| 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. |
