LitCovid-sentences  

PMC:7784786 / 1932-18065 JSONTXT 3 Projects

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Id Subject Object Predicate Lexical cue
T21 0-108 Sentence denotes A group of COVID-19 patients develops severe or critical disease accompanied by the cytokine storm syndrome.
T22 109-287 Sentence denotes Cytokines are essential to the pathophysiology of disease and IL-6, IL-1 and TNF-α appear to be harmful, particularly in the context of the cytokine-release syndrome (CRS) [1,2].
T23 288-368 Sentence denotes CD6 is a membrane glycoprotein expressed primarily in mature, activated T cells.
T24 369-489 Sentence denotes Ligand binding of CD6, increases events such as adhesion, activation, proliferation, differentiation and survival [3–6].
T25 490-628 Sentence denotes In addition, CD6 mediates interaction between T cells and antigen-presenting cells, contributing to the maturation of immune synapses [6].
T26 629-836 Sentence denotes CD6-mediated costimulation contributes to the maturation of a Th1 pattern in human T cells and preferentially promotes a pro-inflammatory response characterized by the secretion of TNF-α, IL-6 and IFN γ [7].
T27 837-958 Sentence denotes The activated leukocyte-cell adhesion molecule (ALCAM), also known as CD166, has been identified as the CD6 ligand [8,9].
T28 959-1094 Sentence denotes ALCAM interaction with CD6 stabilizes the formation of the immune synapse between the lymphocytes and the antigen-presenting cells [5].
T29 1095-1270 Sentence denotes Itolizumab is a humanized monoclonal antibody developed at the Center of Molecular Immunology, in Cuba, that recognizes a region in the distal domain of the human CD6 [10,11].
T30 1271-1454 Sentence denotes The antibody reduces the expression of the intracellular proteins involved in activation and inhibits the proliferation of T cells, even in the presence of the ALCAM and IL-2 [10–12].
T31 1455-1586 Sentence denotes The effect is associated with the reduction of the secretion of pro-inflammatory cytokines including IFN-γ, IL-6 and TNF-α [13,14].
T32 1587-1698 Sentence denotes The antibody has demonstrated to be safe and efficacious in patients with moderate to severe psoriasis [15,16].
T33 1699-1890 Sentence denotes Studies from blood and tissue samples from patients with severe psoriasis showed that itolizumab reduces the proliferation of T cells and serum concentration of IL-6, TNF-α and IFN-γ [13–16].
T34 1891-1975 Sentence denotes A significant reduction of the inflammatory pattern was also observed in the tissue.
T35 1976-2225 Sentence denotes On account of its well proven effect on T-cell activation and proinflammatory cytokines production, itolizumab was included as part of a Cuban expanded access protocol in critical, severe and moderate COVID-19 patients with high risk of aggravation.
T36 2226-2373 Sentence denotes The study will be published soon (manuscript accepted) and here we describe in detail the outcome of three initial patients receiving the antibody.
T37 2375-2392 Sentence denotes Cases description
T38 2393-2403 Sentence denotes Patient 1:
T39 2404-2615 Sentence denotes A 53-year old woman with a personal history of essential hypertension and Type 2 diabetes mellitus presented with symptoms of polypnea of more than 40 rpm, use of respiratory ancillary musculature and dry cough.
T40 2616-2680 Sentence denotes She arrived from a foreign country where COVID-19 was spreading.
T41 2681-2812 Sentence denotes Symptoms started on 23 March and COVID-19 was diagnosed on 26 March on the basis of positive real time PCR (RT-PCR) for SARS-CoV-2.
T42 2813-2969 Sentence denotes Initial gasometry showed moderate hypoxemia and respiratory alkalosis with a partial pressure of oxygen/fraction of inspired oxygen (PO2/FiO2) ratio of 191.
T43 2970-3031 Sentence denotes Chest x-rays showed interstitial lesions in both lung fields.
T44 3032-3125 Sentence denotes She started therapy with lopinavir/ritonavir, chloroquine, recombinant IFN α-2b and rocephin.
