Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients with COVID-19

Tao K., Tzou P.L., Kosakovsky Pond S.L., Ioannidis J.P., Shafer R.W.

Monoclonal antibodies (MAbs) targeting the SARS-CoV-2 spike protein are among the most effective measures for preventing and treating COVID-19. However, SARS-CoV-2 Omicron variants contain many mutations in their spike receptor-binding domains, the target of all authorized MAbs.

Naggie S.

AbstractBackgroundThe effectiveness of ivermectin to shorten symptom duration or prevent hospitalization among outpatients in the United States with mild-to-moderate symptomatic coronavirus disease 2019 (COVID-19) is unknown.ObjectiveWe evaluated the efficacy of ivermectin 400 µg/kg daily for 3 days compared with placebo for the treatment of early mild-to-moderate COVID-19.MethodsACTIV-6 is an ongoing, decentralized, double-blind, randomized, placebo-controlled platform trial to evaluate repurposed therapies in outpatients with mild-to-moderate COVID-19. Non-hospitalized adults age ≥30 years with confirmed COVID-19, experiencing ≥2 symptoms of acute infection for ≤7 days were randomized to receive ivermectin 400 µg/kg daily for 3 days or placebo. The main outcome measure was time to sustained recovery, defined as achieving at least 3 consecutive days without symptoms. Secondary outcomes included a composite of hospitalization or death by day 28.ResultsOf the 3457 participants who consented to be evaluated for inclusion in the ivermectin arm, 1591 were eligible for this study arm, randomized to receive ivermectin 400 µg/kg (n=817) or placebo (n=774), and received study drug. Of those enrolled, 47% reported receiving at least 2 doses of SARS-CoV-2 vaccination. The posterior probability for any improvement in time to recovery was 0.91 (hazard ratio 1.07, 95% credible interval 0.96–1.17). The posterior probability of this benefit exceeding 24 hours was less than 0.01, as measured by the difference in mean time unwell. Hospitalizations or deaths were uncommon (ivermectin [n=10]; placebo [n=9]). Ivermectin at 400 µg/kg was safe and without serious adverse events as compared with placebo (ivermectin [n=10]; placebo [n=9]).ConclusionsIvermectin dosed at 400 µg/kg daily for 3 days resulted in less than one day of shortening of symptoms and did not lower incidence of hospitalization or death among outpatients with COVID-19 in the United States during the delta and omicron variant time periods.Trial registrationClinicalTrials.gov Identifier: NCT04885530.

Gorial F.I., Maulood M.F., Abdulamir A.S., Alnuaimi A.S., abdulrrazaq M.K., Bonyan F.A.

COVID19 complications cause inflammatory storm. Colchicine is a potent anti-inflammatory medication that has been proposed as a possible treatment option for COVID-19.to assess effectiveness and safety of add on use of colchicine to the standard treatment in moderate and severe COVID-19.In this randomized controlled open label clinical trial, 160 patients hospitalized equally divided between moderate and severe COVID19 categories were randomized to 4 study groups in a 1:1:1:1 allocation (n = 40 for each group) according to type of treatment. Patients were randomly assigned to receive the standard treatment for 14 days (control group) or colchicine add on to the standard treatment 1 mg daily orally for 7 days then 0.5 mg daily for another 7 days. Survival rate, time to cure in days, and side effects were assessed.Colchicine add on treatment was associated with a significantly shorter time to cure (referring to start of first symptom) by an average of 5 days in severe disease and 2 days in moderate disease (log-rank P=

Levin M.J., Ustianowski A., De Wit S., Launay O., Avila M., Templeton A., Yuan Y., Seegobin S., Ellery A., Levinson D.J., Ambery P., Arends R.H., Beavon R., Dey K., Garbes P., et. al.

The monoclonal-antibody combination AZD7442 is composed of tixagevimab and cilgavimab, two neutralizing antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that have an extended half-life and have been shown to have prophylactic and therapeutic effects in animal models. Pharmacokinetic data in humans indicate that AZD7442 has an extended half-life of approximately 90 days.In an ongoing phase 3 trial, we enrolled adults (≥18 years of age) who had an increased risk of an inadequate response to vaccination against coronavirus disease 2019 (Covid-19), an increased risk of exposure to SARS-CoV-2, or both. Participants were randomly assigned in a 2:1 ratio to receive a single dose (two consecutive intramuscular injections, one containing tixagevimab and the other containing cilgavimab) of either 300 mg of AZD7442 or saline placebo, and they were followed for up to 183 days in the primary analysis. The primary safety end point was the incidence of adverse events after a single dose of AZD7442. The primary efficacy end point was symptomatic Covid-19 (SARS-CoV-2 infection confirmed by means of reverse-transcriptase-polymerase-chain-reaction assay) occurring after administration of AZD7442 or placebo and on or before day 183.A total of 5197 participants underwent randomization and received one dose of AZD7442 or placebo (3460 in the AZD7442 group and 1737 in the placebo group). The primary analysis was conducted after 30% of the participants had become aware of their randomized assignment. In total, 1221 of 3461 participants (35.3%) in the AZD7442 group and 593 of 1736 participants (34.2%) in the placebo group reported having at least one adverse event, most of which were mild or moderate in severity. Symptomatic Covid-19 occurred in 8 of 3441 participants (0.2%) in the AZD7442 group and in 17 of 1731 participants (1.0%) in the placebo group (relative risk reduction, 76.7%; 95% confidence interval [CI], 46.0 to 90.0; P

Gupta A., Gonzalez-Rojas Y., Juarez E., Crespo Casal M., Moya J., Rodrigues Falci D., Sarkis E., Solis J., Zheng H., Scott N., Cathcart A.L., Parra S., Sager J.E., Austin D., Peppercorn A., et. al.

