Associations between clinical data, vaccination status, antibody responses, and post-COVID-19 symptoms in Thais infected with SARS-CoV-2 Delta and Omicron variants: a 1-year follow-up study.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), led to a global pandemic from 2020. In Thailand, five waves of outbreaks were recorded, with the fourth and fifth waves driven by the Delta and Omicron variants, resulting in over 20,000 new confirmed cases daily at their peaks. METHODS: This cross-sectional study investigated the associations between clinical symptoms, vaccination status, antibody responses, and post-COVID-19 sequelae in COVID-19 patients. Plasma samples and clinical data were collected from participants admitted to hospitals in Thailand between July 2021 and August 2022, with follow-ups conducted for one year. The study included 110 participants infected with either the Delta (n = 46) or Omicron (n = 64) variants. Virus genotypes were confirmed by RT-PCR of nasal swab RNA and partial nucleotide sequencing of the S gene. IgG and IgA antibody levels against the receptor-binding domain (RBD) of SARS-CoV-2 Delta and Omicron variants were measured in plasma samples using ELISA. RESULTS: Pneumonia was found to be associated with Delta variant infections, while sore throat, congestion or runny nose, and headache were linked to Omicron infections. Vaccination with fewer than two doses and diabetes mellitus were significantly associated with higher disease severity. Specific IgG and IgA antibodies against the RBD of the Delta variant generally rose by day 14 and were maintained for up to two months, whereas the pattern of antibody response to the Omicron variant was less clear. Antibody risings were found to be positively associated with pneumonia, certain underlying conditions (obesity, hypertension, dyslipidemia, and diabetes mellitus), and age ≥ 60 years. Delta variant infections were associated with forgetfulness, hair loss, and headache during the 1-year post-infection period. Females were more likely to experience hair loss, forgetfulness, and joint pain, while older age was associated with joint pain. CONCLUSIONS: This study enhances our understanding of SARS-CoV-2 infections in Thais, particularly concerning the Delta and Omicron variants. The findings can inform public health planning and response strategies for future outbreaks of SARS-CoV-2 or other emerging viral diseases.

Temporal changes in SARS-CoV-2 clearance kinetics and the optimal design of antiviral pharmacodynamic studies: an individual patient data meta-analysis of a randomised, controlled, adaptive platform study (PLATCOV).

BACKGROUND: Effective antiviral drugs prevent hospitalisation and death from COVID-19. Antiviral efficacy can be efficiently assessed in vivo by measuring rates of SARS-CoV-2 clearance estimated from serial viral genome densities quantitated in nasopharyngeal or oropharyngeal swab eluates. We conducted an individual patient data meta-analysis of unblinded arms in the PLATCOV platform trial to characterise changes in viral clearance kinetics and infer optimal design and interpretation of antiviral pharmacometric evaluations. METHODS: Serial viral density data were analysed from symptomatic, previously healthy, adult patients (within 4 days of symptom onset) enrolled in a large multicentre, randomised, adaptive, pharmacodynamic, platform trial (PLATCOV) comparing antiviral interventions for SARS-CoV-2. Viral clearance rates over 1 week were estimated under a hierarchical Bayesian linear model with B-splines used to characterise temporal changes in enrolment viral densities and clearance rates. Bootstrap re-sampling was used to assess the optimal duration of follow-up for pharmacometric assessment, where optimal was defined as maximising the expected Z score when comparing effective antivirals with no treatment. PLATCOV is registered at ClinicalTrials.gov, NCT05041907. FINDINGS: Between Sept 29, 2021, and Oct 20, 2023, 1262 patients were randomly assigned in the PLATCOV trial. Unblinded data were available from 800 patients (who provided 16 818 oropharyngeal viral quantitative PCR [qPCR] measurements), of whom 504 (63%) were female. 783 (98%) patients had received at least one vaccine dose and 703 (88%) were fully vaccinated. SARS-CoV-2 viral clearance was biphasic (bi-exponential). The first phase (α) was accelerated by effective interventions. For all the effective interventions studied, maximum discriminative power (maximum expected Z score) was obtained when evaluating serial data from the first 5 days after enrolment. Over the 2-year period studied, median viral clearance half-lives estimated over 7 days shortened from 16·6 h (IQR 15·3 to 18·2) in September, 2021, to 9·2 h (8·0 to 10·6) in October, 2023, in patients receiving no antiviral drugs, equivalent to a relative reduction of 44% (95% credible interval [CrI] 19 to 64). A parallel reduction in viral clearance half-lives over time was observed in patients receiving antiviral drugs. For example, in the 158 patients assigned to ritonavir-boosted nirmatrelvir (3380 qPCR measurements), the median viral clearance half-life reduced from 6·4 h (IQR 5·7 to 7·3) in June, 2022, to 4·8 h (4·2 to 5·5) in October, 2023, a relative reduction of 26% (95% CrI -4 to 42). INTERPRETATION: SARS-CoV-2 viral clearance kinetics in symptomatic, vaccinated individuals accelerated substantially over 2 years of the pandemic, necessitating a change to how new SARS-CoV-2 antivirals are compared (ie, shortening the period of pharmacodynamic assessment). As of writing (October, 2023), antiviral efficacy in COVID-19 can be efficiently assessed in vivo using serial qPCRs from duplicate oropharyngeal swab eluates taken daily for 5 days after drug administration. FUNDING: Wellcome Trust.

