Inflammatory Profiles Are Associated with Long Covid 6 Months after Illness Onset

Background: Systemic hyperinflammation is key to the pathogenesis of severe, acute COVID-19. However, few studies have analysed inflammatory profiles in adults with mild/moderate COVID-19, or in those with post-acute sequelae of COVID-19 (PASC). We aimed to i) describe trajectories of cytokines in a prospective cohort of adults with mild to severe COVID-19, compared to uninfected, healthy controls and ii) identify early (< 4 weeks after illness onset onset) predictors of ongoing PASC and inflammation at 6 months after illness onset. Method(s): RECoVERED is a prospective cohort of adults with laboratoryconfirmed SARS-CoV-2 infection between May 2020 and June 2021 in Amsterdam, the Netherlands. Serum was collected at weeks 4, 12 and 24. Participants completed monthly symptom questionnaires. PASC was defined as having at least one ongoing symptom that originated < 1 month of illness onset. Cytokine concentrations were analysed by human magnetic Luminex screening assay. We performed random forest regression to identify early predictors of PASC and raised CRP/IL-6 at 24 weeks, using Shapley additive explanation values as measures of importance for the different predictors. Result(s): Of 349 RECoVERED participants, 186 (53%) had >=2 serum samples and were included in current analyses. Of these, 101 (54%: 45/101 [45%] female, median age 55 years [IQR=45-64]) reported PASC at 12 weeks after illness onset, of whom none recovered by 24 weeks. We included 37 uninfected controls (17/37 [46%] female, median age 49 years [IQR=40-56]). At 4 weeks after illness onset, levels of IP10, IL10, IL17, IL1beta, IL6 and TNFalpha were significantly elevated among participants infected with SARS-CoV-2 compared to controls. Ongoing PASC was independently associated with raised CRP at 24 weeks. Early raised IL1beta and sCD14 levels and greater BMI at illness onset were the strongest predictors of PASC at 24 weeks. Those with higher early sCD14 or IL1beta and TNFalpha levels were also more likely to have persistently raised CRP and IL6, respectively, at 24 weeks (Fig.1). Conclusion(s): Differences in cytokine concentrations between individuals with COVID-19 and uninfected controls largely were greatest < 4 weeks after illness onset. In our study, ongoing PASC was associated with persistently elevated CRP at 24 weeks. Early immune dysregulation was, alongside BMI, an important determinant for persistent PASC. Further investigation of individuals with PASC and long-term aberrant cytokine levels may help improve our understanding of the condition. (Figure Presented).

EARLY INTESTINAL ULTRASOUND PREDICTS ENDOSCOPIC RESPONSE ON ANTI-INFLAMMATORY TREATMENT AND SHOWS DRUG-SPECIFIC RESPONSE TO BIOLOGICALS AND TOFACITINIB IN ULCERATIVE COLITIS