Older patients and those with comorbidities who are infected with SARS-CoV-2 may be at increased risk of hospitalization and death. Sotrovimab is a neutralizing antibody for the treatment of high-risk patients to prevent COVID-19 progression.To evaluate the efficacy and adverse events of sotrovimab in preventing progression of mild to moderate COVID-19 to severe disease.Randomized clinical trial including 1057 nonhospitalized patients with symptomatic, mild to moderate COVID-19 and at least 1 risk factor for progression conducted at 57 sites in Brazil, Canada, Peru, Spain, and the US from August 27, 2020, through March 11, 2021; follow-up data were collected through April 8, 2021.Patients were randomized (1:1) to an intravenous infusion with 500 mg of sotrovimab (n = 528) or placebo (n = 529).The primary outcome was the proportion of patients with COVID-19 progression through day 29 (all-cause hospitalization lasting >24 hours for acute illness management or death); 5 secondary outcomes were tested in hierarchal order, including a composite of all-cause emergency department (ED) visit, hospitalization of any duration for acute illness management, or death through day 29 and progression to severe or critical respiratory COVID-19 requiring supplemental oxygen or mechanical ventilation.Enrollment was stopped early for efficacy at the prespecified interim analysis. Among 1057 patients randomized (median age, 53 years [IQR, 42-62], 20% were ≥65 years of age, and 65% Latinx), the median duration of follow-up was 103 days for sotrovimab and 102 days for placebo. All-cause hospitalization lasting longer than 24 hours or death was significantly reduced with sotrovimab (6/528 [1%]) vs placebo (30/529 [6%]) (adjusted relative risk [RR], 0.21 [95% CI, 0.09 to 0.50]; absolute difference, -4.53% [95% CI, -6.70% to -2.37%]; P < .001). Four of the 5 secondary outcomes were statistically significant in favor of sotrovimab, including reduced ED visit, hospitalization, or death (13/528 [2%] for sotrovimab vs 39/529 [7%] for placebo; adjusted RR, 0.34 [95% CI, 0.19 to 0.63]; absolute difference, -4.91% [95% CI, -7.50% to -2.32%]; P < .001) and progression to severe or critical respiratory COVID-19 (7/528 [1%] for sotrovimab vs 28/529 [5%] for placebo; adjusted RR, 0.26 [95% CI, 0.12 to 0.59]; absolute difference, -3.97% [95% CI, -6.11% to -1.82%]; P = .002). Adverse events were infrequent and similar between treatment groups (22% for sotrovimab vs 23% for placebo); the most common events were diarrhea with sotrovimab (n = 8; 2%) and COVID-19 pneumonia with placebo (n = 22; 4%).Among nonhospitalized patients with mild to moderate COVID-19 and at risk of disease progression, a single intravenous dose of sotrovimab, compared with placebo, significantly reduced the risk of a composite end point of all-cause hospitalization or death through day 29. The findings support sotrovimab as a treatment option for nonhospitalized, high-risk patients with mild to moderate COVID-19, although efficacy against SARS-CoV-2 variants that have emerged since the study was completed is unknown.ClinicalTrials.gov Identifier: NCT04545060.

Lim S.C., Hor C.P., Tay K.H., Mat Jelani A., Tan W.H., Ker H.B., Chow T.S., Zaid M., Cheah W.K., Lim H.H., Khalid K.E., Cheng J.T., Mohd Unit H., An N., Nasruddin A.B., et. al.

Ivermectin, an inexpensive and widely available antiparasitic drug, is prescribed to treat COVID-19. Evidence-based data to recommend either for or against the use of ivermectin are needed.To determine the efficacy of ivermectin in preventing progression to severe disease among high-risk patients with COVID-19.The Ivermectin Treatment Efficacy in COVID-19 High-Risk Patients (I-TECH) study was an open-label randomized clinical trial conducted at 20 public hospitals and a COVID-19 quarantine center in Malaysia between May 31 and October 25, 2021. Within the first week of patients' symptom onset, the study enrolled patients 50 years and older with laboratory-confirmed COVID-19, comorbidities, and mild to moderate disease.Patients were randomized in a 1:1 ratio to receive either oral ivermectin, 0.4 mg/kg body weight daily for 5 days, plus standard of care (n = 241) or standard of care alone (n = 249). The standard of care consisted of symptomatic therapy and monitoring for signs of early deterioration based on clinical findings, laboratory test results, and chest imaging.The primary outcome was the proportion of patients who progressed to severe disease, defined as the hypoxic stage requiring supplemental oxygen to maintain pulse oximetry oxygen saturation of 95% or higher. Secondary outcomes of the trial included the rates of mechanical ventilation, intensive care unit admission, 28-day in-hospital mortality, and adverse events.Among 490 patients included in the primary analysis (mean [SD] age, 62.5 [8.7] years; 267 women [54.5%]), 52 of 241 patients (21.6%) in the ivermectin group and 43 of 249 patients (17.3%) in the control group progressed to severe disease (relative risk [RR], 1.25; 95% CI, 0.87-1.80; P = .25). For all prespecified secondary outcomes, there were no significant differences between groups. Mechanical ventilation occurred in 4 (1.7%) vs 10 (4.0%) (RR, 0.41; 95% CI, 0.13-1.30; P = .17), intensive care unit admission in 6 (2.4%) vs 8 (3.2%) (RR, 0.78; 95% CI, 0.27-2.20; P = .79), and 28-day in-hospital death in 3 (1.2%) vs 10 (4.0%) (RR, 0.31; 95% CI, 0.09-1.11; P = .09). The most common adverse event reported was diarrhea (14 [5.8%] in the ivermectin group and 4 [1.6%] in the control group).In this randomized clinical trial of high-risk patients with mild to moderate COVID-19, ivermectin treatment during early illness did not prevent progression to severe disease. The study findings do not support the use of ivermectin for patients with COVID-19.ClinicalTrials.gov Identifier: NCT04920942.

