Dose Optimisation and Scarce Resource Allocation: Two Sides of the Same Coin

Objective: A deep understanding of the relationship between a scarce drug\u27s dose and clinical response is necessary to appropriately distribute a supply-constrained drug along these lines. Summary of key data: The vast majority of drug development and repurposing during the COVID-19 pandemic – an event that has made clear the ever-present scarcity in health care systems –has been ignorant of scarcity and dose optimisation\u27s ability to help address it. Conclusions: Future pandemic clinical trials systems should obtain dose optimisation data, as these appear necessary to enable appropriate scarce resource allocation according to societal values

The effect of tocilizumab on procalcitonin and other biochemical and clinical markers in severe COVID-19 infection : time to rethink our interpretation of results?

BACKGROUND: Tocilizumab is an interleukin-6 inhibitor approved for use in patients severely affected by COVID-19. It has reduced mortality and duration of mechanical ventilation but the effects of tocilizumab on routinely monitored biochemical parameters in the critically ill COVID-19 population are unclear. In Malta, tocilizumab started being administered to acutely deteriorating COVID-19 patients in January 2021. This study aims to assess the effect of tocilizumab on procalcitonin primarily, and white cell count, lymphocyte and neutrophil counts, neutrophil to lymphocyte ratio, C-reactive protein and PaO2/FiO2 ratio as secondary measures.METHODS: 50 patients who received tocilizumab were recruited to the treatment group along with a matched control group of 50 patients who did not receive the drug. Serum procalcitonin and other biochemical markers were recorded daily for both groups along with results of blood cultures for 20 days or until discharge or death. Non-parametric univariate analysis and linear mixed model analysis was used to check for differences between the two groups. Outcome measures included differences between the biomarkers at 5, 10 and 15 days, and differences in the trajectories of the biomarkers between the two groups.RESULTS: Procalcitonin and C-reactive protein are significantly lowered by administration of tocilizumab on Day 5. White cell count, lymphocyte and neutrophil counts and PaO2/FiO2 ratios were not affected. There was no difference in positive blood culture results between the two groups.CONCLUSION: Procalcitonin and C-reactive protein may not be reliable indicators of bacterial superinfection in severe COVID-19 pneumonia patients who have been given tocilizumab.peer-reviewe

Defining Potential Therapeutic Targets in Coronavirus Disease 2019: A Cross-Sectional Analysis of a Single-Center Cohort

OBJECTIVES: Multiple mechanisms have been proposed to explain disease severity in coronavirus disease 2019. Therapeutic approaches need to be underpinned by sound biological rationale. We evaluated whether serum levels of a range of proposed coronavirus disease 2019 therapeutic targets discriminated between patients with mild or severe disease. DESIGN: A search of ClinicalTrials.gov identified coronavirus disease 2019 immunological drug targets. We subsequently conducted a retrospective observational cohort study investigating the association of serum biomarkers within the first 5 days of hospital admission relating to putative therapeutic biomarkers with illness severity and outcome. SETTING: University College London, a tertiary academic medical center in the United Kingdom. PATIENTS: Patients admitted to hospital with a diagnosis of coronavirus disease 2019. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Eighty-six patients were recruited, 44 (51%) with mild disease and 42 (49%) with severe disease. We measured levels of 10 cytokines/signaling proteins related to the most common therapeutic targets (granulocyte-macrophage colony-stimulating factor, interferon-α2a, interferon-β, interferon-γ, interleukin-1β, interleukin-1 receptor antagonist, interleukin-6, interleukin-7, interleukin-8, tumor necrosis factor-α), immunoglobulin G antibodies directed against either coronavirus disease 2019 spike protein or nucleocapsid protein, and neutralization titers of antibodies. Four-hundred seventy-seven randomized trials, including 168 different therapies against 83 different pathways, were identified. Six of the 10 markers (interleukin-6, interleukin-7, interleukin-8, interferon-α2a, interferon-β, interleukin-1 receptor antagonist) discriminated between patients with mild and severe disease, although most were similar or only modestly raised above that seen in healthy volunteers. A similar proportion of patients with mild or severe disease had detectable spike protein or nucleocapsid protein immunoglobulin G antibodies with equivalent levels between groups. Neutralization titers were higher among patients with severe disease. CONCLUSIONS: Some therapeutic and prognostic biomarkers may be useful in identifying coronavirus disease 2019 patients who may benefit from specific immunomodulatory therapies, particularly interleukin-6. However, biomarker absolute values often did not discriminate between patients with mild and severe disease or death, implying that these immunomodulatory treatments may be of limited benefit

Dose optimisation and scarce resource allocation: two sides of the same coin

Objective: A deep understanding of the relationship between a scarce drug's dose and clinical response is necessary to appropriately distribute a supply-constrained drug along these lines. Summary of key data: The vast majority of drug development and repurposing during the COVID-19 pandemic – an event that has made clear the ever-present scarcity in healthcare systems –has been ignorant of scarcity and dose optimisation's ability to help address it. Conclusions: Future pandemic clinical trials systems should obtain dose optimisation data, as these appear necessary to enable appropriate scarce resource allocation according to societal values