Clinical antiviral efficacy of favipiravir in early COVID-19 (PLATCOV): an open-label, randomised, controlled, adaptive platform trial.

In early symptomatic COVID-19 treatment, high dose oral favipiravir did not accelerate viral clearance. BACKGROUND: Favipiravir, an anti-influenza drug, has in vitro antiviral activity against SARS-CoV-2. Clinical trial evidence to date is inconclusive. Favipiravir has been recommended for the treatment of COVID-19 in some countries. METHODS: In a multicentre open-label, randomised, controlled, adaptive platform trial, low-risk adult patients with early symptomatic COVID-19 were randomised to one of ten treatment arms including high dose oral favipiravir (3.6g on day 0 followed by 1.6g daily to complete 7 days treatment) or no study drug. The primary outcome was the rate of viral clearance (derived under a linear mixed-effects model from the daily log10 viral densities in standardised duplicate oropharyngeal swab eluates taken daily over 8 days [18 swabs per patient]), assessed in a modified intention-to-treat population (mITT). The safety population included all patients who received at least one dose of the allocated intervention. This ongoing adaptive platform trial was registered at ClinicalTrials.gov (NCT05041907) on 13/09/2021. RESULTS: In the final analysis, the mITT population contained data from 114 patients randomised to favipiravir and 126 patients randomised concurrently to no study drug. Under the linear mixed-effects model fitted to all oropharyngeal viral density estimates in the first 8 days from randomisation (4,318 swabs), there was no difference in the rate of viral clearance between patients given favipiravir and patients receiving no study drug; a -1% (95% credible interval: -14 to 14%) difference. High dose favipiravir was well-tolerated. INTERPRETATION: Favipiravir does not accelerate viral clearance in early symptomatic COVID-19. The viral clearance rate estimated from quantitative measurements of oropharyngeal eluate viral densities assesses the antiviral efficacy of drugs in vivo with comparatively few studied patients.

Antiviral efficacy of molnupiravir versus ritonavir-boosted nirmatrelvir in patients with early symptomatic COVID-19 (PLATCOV): an open-label, phase 2, randomised, controlled, adaptive trial.