Ely E.W., Ramanan A.V., Kartman C.E., de Bono S., Liao R., Piruzeli M.L., Goldman J.D., Saraiva J.F., Chakladar S., Marconi V.C., Alatorre-Alexander J., Altclas J.D., Casas M., CevoliRecio V., Ellerin T., et. al.

SummaryBackground The oral, selective Janus kinase 1/2 inhibitor baricitinib has shown efficacy in studies of hospitalised adults with COVID-19. COV-BARRIER (NCT04421027) was a multinational, phase 3, randomised, double-blind, placebo-controlled trial of baricitinib in patients with confirmed SARS-CoV-2 infection. We aimed to evaluate the efficacy and safety of baricitinib plus standard of care in critically ill hospitalised adults with COVID-19 requiring invasive mechanical ventilation or extracorporeal membrane oxygenation. Methods This exploratory trial followed the study design of COV-BARRIER in a critically ill cohort not included in the main phase 3 trial. The study was conducted across 18 hospitals in Argentina, Brazil, Mexico, and the USA. Participants (aged ≥18 years) hospitalised with laboratory-confirmed SARS-CoV-2 infection on baseline invasive mechanical ventilation or extracorporeal membrane oxygenation were randomly assigned (1:1) to baricitinib (4 mg) or placebo once daily for up to 14 days in combination with standard of care. Participants, study staff, and investigators were masked to study group assignment. Prespecified endpoints included all-cause mortality through days 28 and 60, number of ventilator-free days, duration of hospitalisation, and time to recovery through day 28. The efficacy analysis was done in the intention-to-treat population and the safety analysis was done in the safety population. This trial is registered with ClinicalTrials.gov, NCT04421027. Findings Between Dec 23, 2020, and April 10, 2021, 101 participants were enrolled into the exploratory trial and assigned to baricitinib (n=51) or placebo (n=50) plus standard of care. Standard of care included baseline systemic corticosteroid use in 87 (86%) participants. Treatment with baricitinib significantly reduced 28-day all-cause mortality compared with placebo (20 [39%] of 51 participants died in the baricitinib group vs 29 [58%] of 50 in the placebo group; hazard ratio [HR] 0·54 [95% CI 0·31–0·96]; p=0·030; 46% relative reduction; absolute risk reduction 19%). A significant reduction in 60-day mortality was also observed in the baricitinib group compared with the placebo group (23 [45%] events vs 31 [62%]; HR 0·56 [95% CI 0·33–0·97]; p=0·027; 44% relative reduction; absolute risk reduction 17%). In every six baricitinib-treated participants, one additional death was prevented compared with placebo at days 28 and 60. The number of ventilator-free days did not differ significantly between treatment groups (mean 8·1 days [SD 10·2] in the baricitinib group vs 5·5 days [8·4] in the placebo group; p=0·21). The mean duration of hospitalisation in baricitinib-treated participants was not significantly shorter than in placebo-treated participants (23·7 days [SD 7·1] vs 26·1 days [3·9]; p=0·050). The rates of infections, blood clots, and adverse cardiovascular events were similar between treatment groups. Interpretation In critically ill hospitalised patients with COVID-19 who were receiving invasive mechanical ventilation or extracorporeal membrane oxygenation, treatment with baricitinib compared with placebo (in combination with standard of care, including corticosteroids) reduced mortality, which is consistent with the mortality reduction observed in less severely ill patients in the hospitalised primary COV-BARRIER study population. However, this was an exploratory trial with a relatively small sample size; therefore, further phase 3 trials are needed to confirm these findings. Funding Eli Lilly and Company.

Reis G., Silva E.A., Silva D.C., Thabane L., Milagres A.C., Ferreira T.S., dos Santos C.V., Campos V.H., Nogueira A.M., de Almeida A.P., Callegari E.D., Neto A.D., Savassi L.C., Simplicio M.I., Ribeiro L.B., et. al.