T45 3126-3279 Sentence denotes In spite of treatment, the illness subsequently progressed to hypoxemic respiratory failure warranting the initiation of invasive mechanical ventilation.
T46 3280-3464 Sentence denotes At day 13 of her admission in the ICU, she showed radiologic worsening of the interstitial multifocal pneumonia, with elevation of ALP, LDH, erythrocyte sedimentation rate and D-dimer.
T47 3465-3520 Sentence denotes Physicians administered itolizumab at a dose of 200 mg.
T48 3521-3649 Sentence denotes After 48 h of the first itolizumab dose, PO2/FiO2 improved and there were evidences of radiological improvement (Figure 1A & B).
T49 3650-3756 Sentence denotes Patient was extubated after the first dose of the antibody and her status changed from critical to severe.
T50 3757-3840 Sentence denotes She received a second dose of the antibody (200 mg), 48 h after the first infusion.
T51 3841-3947 Sentence denotes 3 days after the first administration, patient was hemodynamically stable and has spontaneous ventilation.
T52 3948-4059 Sentence denotes IL-6 levels were evaluated before itolizumab administration and after 2 and 7 days of the first administration.
T53 4060-4149 Sentence denotes IL-6 levels reduced overtime from 172 pg/ml to 60 pg/ml (day 7) as depicted in Figure 2A.
T54 4150-4221 Sentence denotes IL-1 was evaluated at the same time intervals, but it was undetectable.
T55 4222-4391 Sentence denotes In addition, aspartate amino transferase (AST) concentrations were evaluated at different time points showing a reduction from 43 U/l to 24 U/l after 7 days (Figure 2B).
T56 4392-4448 Sentence denotes No adverse events related with itolizumab were reported.
T57 4449-4458 Sentence denotes Figure 1.
T58 4460-4520 Sentence denotes Radiological images before and after one dose of itolizumab.
T59 4521-4648 Sentence denotes Patient 1 (A) Before itolizumab (D0): diffuse Interstitial-alveolar infiltrate in both lung fields, predominantly in the bases.
T60 4649-4852 Sentence denotes Minor left pleural effusion. (B) After itolizumab (48 h): radiological improvement with decreased diffuse infiltrate and radio-opacity at the top of both lungs and in both lung bases, in less proportion.
T61 4853-4889 Sentence denotes The minor pleural effusion persists.
T62 4890-5162 Sentence denotes Patient 3 (C) Before itolizumab (D0): alveolar interstitial inflammatory infiltrate in both lung fields, predominantly on the right side. (D) After itolizumab (48 h): radiological improvement with significant decrease of the alveolar interstitial infiltrate of both lungs.
T63 5163-5172 Sentence denotes Figure 2.
T64 5174-5215 Sentence denotes Circulating biomarkers in patient's sera.
T65 5216-5324 Sentence denotes IL-6 and AST concentrations kinetics (A & B, respectively) measured in patients during itolizumab treatment.
T66 5325-5335 Sentence denotes Patient 2:
T67 5336-5475 Sentence denotes An 89-year old man with a personal history of chronic ischemic cardiopathy, permanent atrial fibrillation, hypertension and hypothyroidism.
T68 5476-5615 Sentence denotes He has a previous history of alcoholism and several hospital admissions in the last 3 months on account of infectious respiratory diseases.
T69 5616-5718 Sentence denotes He came to the hospital on 2 April after 7 days of shortness of breath, fever, asthenia and dry cough.
T70 5719-5817 Sentence denotes He was in contact with a person who returned from a foreign country, where COVID-19 was extending.
T71 5818-6041 Sentence denotes Physical examination shows signs of respiratory failure characterized by tachycardia, polypnea, intercostal and supraclavicular muscle retraction, high blood pressure, oxygen saturation of 82%, poor diuresis and drowsiness.
T72 6042-6140 Sentence denotes Chest x-rays showed bilateral pulmonary inflammatory infiltrates, predominantly in the right lung.
T73 6141-6293 Sentence denotes Admission ECG showed an atrial fibrillation with rapid ventricular response and the initial gasometry showed severe hypoxemia and respiratory alkalosis.