BACKGROUND: Molnupiravir and ritonavir-boosted nirmatrelvir are the two leading oral COVID-19 antiviral treatments, but their antiviral activities in patients have not been compared directly. The aim of this ongoing platform trial is to compare different antiviral treatments using the rate of viral clearance as the measure of antiviral effect. METHODS: PLATCOV is an open-label, multicentre, phase 2, randomised, controlled, adaptive pharmacometric platform trial running in Thailand, Brazil, Pakistan, and Laos. The component of the trial reported here was conducted in the Hospital for Tropical Diseases, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. We recruited low-risk adult patients aged 18-50 years with early symptomatic COVID-19 (<4 days of symptoms). Eligible patients were randomly assigned using block randomisation via a centralised web app to one of seven treatment groups: molnupiravir, ritonavir-boosted nirmatrelvir, casirivimab-imdevimab, tixagevimab-cilgavimab, favipiravir, fluoxetine, or no study drug. The no study drug group comprised a minimum proportion of 20% of patients at all times, with uniform randomisation ratios applied across the active treatment groups. Results for the concurrently randomised molnupiravir, ritonavir-boosted nirmatrelvir, and no study drug groups are reported here. The primary endpoint was the rate of oropharyngeal viral clearance assessed in a modified intention-to-treat population, defined as patients with more than 2 days of follow-up. Safety was assessed in all participants who took at least one dose of the medication. The viral clearance rate was derived under a Bayesian hierarchical linear model fitted to the log10 viral densities in standardised duplicate oropharyngeal swab eluates taken daily over 1 week (18 measurements). Treatment groups with a probability of more than 0·9 that viral clearance was accelerated by more than 20% compared with no drug entered a non-inferiority comparison (with a 10% non-inferiority margin) compared with the platform's current most effective drug. This ongoing trial is registered at ClinicalTrials.gov, NCT05041907. FINDINGS: Between June 6, 2022, and Feb 23, 2023, 209 patients in Thailand were enrolled and concurrently randomly assigned to molnupiravir (n=65), ritonavir-boosted nirmatrelvir (n=59), or no study drug (n=85). 129 (62%) of the patients were female and 80 (38%) were male. Relative to the no study drug group, the rates of viral clearance were 37% (95% credible interval 16-65) faster with molnupiravir and 84% (54-119) faster with ritonavir-boosted nirmatrelvir. In the non-inferiority comparison, viral clearance was 25% (10-38) slower with molnupiravir than ritonavir-boosted nirmatrelvir. Molnupiravir was removed from the study platform when it reached the prespecified inferiority margin of 10% compared with ritonavir-boosted nirmatrelvir. Median estimated viral clearance half-lives were 8·5 h (IQR 6·7-10·1) with ritonavir-boosted nirmatrelvir, 11·6 h (8·6-15·4) with molnupiravir, and 15·5 h (11·9-21·2) with no study drug. Viral rebound occurred more frequently following nirmatrelvir (six [10%] of 58) compared with the no study drug (one [1%] of 84; p=0·018) or the molnupiravir (one [2%] of 65; p=0·051) groups. Persistent infections following molnupiravir had more viral mutations (three of nine patients had an increased number of single nucleotide polymorphisms in samples collected at 7 or more days compared with those at baseline) than after nirmatrelvir (zero of three) or no study drug (zero of 19). There were no adverse events of grade 3 or worse, or serious adverse events in any of the reported treatment groups. INTERPRETATION: Both molnupiravir and ritonavir-boosted nirmatrelvir accelerate oropharyngeal SARS-CoV-2 viral clearance in patients with COVID-19, but the antiviral effect of ritonavir-boosted nirmatrelvir was substantially greater. Measurement of oropharyngeal viral clearance rates provides a rapid and well tolerated approach to the assessment and comparison of antiviral drugs in patients with COVID-19. It should be evaluated in other acute viral respiratory infections. FUNDING: Wellcome Trust through the COVID-19 Therapeutics Accelerator.

Clinical and immunological characteristics for BK polyomavirus-associated nephropathy after kidney transplantation.