Introduction Objective evaluation of treatment response is the gold standard in ulcerative colitis (UC). In this setting, intestinal ultrasound (IUS) is a non-invasive alternative to endoscopy. Recent studies showed change in IUS parameters after treatment initiation but studies with an endoscopic reference standard are scarce. The aim of this study was to evaluate early change of IUS parameters and determine cut-off values for endoscopic endpoints in UC patients starting anti-inflammatory treatment. Methods In this longitudinal prospective study consecutive patients with moderate-severe UC (baseline endoscopic Mayo score (EMS)≥2) starting an anti-inflammatory treatment were included. Clinical scores, biochemical parameters and IUS parameters were collected at baseline, after 2 (T1), 6 (T2) and 8-26 weeks (T3) around time of the second sigmoidoscopy/colonoscopy. Bowel wall thickness (BWT), Colour Doppler signal (CDS), haustrations, inflammatory fat and wall layer stratification were measured as previously established1. Endoscopic remission (ER) and mucosal healing (MH) were evaluated in the sigmoid and defined as EMS=0 and EMS≤1, respectively. The ultrasonographist and endoscopist were blinded for the outcomes of endoscopy and IUS, respectively. Results 51 consecutive patients were included (Table 1) of whom 31 underwent a second endoscopy. Two additional patients underwent colectomy and were considered non-responders. 18 patients did not undergo second endoscopy due to the COVID-19 pandemic (n=2), refusal (n=5), loss to follow-up (n=1) or treatment escalation because of clinical deterioration confirmed by IUS and biomarkers before second endoscopy was performed (n=10). BWT was significantly lower from T2 onwards in patients reaching MH (p=0.026) and ER (p=0.002) at T3 (Fig 1). A significant decrease in BWT was already visible at T1 in patients receiving infliximab (median DBWT T0-T1: -26% [-43% - -6%], p=0.001) or tofacitinib (median ∆BWT T0-T1: -33% [-46% - -5%], p=0.001) but not in patients treated with vedolizumab (median ∆BWT T0-T1: -14% [-43% - 5%], p=0.11). Most accurate BWT cut-off values at T3 to determine MH and ER were 3.52 mm (AUROC: 0.95, 95% CI: 0.86-1.00, p<0.0001, sens:91%, spec:91%) and 2.98 mm (AUROC: 0.94, 95% CI: 0.85-1.00, p=0.001, sens:87%, spec:100%), respectively. At T2, BWT per 1 mm increase and CDS were inversely associated with MH (BWT: OR: 0.48 (0.24-0.96, p=0.038);CDS: OR 0.16 (0.03-0.83), p=0.028) and ER (BWT: OR: 0.30 (0.11-0.76), p=0.01). Conclusion BWT and CDS 6 weeks after start of treatment could predict MH and ER. In addition, treatment response at IUS is drug-specific. Furthermore, we have provided accurate BWT cut-off values for endoscopic outcomes. In a point-of-care setting, (early) treatment evaluation with IUS could guide treatment decision in UC in order to optimize treatment response. 1. Bots et al. JCC 2021

STRAIN-SPECIFIC SEROLOGICAL RESPONSE FOLLOWING SARS-CoV-2 VOC INFECTION

Background: The emergence of new SARS-CoV-2 variants raises concerns whether preexisting artificial (vaccine-induced) and natural immunity from prior COVID-19 prevents re-infections. Here, we investigated the differences in primary humoral immune response following SARS-CoV-2 variants of concern (VOCs) infection and aimed to identify the key mutations involved in these differences. Methods: Patients with primary PCR-proven SARS-CoV-2 infection with no history of previous COVID-19 vaccination were included between October 2020 and May 2021 at Amsterdam UMC and via the Dutch SARS-CoV-2 sequence surveillance program. Serum was collected 4-8 weeks after symptom onset and tested for IgG binding and pseudovirus neutralization of the wild-type (WT, Wuhan/D614G), Alpha, Beta and Delta variants. Results: We included 51 COVID-19 patients, who were infected with the WT (n=20), Alpha (n=10), Beta (n=9) or Delta variant (n=12). Generally, the highest neutralization titers were against the autologous virus. After stratifying for hospitalization status, non-hospitalized patients infected with the WT (ID50 817) or Alpha (ID50 2524) variant showed the strongest geometric mean autologous neutralization, followed by the Delta variant (ID50 704) infected participants. By contrast, only one participant infected with the Beta variant showed strong autologous neutralization (median ID50 171). The VOCs also differed in their ability to induce cross-neutralizing responses, with WT-infected patients showing the broadest immune response, followed by Alpha, Delta and Beta infected participants. Additionally, participants infected with the WT, Alpha or Delta variant showed the lowest cross-neutralization against the Beta variant, with a median 5.0-fold (2 to 16-fold), 7.7-fold (2 to 32-fold), and 5.3-fold (1 to 19-fold) reduction compared to the autologous neutralization, respectively. We identified the E484K mutation as the key mutation responsible for this low cross-neutralization. Conclusion: We demonstrated that even small differences in the S protein influences the polyclonal antibody response following infection. The low level of (cross-)neutralization induced by the Beta variant may implicate a higher re-infection risk, but further research of the memory B cell compartment and clinical studies are needed. The broadest cross-neutralizing response observed for WT-infected patients suggests that artificial immunity induced by the current approved COVID-19 vaccines already protects against many re-infections.