T74 6294-6441 Sentence denotes Patient also had leukocytosis, altered globular sedimentation rate as well as elevated values of AST, LDH, D-dimer and positive C-reactive protein.
T75 6442-6513 Sentence denotes He was admitted into the ICU requiring invasive mechanical ventilation.
T76 6514-6611 Sentence denotes Treatment with lopinavir–ritonavir, chloroquine, IFN α-2b, meropenem and linezolid was initiated.
T77 6612-6811 Sentence denotes 3 days after his admission into the ICU, itolizumab was prescribed, due to worsening of the bilateral pulmonary infiltrates together with a deterioration of the ventilatory function (PO2/FiO2 = 173).
T78 6812-6950 Sentence denotes After the first antibody infusion, PO2/FiO2 significantly increased (PO2/FiO2 = 320) and there were evidences of radiological improvement.
T79 6951-7121 Sentence denotes 3 days after, patient showed radiological worsening of the left lung, characterized by alveolar hypoventilation and atelectasis; then, a 70% pneumothorax was established.
T80 7122-7234 Sentence denotes Treatment of the pneumothorax with minimal pleurotomy was very demanding and required 3 days for the resolution.
T81 7235-7429 Sentence denotes The patient received a second infusion of the monoclonal antibody 72 h after the first, while a third dose was administered at the discretion of the treating physicians, 2 days after the second.
T82 7430-7526 Sentence denotes In total, patient received three doses of itolizumab (200 mg) without any related adverse event.
T83 7527-7641 Sentence denotes IL-6 levels were evaluated before itolizumab administration and after 2, 4 and 7 days of the first administration.
T84 7642-7798 Sentence denotes IL-6 was extremely high at baseline (623 pg/ml) and even though cytokine levels reduced roughly 50%, the lowest value remained above 300 pg/ml after 7 days.
T85 7799-7835 Sentence denotes IL-6 kinetics is shown in Figure 2A.
T86 7836-7909 Sentence denotes Apart from IL-6, IL-1 was undetectable at this time point of the disease.
T87 7910-8003 Sentence denotes Interesting, in the case of AST, a significant reduction is detecting at day 7 (pretreatment:
T88 8004-8016 Sentence denotes 156 U/l, D7:
T89 8017-8051 Sentence denotes 40 U/l) as is showed in Figure 2B.
T90 8052-8199 Sentence denotes After 10 days of admission into the ICU, patient presented a myocardial dysfunction and shock that required vasoactive support with norepinephrine.
T91 8200-8289 Sentence denotes On day 13, he finally died, on account of a mixed cardiovascular and respiratory failure.
T92 8290-8300 Sentence denotes Patient 3:
T93 8301-8409 Sentence denotes An 81-year old female, who is COVID-19 positive contact was not identified at the moment of hospitalization.
T94 8410-8568 Sentence denotes She started symptoms on 2 April and entered the ICU on 5 April. Patient has a previous history of hypertension, diabetes mellitus, glaucoma and smoking habit.
T95 8569-8629 Sentence denotes She was admitted with frequent cough, wheezing and diarrhea.
T96 8630-8710 Sentence denotes The diagnosis of viral pneumonia by COVID-19 was confirmed by RT-PCR on 7 April.
T97 8711-8829 Sentence denotes Oxygen support at 5 l/min and treatment with ceftriaxone, lopinavir–ritonavir, chloroquine and IFN α-2b was indicated.
T98 8830-8900 Sentence denotes Chest images showed bilateral interstitial infiltration in both lungs.
T99 8901-9006 Sentence denotes Patient condition was classified as severe, although she did not require invasive mechanical ventilation.
T100 9007-9088 Sentence denotes A dose of itolizumab (200 mg) was given the day after her admission into the ICU.
T101 9089-9335 Sentence denotes Two days after the antibody administration, together with the rest of the therapy, there was an improvement of the respiratory distress while the chest image showed a decrease of the alveolar interstitial infiltrate of both lungs (Figure 1C & D).
T102 9336-9411 Sentence denotes Patient left the ICU after a favorable clinical and radiological evolution.
T103 9412-9488 Sentence denotes IL-6 concentration was measured prior and after the antibody administration.