INTRODUCTION: BK polyomavirus (BKPyV)-associated nephropathy (BKPyVAN) can cause a significant risk of allograft impairment after kidney transplantation (KT). Intact BKPyV-specific immunity is associated with viral containment. This study investigated BKPyV-specific immunological factors among KT recipients. METHODS: This prospective study in a single transplant center from January 2019 to August 2019 assessed associations between clinical and immunological characteristics, with a focus on BKPyV-cell-specific immunity and BKPyVAN, among KT recipients aged ≥15 years. The numbers of interferon-gamma (IFN-γ)-producing CD4+  T, CD8+  T, natural killer (NK), and natural killer T (NKT) cells were measured after stimulation with large T antigen and viral capsid protein 1 (VP1). RESULTS: In total, 100 KT recipients were included (mean age ± SD, 42 ± 11 years); 35% of the recipients were female patients, and 70% had received induction immunosuppressive therapy. The 1-year cumulative incidence of high-level BKPyV DNAuria (possible BKPyVAN) and (presumptive BKPyVAN) was 18%. Among 40 patients with immunological factor data, pre-KT %NK cells (hazard ratio [HR], 1.258; 95% confidence interval [CI], 1.077-1.469; p = .004) and %VP1-specific NK cells (HR, 1.209; 95% CI, 1.055-1.386; p = .006) were factors independently associated with possible and presumptive BKPyVAN. KT recipients with possible and presumptive BKPyVAN were more likely to exhibit significant mean coefficients of %NK, %VP1-specific NK, and %NKT cells at 1 month after KT than before KT (all p < .05). CONCLUSION: Individuals with nonspecific and VP1-specific NK cells before KT and increasing numbers of these cells after KT may be at risk for high-level BKPyV DNAuria and presumptive BKPyVAN. Further studies are needed to determine the utility of BKPyV-specific innate immune surveillance in predicting the occurrence of BKPyVAN.

Clinical Antiviral Efficacy of Remdesivir in Coronavirus Disease 2019: An Open-Label, Randomized Controlled Adaptive Platform Trial (PLATCOV).

BACKGROUND: Uncertainty over the therapeutic benefit of parenteral remdesivir in coronavirus disease 2019 (COVID-19) has resulted in varying treatment guidelines. METHODS: In a multicenter open-label, controlled, adaptive, pharmacometric platform trial, low-risk adult patients with early symptomatic COVID-19 were randomized to 1 of 8 treatment arms including intravenous remdesivir (200 mg followed by 100 mg daily for 5 days) or no study drug. The primary outcome was the rate of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) clearance (estimated under a linear model fit to the daily log10 viral densities, days 0-7) in standardized duplicate oropharyngeal swab eluates, in a modified intention-to-treat population. This ongoing adaptive trial is registered at ClinicalTrials.gov (NCT05041907). RESULTS: The 2 study arms enrolled 131 patients (remdesivir n = 67, no study drug n = 64) and estimated viral clearance rates from a median of 18 swab samples per patient (a total of 2356 quantitative polymerase chain reactions). Under the linear model, compared with the contemporaneous control arm (no study drug), remdesivir accelerated mean estimated viral clearance by 42% (95% credible interval, 18%-73%). CONCLUSIONS: Parenteral remdesivir accelerates viral clearance in early symptomatic COVID-19. Pharmacometric assessment of therapeutics using the method described can determine in vivo clinical antiviral efficacy rapidly and efficiently.

Pharmacometrics of high-dose ivermectin in early COVID-19 from an open label, randomized, controlled adaptive platform trial (PLATCOV).

Background: There is no generally accepted methodology for in vivo assessment of antiviral activity in SARS-CoV-2 infections. Ivermectin has been recommended widely as a treatment of COVID-19, but whether it has clinically significant antiviral activity in vivo is uncertain. Methods: In a multicentre open label, randomized, controlled adaptive platform trial, adult patients with early symptomatic COVID-19 were randomized to one of six treatment arms including high-dose oral ivermectin (600 µg/kg daily for 7 days), the monoclonal antibodies casirivimab and imdevimab (600 mg/600 mg), and no study drug. The primary outcome was the comparison of viral clearance rates in the modified intention-to-treat population. This was derived from daily log10 viral densities in standardized duplicate oropharyngeal swab eluates. This ongoing trial is registered at https://clinicaltrials.gov/ (NCT05041907). Results: Randomization to the ivermectin arm was stopped after enrolling 205 patients into all arms, as the prespecified futility threshold was reached. Following ivermectin, the mean estimated rate of SARS-CoV-2 viral clearance was 9.1% slower (95% confidence interval [CI] -27.2% to +11.8%; n=45) than in the no drug arm (n=41), whereas in a preliminary analysis of the casirivimab/imdevimab arm it was 52.3% faster (95% CI +7.0% to +115.1%; n=10 (Delta variant) vs. n=41). Conclusions: High-dose ivermectin did not have measurable antiviral activity in early symptomatic COVID-19. Pharmacometric evaluation of viral clearance rate from frequent serial oropharyngeal qPCR viral density estimates is a highly efficient and well-tolerated method of assessing SARS-CoV-2 antiviral therapeutics in vitro. Funding: 'Finding treatments for COVID-19: A phase 2 multi-centre adaptive platform trial to assess antiviral pharmacodynamics in early symptomatic COVID-19 (PLAT-COV)' is supported by the Wellcome Trust Grant ref: 223195/Z/21/Z through the COVID-19 Therapeutics Accelerator. Clinical trial number: NCT05041907.