The efficacy of ivermectin in preventing hospitalization or extended observation in an emergency setting among outpatients with acutely symptomatic coronavirus disease 2019 (Covid-19), the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is unclear.We conducted a double-blind, randomized, placebo-controlled, adaptive platform trial involving symptomatic SARS-CoV-2-positive adults recruited from 12 public health clinics in Brazil. Patients who had had symptoms of Covid-19 for up to 7 days and had at least one risk factor for disease progression were randomly assigned to receive ivermectin (400 μg per kilogram of body weight) once daily for 3 days or placebo. (The trial also involved other interventions that are not reported here.) The primary composite outcome was hospitalization due to Covid-19 within 28 days after randomization or an emergency department visit due to clinical worsening of Covid-19 (defined as the participant remaining under observation for >6 hours) within 28 days after randomization.A total of 3515 patients were randomly assigned to receive ivermectin (679 patients), placebo (679), or another intervention (2157). Overall, 100 patients (14.7%) in the ivermectin group had a primary-outcome event, as compared with 111 (16.3%) in the placebo group (relative risk, 0.90; 95% Bayesian credible interval, 0.70 to 1.16). Of the 211 primary-outcome events, 171 (81.0%) were hospital admissions. Findings were similar to the primary analysis in a modified intention-to-treat analysis that included only patients who received at least one dose of ivermectin or placebo (relative risk, 0.89; 95% Bayesian credible interval, 0.69 to 1.15) and in a per-protocol analysis that included only patients who reported 100% adherence to the assigned regimen (relative risk, 0.94; 95% Bayesian credible interval, 0.67 to 1.35). There were no significant effects of ivermectin use on secondary outcomes or adverse events.Treatment with ivermectin did not result in a lower incidence of medical admission to a hospital due to progression of Covid-19 or of prolonged emergency department observation among outpatients with an early diagnosis of Covid-19. (Funded by FastGrants and the Rainwater Charitable Foundation; TOGETHER ClinicalTrials.gov number, NCT04727424.).

Abbas K.U., Muhammad S., Ding S.F.

Horby P.W., Emberson J.R., Mafham M., Campbell M., Peto L., Pessoa-Amorim G., Spata E., Staplin N., Lowe C., Chadwick D.R., Brightling C., Stewart R., Collini P., Ashish A., Green C.A., et. al.

SUMMARYBackgroundWe evaluated the use of baricitinib, a Janus kinase (JAK) 1/2 inhibitor, for the treatment of patients admitted to hospital because of COVID-19.MethodsThis randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple possible treatments in patients hospitalised for COVID-19. Eligible and consenting patients were randomly allocated (1:1) to either usual standard of care alone (usual care group) or usual care plus baricitinib 4 mg once daily by mouth for 10 days or until discharge if sooner (baricitinib group). The primary outcome was 28-day mortality assessed in the intention-to-treat population. A meta-analysis was conducted that included the results from the RECOVERY trial and all previous randomised controlled trials of baricitinib or other JAK inhibitor in patients hospitalised with COVID-19. The RECOVERY trial is registered with ISRCTN (50189673) and clinicaltrials.gov (NCT04381936).FindingsBetween 2 February 2021 and 29 December 2021, 8156 patients were randomly allocated to receive usual care plus baricitinib versus usual care alone. At randomisation, 95% of patients were receiving corticosteroids and 23% receiving tocilizumab (with planned use within the next 24 hours recorded for a further 9%). Overall, 513 (12%) of 4148 patients allocated to baricitinib versus 546 (14%) of 4008 patients allocated to usual care died within 28 days (age-adjusted rate ratio 0·87; 95% CI 0·77-0·98; p=0·026). This 13% proportional reduction in mortality was somewhat smaller than that seen in a meta-analysis of 8 previous trials of a JAK inhibitor (involving 3732 patients and 425 deaths) in which allocation to a JAK inhibitor was associated with a 43% proportional reduction in mortality (rate ratio 0.57; 95% CI 0.45-0.72). Including the results from RECOVERY into an updated meta-analysis of all 9 completed trials (involving 11,888 randomised patients and 1484 deaths) allocation to baricitinib or other JAK inhibitor was associated with a 20% proportional reduction in mortality (rate ratio 0.80; 95% CI 0.71-0.89; p<0.001). In RECOVERY, there was no significant excess in death or infection due to non-COVID-19 causes and no excess of thrombosis, or other safety outcomes.InterpretationIn patients hospitalised for COVID-19, baricitinib significantly reduced the risk of death but the size of benefit was somewhat smaller than that suggested by previous trials. The total randomised evidence to date suggests that JAK inhibitors (chiefly baricitinib) reduce mortality in patients hospitalised for COVID-19 by about one-fifth.FundingUK Research and Innovation (Medical Research Council) and National Institute of Health Research (Grant ref: MC_PC_19056).

Beltran Gonzalez J.L., González Gámez M., Mendoza Enciso E.A., Esparza Maldonado R.J., Hernández Palacios D., Dueñas Campos S., Robles I.O., Macías Guzmán M.J., García Díaz A.L., Gutiérrez Peña C.M., Martinez Medina L., Monroy Colin V.A., Arreola Guerra J.M.

During the first year of the COVID-19 pandemic, unauthorized drugs were widely used. Ivermectin and hydroxychloroquine are drugs that inhibit viral replication in vitro and that have been used in several medical centers. This clinical trial analyzes their efficacy in hospitalized patients with moderate COVID-19. Methods: This a controlled, clinical, randomized, double-blind trial that included hospitalized patients with COVID-19-induced pneumonia, without severe respiratory failure. Patients were randomized to one of three groups: Group 1—hydroxychloroquine, 400 mg every 12 h on the first day and, subsequently, 200 mg every 12 h for 4 days; Group 2—ivermectin, 12 mg or 18 mg, according to patient weight; and Group 3—placebo. At inclusion, blood samples for arterial blood gases and biochemical markers were obtained. The primary outcome was established as the length of stay due to patient improvement and the rate of respiratory deterioration or death. Results: During the month of August 2020, the admission of patients requiring hospitalization mostly encompassed cases with severe respiratory failure, so we ended the recruitment process and analyzed the data that was available at the time. One hundred and six (106) patients with an average age of 53 yrs (±16.9) were included, with a greater proportion of males (n = 66, 62.2%). Seventy-two percent (72%) (n = 76) had an associated comorbidity. Ninety percent (90%) of patients were discharged due to improvement (n = 96). The average duration of hospitalization was 6 days (IQR, 3–10). No difference in hospitalization duration was found between the treatment groups (Group1: 7 vs. Group 2: 6 vs. Group 3: 5, p = 0.43) nor in respiratory deterioration or death (Group 1: 18% vs. Group 2: 22.2% vs. Group 3: 24.3%, p = 0.83). Conclusions: In non-critical hospitalized patients with COVID-19 pneumonia, neither ivermectin nor hydroxychloroquine decreases the number of in-hospital days, respiratory deterioration, or deaths.

