Transcriptional response modules characterise IL-1β and IL-6 activity in COVID-19

Bell, Lucy; Meydan, Cem; Kim, Jacob; Foox, Jonathan; Butler, Daniel; Mason, Christopher E.; Shapira, Sagi; Noursadeghi, Mahdad; Pollara, Gabriele

doi:10.1101/2020.07.22.202275

Cited by 3 publications

(7 citation statements)

References 46 publications

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“…Indeed, in the very recent study by Abers et al [40] , the IL-1b levels although higher than healthy, did not correlate either at baseline or after serial determinations during the disease process with the severity of COVID-19 and patient mortality. In parallel with the previous study, Bell et al [41] have shown that the elevated expression of IL-1b and IL-6 response modules was a characteristic feature of SARS-CoV-2 infection but was not associated with the disease severity, length of stay or mortality.…”

Section: Discussionsupporting

confidence: 79%

“…However, in another recent study, TNF-α levels -although increased in patients with SARS-CoV-2 infection compared to healthy- were not associated with disease severity and survival [40] . Moreover, the relative role of abnormal IL-1b responses in the immunopathology of severe COVID-19 remains controversial [ 4 , 5 , 40 , 41 , 42 ]. Indeed, in the very recent study by Abers et al [40] , the IL-1b levels although higher than healthy, did not correlate either at baseline or after serial determinations during the disease process with the severity of COVID-19 and patient mortality.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, the serum levels of the above cytokines may be in the normal range in patients with sHLH-like syndromes, though they might be elevated at local sites of injury, and frequently do not correlate with the outcome following therapy with specific IL-1b or IL-6 inhibitors [20] . Another point concerning the determination of these cytokines in patients’ sera, might be the technical difficulties because of assays variability making comparisons among laboratories inefficient and the fact that determination of individual cytokines at the protein level may not reflect precisely their biological activity [ 20 , 41 ].…”

Section: Discussionmentioning

confidence: 99%

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Lessons from pathophysiology: Use of individualized combination treatments with immune interventional agents to tackle severe respiratory failure in patients with COVID-19

Dalekos

Stefos

Georgiadou

et al. 2021

European Journal of Internal Medicine

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Aims: Infection by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) may lead to the development of severe respiratory failure. In hospitalized-patients, prompt interruption of the virus-driven inflammatory process by using combination treatments seems theoretically of outmost importance. Our aim was to investigate the hypothesis of multifaceted management of these patients. Methods: A treatment algorithm based on ferritin was applied in 311 patients (67.2% males; median age 63-years; moderate disease, n=101; severe, n=210). Patients with ferritin <500ng/ml received anakinra 2-4mg/kg/day ± corticosteroids (Arm A, n=142) while those with ≥500ng/ml received anakinra 5-8mg/kg/day with corticosteroids and γ-globulins (Arm B, n=169). In case of no improvement a single dose of tocilizumab (8mg/kg; maximum 800mg) was administered with the potential of additional second and/or third pulses. Treatment endpoints were the rate of the development of respiratory failure necessitating intubation and the SARS-CoV-2-related mortality. The proposed algorithm was also validated in matched hospitalized-patients treated with standard-of-care during the same period. Results: In overall, intubation and mortality rates were 5.8% and 5.1% (0% in moderate; 8.6% and 7.6% in severe). Low baseline pO 2 /FiO 2 and older age were independent risk factors. Comparators had significantly higher intubation (HR=7.4; 95%CI: 4.1-13.4; p<0.001) and death rates (HR=4.5, 95%CI: 2.1-9.4, p<0.001). Significant adverse events were rare, including severe secondary infections in only 7/311 (2.3%). Conclusions: Early administration of personalized combinations of immunomodulatory agents may be life-saving in hospitalized-patients with COVID-19. An immediate intervention (the sooner the better) could be helpful to avoid development of full-blown acute respiratory distress syndrome and improve survival.