Dynamics of Different Classes and Subclasses of Antibody Responses to Severe Acute Respiratory Syndrome Coronavirus 2 Variants after Coronavirus Disease 2019 and CoronaVac Vaccination in Thailand.

The humoral immune response plays a key role in protecting the population from SARS-CoV-2 transmission. Patients who recovered from COVID-19 as well as fully vaccinated individuals have elevated levels of antibodies. The dynamic levels of the classes and subclasses of antibody responses to new variants that occur in different populations remain unclear. We prospectively recruited 60 participants, including COVID-19 patients and CoronaVac-vaccinated individuals, in Thailand from May to August 2021. Plasma samples were collected on day 0, day 14, and day 28 to determine the dynamic levels of the classes and subclasses of plasma antibodies against the receptor-binding domain (RBD) in the spike protein (S) of four SARS-CoV-2 strains (Wuhan, Alpha, Delta, and Omicron) via enzyme-linked immunosorbent assay. Our results indicated that the patients with SARS-CoV-2 infections had broader class and subclass profiles as well as higher levels of anti-S RBD antibodies to the Wuhan, Alpha, and Delta strains than did the CoronaVac-vaccinated individuals. The median antibody levels increased and subsequently declined in a month in the COVID-19 patients and in the vaccinated group. Correlations of the classes and subclasses of antibodies were observed in the COVID-19 patients but not in the vaccinated individuals. The levels of all of the anti-S RBD antibodies against the Omicron variant were low in the patients and in the vaccinated individuals. Our study revealed distinct antibody profiles between the two cohorts, suggesting different pathways of immune activation. This could have an impact on protection from infections by new variants of concern (VOC). IMPORTANCE The antibody responses to new SARS-CoV-2 variants that occur in different populations remain unclear. In this study, we recruited 60 participants, including COVID-19 patients and CoronaVac-vaccinated individuals, in Thailand and determined the dynamic levels of the IgG, IgA, IgM, and IgG subclasses of antibodies against the spike protein (S) of four SARS-CoV-2 strains. Our results showed that the patients with SARS-CoV-2 infections had broader profiles and higher levels of antibodies to the Wuhan, Alpha, and Delta strains than did the CoronaVac-vaccinated individuals. The antibody levels of both groups increased and subsequently decreased within 1 month. Higher and functional correlations of these antibodies were observed in the COVID-19 patients. The levels of all anti-S RBD antibodies against the Omicron variant were low in patients and vaccinated individuals. Our study revealed distinct antibody responses between the two groups, suggesting different pathways of immune response, which may have an impact on protection from infections by new SARS-CoV-2 variants.

Prevalence, Risk Factors, and Prognosis of Liver Involvement in Adult Patients with Chikungunya in Thailand.

Chikungunya is a mosquito-borne disease mainly characterized by fever with polyarthralgia. Currently, liver complications of chikungunya remain rarely described. This study assesses the prevalence, severity, and risk factors of liver involvement, and the association between liver involvement severity and prognosis. We conducted a retrospective cohort study at two referral centers for tropical infectious diseases-the Hospital for Tropical Diseases and Bamrasnaradura Infectious Diseases Institute in Thailand-from January 2016 to April 2021. The study included 400 patients diagnosed with chikungunya. Of them, 254 (63.5%) were female with a mean age of 41.5 ± 14.1 years, and 98.5% of them presented with fever with arthralgia. Gastrointestinal presentations included nausea or vomiting (n = 62, 15.5%), diarrhea (n = 33, 8.3%), and abdominal pain (n = 4, 1%). Of 88 patients with available liver function tests, 39.8% had hepatitis (abnormal alanine aminotransferase levels), of whom 5.7% had moderate hepatitis. Nausea or vomiting is a clinical risk factor associated with liver involvement (adjusted odds ratio, 5.17; 95% CI, 1.20-22.34). Liver involvement was usually observed during the first 2 weeks of illness and resolved eventually. None of the patients experienced severe hepatitis, liver failure, or death caused by a liver problem. In conclusion, most of the patients with chikungunya did not have significant liver involvement. In those patients with severe liver injury, coexisting causes should be considered.

