outcomes included proportion hospitalized, proportion who died overall and by highest healthcare setting at the end of the acute phase, quality-adjusted life-years (QALYs), and incremental costs per QALY gained over a lifetime (100 years) horizon, discounted at 3% annually and assessed at a willingness-to-pay (WTP) threshold of $100,000 per QALY.ResultsIn this model, the use of molnupiravir led to an increase in QALYs (0.210) and decrease in direct total medical costs (−$895) per patient across a lifetime horizon, compared with best supportive care in COVID-19 outpatients. Molnupiravir was the dominant intervention when compared with best supportive care. Patients treated with molnupiravir were less likely to be hospitalized (6.38% vs. 9.20%) and more likely to remain alive (99.88% vs. 98.71%) during the acute phase. Through DSA, molnupiravir treatment effect of hospitalization reduction was identified to be the most influential parameter, and through PSA, molnupiravir remained dominant in 84% of the total simulations and, overall, 100% cost effective.ConclusionThis analysis suggests that molnupiravir is cost effective compared with best supportive care for the treatment of adult outpatients with COVID-19. However, our study was limited by the unavailability of the most recent information on the rapidly evolving pandemic, including new viral variants, patient populations affected, and changes in standards of care. Further research should explore the impact of vaccination on the cost effectiveness of molnupiravir and other therapies, based on real-world data, to account for these changes, including the impact of vaccination and immunity.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40273-022-01168-0.