Pahwani S., Jadwani M., Dhanwani A., Gul M., Lal D., Rakesh F., Shabbir R., Rizwan A.

Hammond J., Leister-Tebbe H., Gardner A., Abreu P., Bao W., Wisemandle W., Baniecki M., Hendrick V.M., Damle B., Simón-Campos A., Pypstra R., Rusnak J.M.

Nirmatrelvir is an orally administered severe acute respiratory syndrome coronavirus 2 main protease (Mpro) inhibitor with potent pan-human-coronavirus activity in vitro.We conducted a phase 2-3 double-blind, randomized, controlled trial in which symptomatic, unvaccinated, nonhospitalized adults at high risk for progression to severe coronavirus disease 2019 (Covid-19) were assigned in a 1:1 ratio to receive either 300 mg of nirmatrelvir plus 100 mg of ritonavir (a pharmacokinetic enhancer) or placebo every 12 hours for 5 days. Covid-19-related hospitalization or death from any cause through day 28, viral load, and safety were evaluated.A total of 2246 patients underwent randomization; 1120 patients received nirmatrelvir plus ritonavir (nirmatrelvir group) and 1126 received placebo (placebo group). In the planned interim analysis of patients treated within 3 days after symptom onset (modified intention-to treat population, comprising 774 of the 1361 patients in the full analysis population), the incidence of Covid-19-related hospitalization or death by day 28 was lower in the nirmatrelvir group than in the placebo group by 6.32 percentage points (95% confidence interval [CI], -9.04 to -3.59; P

Brennan C.M., Nadella S., Zhao X., Dima R.J., Jordan-Martin N., Demestichas B.R., Kleeman S.O., Ferrer M., von Gablenz E.C., Mourikis N., Rubin M.E., Adnani H., Lee H., Ha T., Prum S., et. al.

ObjectiveWe assessed whether famotidine improved inflammation and symptomatic recovery in outpatients with mild to moderate COVID-19.DesignRandomised, double-blind, placebo-controlled, fully remote, phase 2 clinical trial (NCT04724720) enrolling symptomatic unvaccinated adult outpatients with confirmed COVID-19 between January 2021 and April 2021 from two US centres. Patients self-administered 80 mg famotidine (n=28) or placebo (n=27) orally three times a day for 14 consecutive days. Endpoints were time to (primary) or rate of (secondary) symptom resolution, and resolution of inflammation (exploratory).ResultsOf 55 patients in the intention-to-treat group (median age 35 years (IQR: 20); 35 women (64%); 18 African American (33%); 14 Hispanic (26%)), 52 (95%) completed the trial, submitting 1358 electronic symptom surveys. Time to symptom resolution was not statistically improved (p=0.4). Rate of symptom resolution was improved for patients taking famotidine (p<0.0001). Estimated 50% reduction of overall baseline symptom scores were achieved at 8.2 days (95% CI: 7 to 9.8 days) for famotidine and 11.4 days (95% CI: 10.3 to 12.6 days) for placebo treated patients. Differences were independent of patient sex, race or ethnicity. Five self-limiting adverse events occurred (famotidine, n=2 (40%); placebo, n=3 (60%)). On day 7, fewer patients on famotidine had detectable interferon alpha plasma levels (p=0.04). Plasma immunoglobulin type G levels to SARS-CoV-2 nucleocapsid core protein were similar between both arms.ConclusionsFamotidine was safe and well tolerated in outpatients with mild to moderate COVID-19. Famotidine led to earlier resolution of symptoms and inflammation without reducing anti-SARS-CoV-2 immunity. Additional randomised trials are required.

Manomaipiboon A., Pholtawornkulchai K., Pupipatpab S., Suraamornkul S., Maneerit J., Ruksakul W., Phumisantiphong U., Trakarnvanich T.

Abstract The emergent outbreak of coronavirus disease (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has emphasized the requirement for therapeutic opportunities to overcome this pandemic. Ivermectin is an antiparasitic drug that has shown to be effective against various agents, including SARS-CoV-2, and is under extensive research in clinical trials. In this randomized, double-blind, placebo-controlled trial among adult hospitalized patients with mild-to-moderate COVID-19, 72 patients (mean age 48.57 ± 14.80 years) were randomly assigned to either the ivermectin (n=36) or placebo (n=36) group, along with receiving standard care. The primary outcomes were a negative reverse transcription polymerase chain reaction (RT-PCR) result at day 7 and 14 of enrolment. The secondary outcomes were duration of hospitalization, frequency of clinical worsening, survival on day 28, and adverse events. At day 7 and 14, a negative RT-PCR result was not significantly different between the two groups. The other secondary outcomes were reported to be comparable. However, the time to resolution of many symptoms were shorter in the ivermectin group, albeit not significantly. No adverse events were reported. In conclusion, early symptomatic recovery was observed with no side effects after treatment with ivermectin and standard care in mild-to-moderate COVID-19 patients.