Strongyloides stercoralis: A Neglected but Fatal Parasite.

Strongyloidiasis is a disease caused by Strongyloides stercoralis and remains a neglected tropical infection despite significant public health concerns. Challenges in the management of strongyloidiasis arise from wide ranging clinical presentations, lack of practical high sensitivity diagnostic tests, and a fatal outcome in immunocompromised hosts. Migration, globalization, and increased administration of immunomodulators, particularly during the COVID-19 era, have amplified the global impact of strongyloidiasis. Here, we comprehensively review the diagnostic tests, clinical manifestations, and treatment of strongyloidiasis. The review additionally focuses on complicated strongyloidiasis in immunocompromised patients and critical screening strategies. Diagnosis of strongyloidiasis is challenging because of non-specific presentations and low parasite load. In contrast, treatment is simple: administration of single dosage ivermectin or moxidectin, a recent anthelmintic drug. Undiagnosed infections result in hyperinfection syndrome and disseminated disease when patients become immunocompromised. Thus, disease manifestation awareness among clinicians is crucial. Furthermore, active surveillance and advanced diagnostic tests are essential for fundamental management.

Temporal Trend of COVID-19 Vaccine Acceptance and Factors Influencing International Travellers.

The COVID-19 pandemic has seen disrupted international travel due to travel restrictions and public health measures aimed at containing the spread of the virus. With increasing evidence of the COVID-19 vaccines' ability to mitigate disease severity, reopening tourism is desirable to promote the recovery of the global economy. However, the COVID-19 vaccine and vaccination passport for international travellers remains an ongoing debate. Little is known of the acceptance of these and the influencing factors among this population group. Therefore, this study sought to determine the temporal trend in COVID-19 vaccine acceptance and influencing factors among international travellers. A cross-sectional study was conducted using a self-administered questionnaire among international travellers who visited the Thai Travel Clinic, Hospital for Tropical Diseases, Mahidol University, Thailand from June 2021 to December 2021 (3 different variants dominated during this period). Study data were analyzed using SPSS software, version 23. Chi-square was used to demonstrate associations. Binary logistic regression was used to evaluate the magnitude of effect, demonstrated by odds ratio with 95% confidence interval. All significant variables were included in a multinomial logistic regression model to estimate adjusted odds ratios. The study enrolled 1068 travellers, 719 (67.3%) Thai and 349 (32.7%) foreign travellers. Most travellers were female (55.4%) and aged 18-30 years. The three main purposes for visiting the clinic were: for study, visiting friends and relatives, and returning to their home country. The overall COVID-19 vaccine acceptance rate among the travellers was 96.2%. The temporal trend of acceptance among Thai and non-Thai travelers varied from 93-99% and 93-100%, respectively. Vaccine efficacy, protective duration of the vaccine, risk of infection, and travel plan were factors strongly associated with COVID-19 vaccine acceptance. In conclusion, the COVID-19 vaccine acceptance rate among these international travellers was very high. The safe and effective reopening of tourism to international travellers will facilitate economic recovery.

Evidence of transmission of influenza A and influenza B co-infection in healthcare workers.