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Section: Discussionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Lessons from pathophysiology: Use of individualized combination treatments with immune interventional agents to tackle severe respiratory failure in patients with COVID-19

Dalekos

Stefos

Georgiadou

et al. 2021

European Journal of Internal Medicine

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“…7D ), using transcriptional modules composed of IL-1β ( fig. S12 and Data File S2 ) ( 34 , 35 ) and IL-6 ( 36 ) inducible genes. Taken together, these data are consistent with a model in which exaggerated Th17 responses at the site of host-pathogen interactions in active TB are driven by recruitment of IL-1β or IL-6 producing monocytes ( fig.…”

Section: Resultsmentioning

confidence: 99%

Exaggerated IL-17A activity in human in vivo recall responses discriminates active tuberculosis from latent infection and cured disease

et al. 2021

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Host immune responses at the site of Mycobacterium tuberculosis infection can mediate pathogenesis of tuberculosis (TB) and onward transmission of infection. We hypothesized that pathological immune responses would be enriched at the site of host-pathogen interactions modeled by a standardized tuberculin skin test (TST) challenge in patients with active TB compared to those without disease, and interrogated immune responses by genome-wide transcriptional profiling. We show exaggerated interleukin-17A (IL-17A) and T helper 17 (TH17) responses among 48 individuals with active TB compared to 191 with latent TB infection, associated with increased neutrophil recruitment and matrix metalloproteinase-1 expression, both involved in TB pathogenesis. Curative antimicrobial treatment reversed these observed changes. Increased IL-1β and IL-6 responses to mycobacterial stimulation were evident both in circulating monocytes and in molecular changes at the site of TST in individuals with active TB, supporting a model in which monocyte-derived IL-1β and IL-6 promote TH17 differentiation within tissues. Modulation of these cytokine pathways may provide a rational strategy for host-directed therapy in active TB.

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“…Unfortunately, we could not investigate PCT as it was not measured routinely in our CAP cohorts. Future studies should also assess, alongside admission WCC and ΔCRP, the discriminatory capacity of PCT, D-dimers [9,22,31], and other novel biomarkers, such as transcriptional signatures that quantify inflammatory cytokine activity [32] or those that discriminate bacterial from viral infections [33].…”

Section: Discussionmentioning

confidence: 99%

Exclusion of bacterial co-infection in COVID-19 using baseline inflammatory markers and their response to antibiotics

Mason

Kanitkar

Richardson

et al. 2020

Preprint

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Background COVID-19 is infrequently complicated by secondary bacterial infection, but nevertheless antibiotic prescriptions are common. We used community-acquired pneumonia (CAP) as a benchmark to define the processes that occur in a bacterial pulmonary infection, and tested the hypothesis that baseline inflammatory markers and their response to antibiotic therapy could distinguish CAP from COVID-19. Methods In patients admitted to Royal Free Hospital (RFH) and Barnet Hospital (BH) we defined CAP by lobar consolidation on chest radiograph, and COVID-19 by SARS-CoV-2 detection by PCR. Data were derived from routine laboratory investigations. Results On admission all CAP and >90% COVID-19 patients received antibiotics. We identified 106 CAP and 619 COVID-19 patients at RFH. CAP was characterised by elevated white cell count (WCC) and C-reactive protein (CRP) compared to COVID-19 (median WCC 12.48 (IQR 8.2-15.3) vs 6.78 (IQR 5.2-9.5) x106 cells/ml and median CRP CRP 133.5 (IQR 65-221) vs 86 (IQR 42-160) mg/L). Blood samples collected 48-72 hours into admission revealed decreasing CRP in CAP but not COVID-19 (CRP difference -33 (IQR -112 to +3.5) vs +15 (IQR -15 to +70) mg/L respectively). In the independent validation cohort (BH) consisting of 169 CAP and 181 COVID-19 patients, admission WCC >8.2x106 cells/ml or falling CRP during admission identified 95% of CAP cases, and predicted the absence of bacterial co-infection in 45% of COVID-19 patients. Conclusions We propose that in COVID-19 the absence of both elevated baseline WCC and antibiotic-related decrease in CRP can exclude bacterial co-infection and facilitate antibiotic stewardship efforts.

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Transcriptional response modules characterise IL-1β and IL-6 activity in COVID-19

Cited by 3 publications

References 46 publications

Lessons from pathophysiology: Use of individualized combination treatments with immune interventional agents to tackle severe respiratory failure in patients with COVID-19

Lessons from pathophysiology: Use of individualized combination treatments with immune interventional agents to tackle severe respiratory failure in patients with COVID-19

Exaggerated IL-17A activity in human in vivo recall responses discriminates active tuberculosis from latent infection and cured disease

Exclusion of bacterial co-infection in COVID-19 using baseline inflammatory markers and their response to antibiotics

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