Yang O.O.

Abstract This review provides a broad overview of lessons learned in the five years since COVID-19 was identified. It is a bimodal disease, starting with an initially virus-driven phase, followed by resolution or ensuing inappropriate immune activation causing severe inflammation that is no longer strictly virus dependent. Humoral immunity is beneficial for preventing or attenuating the early stage, without benefit once the later stage begins. Neutralizing antibodies elicited by natural infection or vaccination are short-lived and highly vulnerable to viral sequence variation. By contrast, cellular immunity, particularly the CD8+ T cell arm, has a role in preventing or attenuating severe disease, is far less susceptible to viral variation, and is longer-lived than antibodies. Finally, an ill-defined phenomenon of prolonged symptoms after acute infection, termed “long COVID,” is poorly understood but may involve various immunologic defects that are hyperactivating or immunosuppressive. Remaining issues include needing to better understand the immune dysregulation of severe disease to allow more tailored therapeutic interventions, developing antibody strategies that cope with the viral spike sequence variability, prolonging vaccine efficacy, and unraveling the mechanisms of long COVID to design therapeutic approaches.

Caffrey A.R., Appaneal H.J., Lopes V.V., Lavoie T., Puzniak L., Zasowski E.J., Jodar L., Arham I., LaPlante K.L., McLaughlin J.M.

ABSTRACT Coronavirus disease 2019 (COVID-19) has complicated the management of acute respiratory infections and impacted antibiotic use. We assessed the relationship between nirmatrelvir/ritonavir (NMV/r) receipt and outpatient antibiotic prescribing among patients with COVID-19 in a large national health system. We conducted a retrospective cohort study among outpatients enrolled in the Veterans Affairs Healthcare System who had a positive severe acute respiratory syndrome coronavirus 2 test or COVID-19 diagnosis and were eligible for NMV/r treatment between 1 April 2022 and 31 March 2024. NMV/r-treated patients were compared with those who did not receive NMV/r and were considered unexposed until NMV/r was dispensed. We assessed the relationship between NMV/r receipt and being prescribed an outpatient antibiotic in the 30 days after a COVID-19 diagnosis using adjusted Cox proportional hazards regression. We included 302,600 NMV/r-eligible outpatients with COVID-19, of whom 67,649 received NMV/r and 234,951 did not receive NMV/r. NMV/r-treated patients were less likely to receive outpatient antibiotics compared to those who did not receive NMV/r (7.2% [4,901/67,649] vs 9.2% [21,533/234,951], respectively; adjusted hazard ratio [HR] 0.65, 95% CI: 0.63‒0.68). After excluding patients who received an antibiotic prescription upon COVID-19 diagnosis (i.e., likely empiric therapy), this relationship was attenuated (HR: 0.91, 95% CI: 0.87‒0.95). NMV/r-eligible patients with COVID-19 who received NMV/r were 35% less likely to be prescribed outpatient antibiotics compared to patients who did not receive NMV/r, possibly driven by a diminished perceived need for empiric antibiotic therapy. Treatment with NMV/r may reduce unnecessary outpatient antibiotic use. Antibiotics should be reserved for patients with a high suspicion of bacterial co-infection. IMPORTANCE Antimicrobial resistance, driven by the overuse of antibiotics, is a major global health threat. The coronavirus disease 2019 (COVID-19) pandemic has complicated this issue, with antibiotics often prescribed to patients with COVID-19 despite being ineffective against viruses. These practices, typically aimed at preventing or empirically treating rare bacterial co-infections, have raised concerns about accelerating resistance. The antiviral nirmatrelvir/ritonavir (NMV/r), widely used in high-risk patients with COVID-19 to prevent severe illness, offers an opportunity to reassess antibiotic use in patients with respiratory infections. Our study of over 300,000 patients in a national healthcare system found that those treated with NMV/r for COVID-19 were 35% less likely to receive antibiotics than those who did not receive the antiviral. Lower antibiotic use among patients treated with NMV/r may reflect a reduction in unnecessary outpatient antibiotic use. These findings highlight the potential role of antivirals in supporting antibiotic stewardship and addressing a critical public health challenge.

Kim S.H., Lee H., Kim M.J., Kim Y., Min K.H., Yoo K.H., Kim J.S., Moon J.

Abstract Background Chronic obstructive pulmonary disease (COPD) is associated with severe Coronavirus disease 2019 (COVID-19) outcomes. However, it is uncertain whether the risk of acute exacerbation of COPD (AECOPD) increases after recovering from COVID-19. Methods This study included 2,118 individuals with COPD from the Korea National Health Insurance Service database who were also diagnosed with COVID-19. Matched controls were chosen using 1:1 propensity score (PS) matching. We compared the risk of AECOPD after COVID-19 recovery between the COVID-19 cohort and matched controls between October 8, 2020, and December 31, 2021, using PS-matched Cox proportional hazard regression models. Results During a median follow-up of 62 days (interquartile range, 29–179 days), including a median of 14 days of recovery time after COVID-19, 68 people (5.6%) in the COVID-19 cohort and 50 (3.9%) in the matched control group experienced AECOPD. Compared to the matched controls, the COVID-19 cohort had a significantly higher risk of overall AECOPD (hazard ratio [HR] = 1.45, 95% confidence interval [CI] = 1.09–1.92). This increased risk was particularly evident for severe AECOPD among individuals who had severe COVID-19 within the first 30days post-recovery (aHR = 8.14, 95% CI = 3.32–19.97). When classified by COVID-19 severity, while severe COVID-19 significantly increased this risk (aHR = 2.97, 95% CI = 2.15–4.11), non-severe COVID did not significantly influence the risk of AECOPD, regardless of time duration or exacerbation severity. Conclusion Individuals with COPD who had severe COVID-19 have increased risk of AECOPD after COVID-19 recovery, especially within the first 30 days after COVID-19 recovery.