Tocilizumab in COVID-19: a meta-analysis, trial sequential analysis, and meta-regression of randomized-controlled trials

PURPOSE: Interleukin-6 (IL-6) levels discriminate between patients with mild and severe COVID-19, making IL-6 inhibition an attractive therapeutic strategy. We conducted a systematic review, meta-analysis, trial sequential analysis (TSA), and meta-regression of randomized-controlled trials to ascertain the benefit of IL-6 blockade with tocilizumab for COVID-19. METHODS: We included randomized-controlled trials (RCTs) allocating patients with COVID-19 to tocilizumab. Our control group included standard care or placebo. Trials co-administering other pharmacological interventions for COVID-19 were not excluded. Primary outcome was 28–30 day mortality. Secondary outcomes included progression-to-severe disease defined as need for mechanical ventilation, intensive-care unit (ICU) admission, or a composite. RESULTS: We identified 10 RCTs using tocilizumab, 9 of which reported primary outcome data (mortality), recruiting 6493 patients with 3358 (52.2%) allocated to tocilizumab. Tocilizumab may be associated with an improvement in mortality (24.4% vs. 29.0%; OR 0.87 [0.74–1.01]; p = 0.07; I2 = 10%; TSA adjusted CI 0.66–1.14). Meta-regression suggested a relationship between treatment effect and mortality risk, with benefit at higher levels of risk (logOR vs %risk beta = −0.018 [−0.037 to −0.002]; p = 0.07). Tocilizumab did reduce the need for mechanical ventilation and was associated with a benefit in the composite secondary outcome but did not reduce ICU admission. CONCLUSIONS: For hospitalized COVID-19 patients, there is some evidence that tocilizumab use may be associated with a short-term mortality benefit, but further high-quality data are required. Its benefits may also lie in reducing the need for mechanical ventilation

Doză redusă de Tocilizumab 200 mg, comparativ cu 400 mg, la pacienții cu forme severe de infecție COVID-19

Introduction. Excessive, deregulated pro-inflammatory cytokine secretion has a detrimental impact on the evolution of COVID-19, aggregating the tissue impairment, organ failure, and an increased risk of death. Several studies have demonstrated the beneficial effect of Tocilizumab (TCZ) in reducing hyperimmune response in severe forms of COVID-19. Material and methods. This is an experimental controlled clinical trial, consisting of 66 patients hospitalized with severe COVID-19. Results. On overage, the decision to administer TCZ was made on average on the 11.34±0.31 day of the disease, when the beginning of Cytokine Storm was suspected in the patients already on dexamethasone treatment. The clinical and paraclinical parameters, including fever, asthenia and dyspnea duration, SpO2 level, oxygen therapy need, improvement of the radiological picture, and duration of hospitalization were more favorable in patients treated with TCZ 400 mg compared to those treated with TCZ 200 mg (p<0.0001). The relative risk of rapid worsening after TCZ (RR=0.88), the relative risk of decreasing blood pressure (RR=0.29) and the relative risk of transfer to intensive care units for invasive or non-invasive ventilation (RR=0.8) was lower in patients treated with TCZ 200 mg compared to the 400 mg TCZ lot. Conclusions. The dose of TCZ had a significant impacton the duration of clinical manifestations, the duration of oxygen therapy and the duration of patient hospitalization, with better results for TCZ 400 mg compared to TCZ 200mg. Although the risk of worsening after TCZ and the risk of transfer to intensive care were lower in patients treated with TCZ 200 mg. So, the 200 mg fixed dose of TCZ can be a life-saving option for severely ill patients with COVID-19 in the context of IL-6 inhibitor supply shortages.Introducere. Eliberarea excesivă a citokinelor proinflamatorii are un impact negativ asupra evoluției infecției COVID-19, sporind afectarea tisulară, insuficiența organică și riscul de deces. Mai multe studii au demonstrat efectul benefic al preparatului Tocilizumab (TCZ) în reducerea răspunsului hiperimun în formele severe de infecție COVID-19. Material și metode. Este un studiu experimental, clinic controlat, care include 66 pacienți, internați cu forme severe de infecție COVID-19. Rezultate. Decizia privind administrarea de TCZ a fost luată în medie în ziua a 11,34±0,31 de boală, când a fost suspectat debutul furtunii de citokine la pacienții aflați deja în tratament cu dexametazonă. Parametri clinici și paraclinici, precum durata febrei, asteniei și a dispneei, nivelul SpO2, necesitatea în terapie cu oxigen, ameliora-rea tabloului imagistic radiologic, și durata spitalizării au fost mai favorabili la pacienții tratați cu TCZ 400 mg față de cei tratați cu TCZ 200 mg (p<0.0001). Riscul relativ de agravare rapidă după administrarea TCZ (RR=0,88), riscul relativ de diminuare a tensiunii arteriale (RR=0,29) și riscul relativ de transfer în secțiile de terapie intensivă pentru ventilație invazivă sau non-invazivă (RR=0,8) a fost mai scăzut la pacienții tratați cu TCZ 200 mg, comparativ cu lotul TCZ 400 mg. Concluzii. Doza de TCZ a influențat durata manifestărilor clinice, durata terapiei cu oxigen și durata spitalizării pacienților, cu rezultate mai bune pentru TCZ 400 mg față de TCZ 200 mg, deși riscul de agravare după TCZ și riscul de transfer în terapie intensivă au fost mai joase la pacienții tratați cu TCZ 200 mg. Deci, doza de TCZ de 200 mg poate fi o opțiune de salvare a vieții pacienților gravi cu infecție COVID-19, în contextul deficitului de aprovizionare cu inhibitori de IL-6