T104 9489-9664 Sentence denotes IL-6 level at baseline was lower than in previous cases (30 pg/ml), but also decreased 48 h and 168 h after itolizumab infusion, in parallel with patient recovery (Figure 2A).
T105 9665-9747 Sentence denotes IL-1 and TNF-α were untraceable before and 48 h after the antibody administration.
T106 9748-9856 Sentence denotes Regarding to AST concentration, the values were in the normal range during the treatment period (Figure 2B).
T107 9858-9877 Sentence denotes Materials & methods
T108 9878-10122 Sentence denotes Three patients with diagnosis of COVID-19 classified as critically ill (two) and severely ill (one) were included in an expanded access trial to receive itolizumab in addition to standard treatment (http://rpcec.sld.cu/trials/RPCEC00000311-En).
T109 10123-10257 Sentence denotes The study was approved by a central ethical review board, created especially for COVID-19 and by the Cuban Regulatory Agency (CECMED).
T110 10258-10332 Sentence denotes Before the treatment, informed consent was obtained from enrolled patient.
T111 10333-10442 Sentence denotes Laboratory results included blood routine, leucocyte subsets and blood biochemical parameters were collected.
T112 10443-10723 Sentence denotes The level of inflammatory cytokines was measured using human validated commercially available kit from R&D Systems (MN, USA): human IL-6 Quantikine ELISA Kit (Cat# S6050), human IL-1 beta/IL-1F2 Quantikine ELISA Kit (Cat# SLB50) and human TNF-α Quantikine ELISA Kit (Cat# STA00D).
T113 10724-10817 Sentence denotes In the case of IL-6, the normal range of this cytokine in sera is between 0 and 7 pg/ml [17].
T114 10818-10918 Sentence denotes We used intra-assay precision and inter-assay precision methods to evaluate precision in this study.
T115 10919-11068 Sentence denotes For intra-assay precision (precision within an assay), three samples of known concentration were tested on one plate to assess intra-assay precision.
T116 11069-11223 Sentence denotes For inter-assay precision (precision between assays), three samples of known concentration were tested in separate assays to assess inter-assay precision.
T117 11225-11235 Sentence denotes Discussion
T118 11236-11298 Sentence denotes CRS is characterized by high levels of inflammatory cytokines.
T119 11299-11381 Sentence denotes Among them, IL-6 is considered a major mediator of this hyperinflammation [18,19].
T120 11382-11490 Sentence denotes Most of the COVID-19 patients-related papers showed the CRS as one of the main hallmark of the disease [20].
T121 11491-11560 Sentence denotes Additionally, IL-6 levels predict severity in COVID-19 patients [21].
T122 11561-11663 Sentence denotes There is high heterogeneity of IL-6 values among papers for classifying severe and nonsevere patients.
T123 11664-11811 Sentence denotes In a large meta-analysis of 52 manuscripts, Elshazli and coworkers found that the IL-6 level associated with COVID-19 severity was 22.9 pg/ml [22].
T124 11812-11975 Sentence denotes In a series of patients treated with itolizumab a cutoff of 28 pg/ml discriminates severe patients from nonsevere (manuscript just accepted in Immunity and Aging).
T125 11976-12065 Sentence denotes In the present study, the IL-6 concentration of the three patients was above this cutoff.
T126 12066-12164 Sentence denotes It confirms the classification of these patients as severe and that the CRS is probably occurring.
T127 12165-12276 Sentence denotes Several anticytokine therapies have been tried for treating the hyperinflammatory phase of COVID-19 [20,23–25].
T128 12277-12404 Sentence denotes Here, we report the use of a well-known anti-inflammatory antibody targeting CD6 to treat the CRS arising in COVID-19 patients.
T129 12405-12636 Sentence denotes Using an anti-CD6 antibody could reduce the concentration of several pro-inflammatory cytokines, including IL-6, IFN-γ, TNF-α and IL-17, among others, representing an advantage as compared with single-cytokine targeting antibodies.
T130 12637-12762 Sentence denotes The antibody would not exacerbate lymphopenia since it does not induce complement or antibody dependent cytotoxicity [10,11].