INTRODUCTION: Co-infection of influenza A and B has been reported, especially in outbreak situations, but epidemiological and clinical information is limited. We aimed to investigate an outbreak of influenza among health care workers in which the index case suffered from influenza A and B co-infection. METHODOLOGY: We investigated the outbreak setting through the utilization of structural questionnaires, molecular methods, and serological tests. RESULTS: Among 13 persons, one index case and five confirmed secondary cases were confirmed. The overall influenza infection rate was 46.2% (6/13), with infection rates for influenza A and B at 38.5% (5/13) and 23.1% (3/13), respectively. Interestingly, one of the secondary cases had influenza A and B co-infection identical to the index case. There was no significant association between vaccination status and influenza infection. CONCLUSIONS: This study unveils the demonstration of human-to-human influenza A and B co-infection transmission for the first time. Surveillance systems, combined with epidemiological case investigation comprising molecular diagnosis, should be strengthened for future influenza outbreak preparedness.

Efficacy and Safety of Immunomodulators in Patients with COVID-19: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials.

INTRODUCTION: Many immunomodulators have been studied in clinical trials for the treatment of coronavirus disease 2019 (COVID-19). However, data identifying the most effective and safest treatment are lacking. We conducted a systematic review and network meta-analysis to rank immunomodulators in the treatment of COVID-19 according to their efficacy and safety. METHODS: Published and peer-reviewed randomized controlled trials assessing the efficacy of immunomodulators in hospitalized patients with COVID-19 were searched up to June 30, 2021. Direct and network meta-analyses were applied to assess the outcomes. The probability of efficacy and safety was estimated, and the drugs were awarded a numerical ranking. RESULTS: Twenty-six studies were eligible. Compared with standard of care, dexamethasone and tocilizumab had significantly lower mortality rates with pooled risk ratios (RRs) of 0.91 (95% confidence interval [CI] 0.84-0.99) and 0.88 (95% CI 0.82-0.96), respectively. Meanwhile, the most effective corticosteroid, interleukin-6 antagonist, and Janus kinase (JAK) inhibitor were hydrocortisone, sarilumab, and ruxolitinib, respectively. However, when superimposed infection was considered, ruxolitinib was the best treatment followed by baricitinib. Moreover, methylprednisolone had the worst combined efficacy and safety among the examined treatments. CONCLUSIONS: Overall, immunomodulators were more effective than standard of care. Important differences exist among immunomodulators regarding both efficacy and safety in favor of ruxolitinib and baricitinib. Further well-conducted randomized controlled trials should focus on JAK inhibitors. Methylprednisolone use should be discouraged because of its poor efficacy and high risk of superimposed infection. TRIAL REGISTRATION: PROSPERO registration identifier CRD 42021257421.

High Mobility Group Box 1 and Interleukin 6 at Intensive Care Unit Admission as Biomarkers in Critically Ill COVID-19 Patients.

Exuberant inflammation manifesting as a "cytokine storm" has been suggested as a central feature in the pathogenesis of severe coronavirus disease 2019 (COVID-19). This study investigated two prognostic biomarkers, the high mobility group box 1 (HMGB1) and interleukin-6 (IL-6), in patients with severe COVID-19 at the time of admission in the intensive care unit (ICU). Of 60 ICU patients with COVID-19 enrolled and analyzed in this prospective cohort study, 48 patients (80%) were alive at ICU discharge. HMGB1 and IL-6 plasma levels at ICU admission were elevated compared with a healthy control, both in ICU nonsurvivors and ICU survivors. HMGB1 and IL-6 plasma levels were higher in patients with a higher Sequential Organ Failure Assessment (SOFA) score (> 10), and the presence of septic shock or acute kidney injury. HMGB1 and IL-6 plasma levels were also higher in patients with a poor oxygenation status (PaO2/FiO2 < 150 mm Hg) and a longer duration of ventilation (> 7 days). Plasma HMGB1 and IL-6 levels at ICU admission also correlated with other prognostic markers, including the maximum neutrophil/lymphocyte ratio, D-dimer levels, and C-reactive protein levels. Plasma HMGB1 and IL-6 levels at ICU admission predicted ICU mortality with comparable accuracy to the SOFA score and the COVID-GRAM risk score. Higher HMGB1 and IL-6 were not independently associated with ICU mortality after adjustment for age, gender, and comorbidities in multivariate analysis models. In conclusion, plasma HMGB1 and IL6 at ICU admission may serve as prognostic biomarkers in critically ill COVID-19 patients.