Defining Potential Therapeutic Targets in Coronavirus Disease 2019: A Cross-Sectional Analysis of a Single-Center Cohort.

OBJECTIVES: Multiple mechanisms have been proposed to explain disease severity in coronavirus disease 2019. Therapeutic approaches need to be underpinned by sound biological rationale. We evaluated whether serum levels of a range of proposed coronavirus disease 2019 therapeutic targets discriminated between patients with mild or severe disease. DESIGN: A search of ClinicalTrials.gov identified coronavirus disease 2019 immunological drug targets. We subsequently conducted a retrospective observational cohort study investigating the association of serum biomarkers within the first 5 days of hospital admission relating to putative therapeutic biomarkers with illness severity and outcome. SETTING: University College London, a tertiary academic medical center in the United Kingdom. PATIENTS: Patients admitted to hospital with a diagnosis of coronavirus disease 2019. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Eighty-six patients were recruited, 44 (51%) with mild disease and 42 (49%) with severe disease. We measured levels of 10 cytokines/signaling proteins related to the most common therapeutic targets (granulocyte-macrophage colony-stimulating factor, interferon-α2a, interferon-β, interferon-γ, interleukin-1β, interleukin-1 receptor antagonist, interleukin-6, interleukin-7, interleukin-8, tumor necrosis factor-α), immunoglobulin G antibodies directed against either coronavirus disease 2019 spike protein or nucleocapsid protein, and neutralization titers of antibodies. Four-hundred seventy-seven randomized trials, including 168 different therapies against 83 different pathways, were identified. Six of the 10 markers (interleukin-6, interleukin-7, interleukin-8, interferon-α2a, interferon-β, interleukin-1 receptor antagonist) discriminated between patients with mild and severe disease, although most were similar or only modestly raised above that seen in healthy volunteers. A similar proportion of patients with mild or severe disease had detectable spike protein or nucleocapsid protein immunoglobulin G antibodies with equivalent levels between groups. Neutralization titers were higher among patients with severe disease. CONCLUSIONS: Some therapeutic and prognostic biomarkers may be useful in identifying coronavirus disease 2019 patients who may benefit from specific immunomodulatory therapies, particularly interleukin-6. However, biomarker absolute values often did not discriminate between patients with mild and severe disease or death, implying that these immunomodulatory treatments may be of limited benefit

COVID-19: новый вызов ревматологам

Currently, the infection caused by the new coronavirus COVID-19 is considered by the global community as an emergency of international concern. Rheumatologists are particularly concerned about this problem, since patients with immune-mediated inflammatory rheumatic diseases (IMIRDs) are at higher risk for infectious diseases and receive immunosuppressive treatment. The use of disease-modifying antirheumatic drugs and biological agents increases the incidence of serious infections, but insufficient/no monitoring of IMIRD activity is an even greater risk factor for infectious complications. In addition, the role of vaccination mainly against influenza and pneumococcal infection is substantially increasing in modern conditions, since the risk of death from respiratory tract infections is quite high in patients with IMIRDs, which is very important in the context of the current COVID-19 pandemic.The paper presents an update on the incidence of viral infections in patients with IMIRDs and also discusses whether antirheumatic drugs can be used to treat COVID-19.В настоящее время инфекция, вызванная новым коронавирусом – COVID-19, рассматривается мировым сообществом как чрезвычайная ситуация глобального значения. Особенно обеспокоены этой проблемой ревматологи, поскольку пациенты с иммуновоспалительными ревматическими заболеваниями (ИВРЗ) имеют повышенный риск развития инфекционных заболеваний и получают лечение препаратами, оказывающими иммуносупрессивное действие. Применение базисных противовоспалительных препаратов и генно-инженерных биологических препаратов увеличивает частоту серьезных инфекций, но недостаточный контроль активности ИВРЗ (или его отсутствие) является еще большим фактором риска инфекционных осложнений. Кроме того, в современных условиях существенно возрастает роль вакцинации, в первую очередь против гриппа и пневмококковой инфекции, поскольку у больных с ИВРЗ риск летальных исходов от инфекций дыхательных путей достаточно высок, что весьма актуально в условиях текущей пандемии COVID-19.В статье представлены современные данные о частоте вирусных инфекций у больных с ИВРЗ, а также рассмотрены возможности применения противоревматических препаратов в терапии COVID-19