T131 12763-12880 Sentence denotes These three SARS-CoV2 patients developed severe respiratory distress together with multifocal interstitial pneumonia.
T132 12881-12985 Sentence denotes Two patients required invasive mechanical ventilation while the third patient only needed oxygen supply.
T133 12986-13171 Sentence denotes They all received the anti-CD6 antibody itolizumab in combination with other drugs incorporated into the Cuban national protocol, including lopinavir/ritonavir, chloroquine and IFNα-2b.
T134 13172-13330 Sentence denotes Regarding to laboratory parameters, AST is strongly associated with mortality risk compared with other parameters, reflecting liver and kidney injury [26,27].
T135 13331-13499 Sentence denotes In our cases, critically ill patients showed a significant reduction of AST concentration after the treatment suggesting an improvement in the function of these organs.
T136 13500-13591 Sentence denotes Itolizumab was very safe and did not seem to exacerbate opportunistic secondary infections.
T137 13592-13717 Sentence denotes Unfortunately, we did no measure neither the frequency nor the total amount of circulating T cells in these initial patients.
T138 13718-13815 Sentence denotes The impact of itolizumab on circulating T cells are being implementing in new recruited patients.
T139 13816-13997 Sentence denotes Our preliminary findings support that IL-6 levels correlated with the severity of the disease and that the antibody was capable of reducing IL-6 concentration in all three subjects.
T140 13998-14077 Sentence denotes One patient died after subsequent respiratory and cardiovascular complications.
T141 14078-14182 Sentence denotes In this particular case, IL-6 concentration was extremely elevated at the moment of itolizumab infusion.
T142 14183-14300 Sentence denotes Although, the levels of IL-6 decreased during treatment, the values at 7 days kept still very high (above 300 pg/ml).
T143 14301-14381 Sentence denotes There was a transient improvement of respiratory function but it was not enough.
T144 14382-14595 Sentence denotes Presumably, the consequences of the hyperinflammatory syndrome (thrombosis, alveolar damage and severe tissue hypoxia) were irreversible at the moment of treatment and patient died as consequence of these factors.
T145 14597-14607 Sentence denotes Conclusion
T146 14608-14715 Sentence denotes In summary, in these severe and critically ill patients, itolizumab was able to reduce IL-6 concentrations.
T147 14716-14777 Sentence denotes Notably, itolizumab-related adverse events were not reported.
T148 14778-14879 Sentence denotes Patients with baseline IL-6 levels below 200 pg/ml, showed prompt clinical and radiological recovery.
T149 14880-15073 Sentence denotes We anticipate that the timely use of this anti-inflammatory antibody in combination with the appropriate antiviral and anticoagulant therapy could reduce the mortality associated with COVID-19.
T150 15074-15136 Sentence denotes The analysis of the complete-series will be published shortly.
T151 15137-15151 Sentence denotes Summary points
T152 15152-15264 Sentence denotes Inflammatory cytokine-release syndrome is associated with the progression of the coronavirus disease (COVID-19).
T153 15265-15348 Sentence denotes No current therapy has proven effective for the management of this syndrome so far.
T154 15349-15507 Sentence denotes Itolizumab is a humanized monoclonal antibody that recognizes human CD6 and its effect is associated with the reduction of pro-inflammatory cytokines release.
T155 15508-15630 Sentence denotes We present three COVID-19 cases who developed severe respiratory distress together with multifocal interstitial pneumonia.
T156 15631-15707 Sentence denotes The patients were treated with itolizumab combined with antiviral therapies.
T157 15708-15790 Sentence denotes Itolizumab reduced circulating IL-6 concentrations in the three COVID-19 patients.
T158 15791-15883 Sentence denotes Two patients showed rapid ventilatory and radiological improvement and were fully recovered.
T159 15884-15936 Sentence denotes Itolizumab-related adverse events were not reported.
T160 15937-16133 Sentence denotes These cases show that the timely use of this anti-inflammatory antibody in combination with the appropriate antiviral and anticoagulant therapy could reduce the mortality associated with COVID-19.