Risk of SARS-CoV-2 transmission upon return to work in RNA-positive healthcare workers.

BACKGROUND: Healthcare workers (HCWs) are at risk for coronavirus disease 2019 (COVID-19), and for spreading severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) amongst colleagues and patients. AIM: To study the presence of SARS-CoV-2 RNA and possible onward transmission by HCWs upon return to work after COVID-19, and association with disease severity and development of antibodies over time. METHODS: Unvaccinated HCWs with positive SARS-CoV-2 reverse transcriptase polymerase chain reaction (RT-PCR) were recruited prospectively. Data on symptoms were collected via telephone questionnaires on days 2, 7, 14 and 21 after a positive test. Upon return to work, repeat SARS-CoV-2 RT-PCR was performed and serum was collected. Repeat serum samples were collected at weeks 4, 8, 12 and 16 to determine antibody dynamics over time. Phylogenetic analysis was conducted to investigate possible transmission events originating from HCWs with a positive repeat RT-PCR. FINDINGS: Sixty-one (84.7%) participants with mild/moderate COVID-19 had a repeat SARS-CoV-2 RT-PCR performed upon return to work (median 13 days after symptom onset), of which 30 (49.1%) were positive with a median cycle threshold (Ct) value of 29.2 (IQR 26.9-29.9). All HCWs developed antibodies against SARS-CoV-2. No significant differences in symptomatology and presence of antibodies were found between repeat RT-PCR-positive and -negative HCWs. Eleven direct colleagues of six participants with a repeat RT-PCR Ct value <30 tested positive after the HCW returned to work. Phylogenetic and epidemiologic analysis did not indicate onward transmission through HCWs who were SARS-CoV-2 RNA positive upon return to work. CONCLUSIONS: HCWs regularly return to work with substantial SARS-CoV-2 RNA loads. However, this study found no evidence for subsequent in-hospital transmission.

[Covid-19 vaccines in times of the Delta variant]

1,5 years into the pandemic, SARS-CoV-2 remains a dynamic and evolving disease. Growing proportions of the population have been vaccinated, but what degree of protection does vaccination actually offer, particularly in the face of an evolving virus and the emergence of viral variants? Here we explore the limits of vaccine protection -providing an overview of emerging data on how well vaccines protect against mild and asymptomatic disease, vaccine effectiveness against the backdrop of variants such as the Delta, and the implications for SARS-CoV-2 transmission. We assess the continued risks for our vulnerable elderly and immune-compromised patient populations, and whether emerging literature should impact our diagnostic strategies.

Update for Anaesthetists on Clinical Features of COVID-19 Patients and Relevant Management. LID - 1495

When preparing for the outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the coronavirus infection disease (COVID-19) questions arose regarding various aspects concerning the anaesthetist. When reviewing the literature it became obvious that keeping up-to-date with all relevant publications is almost impossible. We searched for and summarised clinically relevant topics that could help making clinical decisions. This is a subjective analysis of literature concerning specific topics raised in our daily practice (e.g., clinical features of COVID-19 patients;ventilation of the critically ill COVID-19 patient;diagnostic of infection with SARS-CoV-2;stability of the virus;Covid-19 in specific patient populations, e.g., paediatrics, immunosuppressed patients, patients with hypertension, diabetes mellitus, kidney or liver disease;co-medication with non-steroidal anti-inflammatory drugs (NSDOs);antiviral treatment) and we believe that these answers help colleagues in clinical decision-making. With ongoing treatment of severely ill COVID-19 patients other questions will come up. While respective guidelines on these topics will serve clinicians in clinical practice, regularly updating all guidelines concerning COVID-19 will be a necessary, although challenging task in the upcoming weeks and months. All recommendations during the current extremely rapid development of knowledge must be evaluated on a daily basis, as suggestions made today may be out-dated with the new evidence available tomorrow. FAU - Preckel, Benedikt