Wong Y., Ng C., Huang Y., Chen S.

Background: Patients with liver cirrhosis are at an increased risk of mortality from coronavirus disease 2019 (COVID-19). Remdesivir, an adenosine analog, exhibits activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is thus recommended for inpatients with COVID-19. This study evaluated the effectiveness and safety of remdesivir in patients with COVID-19 and liver cirrhosis. Methods: This retrospective study was conducted using data from Taiwan’s largest healthcare system. The study cohort comprised adult patients with COVID-19 and liver cirrhosis who visited our emergency department between April 2021 and September 2022. Remdesivir’s adverse effects, including bradycardia, anemia, unstable glucose levels, and abnormal liver function test results, were recorded. Treatment outcomes were assessed in terms of hospitalization duration, mortality, intubation, and intensive care unit admission. Results: This study included 1368 patients with COVID-19 and liver cirrhosis, of whom 46 received remdesivir. Remdesivir recipients were older (66.5 vs. 62 years; p = 0.042) and had a higher rate of oxygen therapy use (56.52% vs. 32.22%; p = 0.001) than nonrecipients. Common adverse effects of remdesivir included lower heart rates (83 vs. 96 bpm; p < 0.001) and decreased hemoglobin levels (9.5 vs. 10.2 g/dL; p = 0.003) without fatal consequences. No statistically significant difference between remdesivir recipients and nonrecipients in hospitalization duration, intubation rates, or mortality rates was found. Conclusions: Remdesivir is safe for treating COVID-19 in patients with liver cirrhosis. Although remdesivir recipients exhibited trends toward improved outcomes in our study, large-scale studies are required to confirm its efficacy in this population.

Garcia‐Vidal C., Teijón‐Lumbreras C., Aiello T.F., Chumbita M., Menendez R., Subirà A.M., Peyrony O., Monzó‐Gallo P., Gallardo‐Pizarro A., Méndez R., Calbo Sebastian E., Ballestero‐Tellez M., Cuesta‐Chasco G., Martínez J.A., Marcos M.A., et. al.

ABSTRACTConflicting results from randomized trials regarding the efficacy of remdesivir for COVID‐19 have been reported. We aimed to develop a neural network (NN) to identify COVID‐19 patients who would derive the greatest survival benefit from remdesivir. This multicenter observational study included adults hospitalized for COVID‐19 between February 2020 and February 2021. A derivation cohort from Hospital Clínic (Barcelona) was used to create the NN, which was split into 928/1160 (80%) for training and 232/1160 (20%) for internal validation. The model used three normalized input variables: Ct values from rRT‐PCR, lymphocyte count at diagnosis, and the duration of symptoms before testing. Effectiveness was assessed in an external validation cohort of 898 patients from Hospital Mútua Terrassa and Hospital Universitari La Fe, Valencia. In the derivation cohort (median age 66 years; IQR 55–78), symptom duration, Ct values, and lymphocyte count showed considerable variation. Overall, 60‐day mortality was 165/1160 (14.2%). In the training set, 385/928 (41.5%) patients were identified as benefiting from remdesivir, characterized by lower Ct values, reduced lymphocyte counts, and shorter symptom duration. Mortality in this subgroup was 93/385 (24.2%): 6/385 (7.2%) in patients receiving remdesivir versus 87/385 (28.8%) in those who did not (p < 0.001). In the test set, 296/898 (33%) patients were identified as high‐benefit, with 60‐day mortality rates of 8/296 (11%) for those patients treated with remdesivir compared to 49/296 (22%) for those not treated (p < 0.04). In conclusion, we successfully developed and validated a NN capable of identifying patients with distinct clinical phenotypes who are at higher risk of mortality without remdesivir.

Molloy M.J., Hall M., Markham J.L., Cotter J.M., McCoy E., Tchou M.J., Collins M.E., Steiner M.J., Stephens J.R., Yu A.G., Ugalde I.T., Morse R.B., Goyal M.K., House S.A.

ImportanceRespiratory pathogen testing has been a common deimplementation focus. The COVID-19 pandemic brought new considerations for respiratory testing; recent trends in testing rates are not well understood.ObjectiveTo measure trends in respiratory testing among encounters for acute respiratory infections among children and adolescents (aged &amp;lt;18 years) from 2016 to 2023, assess the association of COVID-19 with these trends, and describe associated cost trends.Design, Setting, and ParticipantsThis retrospective serial cross-sectional study included emergency department (ED) encounters and hospitalizations in US children’s hospitals among children and adolescents with a primary acute infectious respiratory illness diagnosis. Data were ascertained from the Pediatric Health Information System database from January 1, 2016, to December 31, 2023.ExposureRespiratory pathogen testing.Main Outcomes and MeasuresThe primary outcome was the percentage of encounters with respiratory testing over time. Interrupted time series models were created to assess the association of COVID-19 with testing patterns. The inflation-adjusted standardized unit cost associated with respiratory testing was also examined.ResultsThere were 5 090 923 eligible encounters among patients who were children or adolescents (mean [SD] age, 3.36 [4.06] years); 55.0% of the patients were male. Among these encounters, 87.5% were ED only, 77.9% involved children younger than 6 years, and 94.5% involved children without complex chronic conditions. Respiratory testing was performed in 37.2% of all encounters. The interrupted time series models demonstrated increasing prepandemic testing rates in both ED-only encounters (slope, 0.26 [95% CI, 0.21-0.30]; P &amp;lt; .001) and hospitalizations (slope, 0.12 [95% CI, 0.07-0.16]; P &amp;lt; .001). Increases in respiratory testing were seen at the onset of the COVID-19 pandemic in both ED-only encounters (level change, 33.78 [95% CI, 31.77-35.79]; P &amp;lt; .001) and hospitalizations (level change, 30.97 [95% CI, 29.21-32.73]; P &amp;lt; .001), associated initially with COVID-19–only testing. Postpandemic testing rates remained elevated relative to prepandemic levels. The percentage of encounters with respiratory testing increased from 13.6% [95% CI, 13.5%-13.7%] in 2016 to a peak of 62.2% [95% CI, 62.1%-62.3%] in 2022. While COVID-19–only testing decreased after 2020, other targeted testing and large-panel (&amp;gt;5 targets) testing increased. The inflation-adjusted standardized unit cost associated with respiratory testing increased from $34.2 [95% CI, $33.9-$34.6] per encounter in 2017 to $128.2 [95% CI, $127.7-$128.6] per encounter in 2022.Conclusions and RelevanceThe findings of this cross-sectional study suggest that respiratory testing rates have increased over time, with large increases at the onset of the COVID-19 pandemic that have persisted. Respiratory testing rates and related costs increased significantly, supporting a need for future deimplementation efforts.

Tomos I., Grigoropoulos I., Kosti C., Chrysikos S., Digalaki A., Thomas K., Hillas G., Kazakou P., Antoniadou A., Kavatha D., Dimakou K.

Cilloniz C., Torres A.

Ching P.R., Pedersen L.L.

Badia B.D., Serrano P.D., Barile J.P., Seneor D.D., Mendes P.M., Cavalheiro R.B., Peixoto K.O., Farias I.B., Machado R.I., Pinto W.B., Oliveira A.S., Sgobbi P.

Background: Acute hepatic porphyrias (AHPs) represent inherited metabolic disorders of the heme biosynthesis pathway, leading to neurological and systemic impairment. Despite the presence of well-recognized chronic symptoms and signs, acute neurological, both neuromuscular and central neurological complications pose a significant challenge in clinical practice, with a potential risk of greater severity and mortality during acute decompensation episodes of AHPs. Care related to the prescription of medications, considering the risk of porphyrinogenicity, is a major and recurring concern in the acute and chronic management of AHP patients. Infectious clinical complications are significant issues in both outpatient and hospital settings for patients with AHPs. It is crucial to identify therapeutic regimens with the best safety and efficacy profiles for treating such infectious complications in AHP patients. The scarcity of structured knowledge available in guidelines and recommendations often leads to the use of therapeutic options with higher potential risks in treating patients with AHPs. Objectives: This review article aims to provide practical recommendations for managing the most significant infectious complications in clinical practice, with a focus on their impact on the clinical care of patients with AHPs.

Wang J., He C., Shi Y., Su K., Huang Z., Du S., Li X., Wu W., Sheng J.

Mizuno T., Suzuki J., Takahashi S., Imai H., Itagaki H., Yoshida M., Endo S.

Systemic baricitinib and corticosteroids play important roles in treating severely and critically ill patients with coronavirus disease 2019 (COVID-19). However, the efficacy of the combination of baricitinib and corticosteroids compared to that of corticosteroid monotherapy in severely and critically ill hospitalized patients with COVID-19 remains unclear.

Na D., Hong Y., Lee C., Kim M.

The emergence and evolution of SARS-CoV-2 variants, such as Delta and Omicron, pose significant challenges to pandemic management. This study evaluated the effectiveness of reverse-transcription polymerase chain reaction (RT-PCR) and whole-genome sequencing (WGS) in detecting and characterizing SARS-CoV-2 variants using 624 samples collected in South Korea from mid-2021 to mid-2022. Two RT-PCR genotyping assays demonstrated a high concordance rate (90.4%) in identifying the Delta variant during its dominance. In contrast, WGS revealed extensive genetic diversity among Omicron sub-lineages, identifying 29 distinct sub-lineages, including two South Korea-specific variants (BA.1.1.5 and BA.2.3.8). Clustering analysis of WGS data highlighted distinct groupings of BA.1, BA.2, and BA.5 sub-lineages, with overlap in shared mutations suggesting evolutionary convergence. Sub-lineage diversity expanded during rapid transmission phases and subsequently consolidated as dominant lineages emerged. These findings highlight the complementary strengths of RT-PCR and WGS and underscore the importance of integrating these methodologies for effective variant monitoring and public health response.

Lina Z., Tongzeng L., Ma Y., Lijun S., Yang L.

Wong S., Chiu K.H., Yip C.C., Chan J.F., Hung I.F., To K.K., Cheng V.C., Yuen K.

Viruses are obligatory intracellular pathogens with a simple structure consisting of assembled proteins that enclose the nucleic acid genome with or without a lipid envelope. Despite the increasing availability of rapid nucleic acid amplification assays for laboratory diagnosis, effective antivirals, and safe vaccines, the control of most viral infections depends on time-honored surveillance and infection control measures. Furthermore, most viruses can be readily destroyed by common disinfectants. This article focuses on the epidemiology, diagnosis, and control of common and emerging viral diseases.