Administration of tocilizumab to patients with high concentrations of IL-6 in the course of COVID-19 is associated with a better prognosis

SummaryBackgroundDespite the direct viral activity, the pathogenesis of coronavirus disease 2019 (COVID-19) includes an overproduction of cytokines including interleukin 6 (IL-6). Therefore tocilizumab (TCZ), a monoclonal antibody against IL-6 receptors, became considered as a possible therapeutic option.MethodsPatients were selected from the SARSTer national database, which included 2332 individuals with COVID-19 and the current study included 825 adult patients with moderate to severe course. The retrospective analysis was performed in 170 patients treated with TCZ and 655 without this medication or any other anti-cytokine therapy. The end-points of treatment effectiveness were a rate of death, need for mechanical ventilation, and clinical improvement.ResultsPatients treated with TCZ were balanced compared to non-TCZ regarding gender, age, BMI, and prevalence of coexisting conditions. The reduced death rate was demonstrated in patients treated with TCZ and baseline IL-6 >100 pg/ml (hazard ratio [HR]: 0.27, 95% confidence interval [CI]:0.10-0.78), or those needing oxygen supplementations who worsened within 7 days of hospitalization (HR: 0.38, 95% CI:0.16-0.88). The best effectiveness of TCZ was achieved in patients with a combination of baseline IL-6>100 pg/ml and either SpO2≤90% (HR for death, mechanical ventilation, and clinical improvement after 21 or 28 days: 0.07, 0.14, 5.53, 5.18 respectively) or requiring oxygen supplementation (HR for death and clinical improvement after 21 or 28 days, 0.18, 2.66, 2.85 respectively).ConclusionsTocilizumab administered for COVID-19 in patients with a baseline concentration of IL-6>100 pg/ml is associated with reduced mortality and faster clinical improvement, particularly if there is a need for oxygen supplementation due to SpO2≤90%.

Download Full-text

Tocilizumab Improves the Prognosis of COVID-19 in Patients with High IL-6

Journal of Clinical Medicine ◽

10.3390/jcm10081583 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1583

Author(s):

Robert Flisiak ◽

Jerzy Jaroszewicz ◽

Magdalena Rogalska ◽

Tadeusz Łapiński ◽

Aleksandra Berkan-Kawińska ◽

...

Keyword(s):

Monoclonal Antibody ◽

Mechanical Ventilation ◽

Confidence Interval ◽

Clinical Improvement ◽

Interleukin 6 ◽

Death Rate ◽

Treatment Effectiveness ◽

Therapeutic Option ◽

Oxygen Supplementation ◽

End Points

Despite direct viral effect, the pathogenesis of coronavirus disease 2019 (COVID-19) includes an overproduction of cytokines including interleukin 6 (IL-6). Therefore, tocilizumab (TOC), a monoclonal antibody against IL-6 receptors, was considered as a possible therapeutic option. Patients were selected from the SARSTer database, containing 2332 individuals with COVID-19. Current study included 825 adult patients with moderate to severe course. Analysis was performed in 170 patients treated with TOC and 655 with an alternative medication. The end-points of treatment effectiveness were death rate, need for mechanical ventilation, and clinical improvement. Patients treated with TOC were balanced compared to non-TOC regarding gender, age, BMI, and prevalence of coexisting conditions. Significant effect of TOC on death was demonstrated in patients with baseline IL-6 > 100 pg/mL (hazard ratio [HR]: 0.21, 95% confidence interval [CI]: 0.08–0.57). The best effectiveness of TOC was achieved in patients with a combination of baseline IL-6 > 100 pg/mL and either SpO2 ≤ 90% (HR: 0.07) or requiring oxygen supplementation (HR: 0.18). Tocilizumab administration in COVID-19 reduces mortality and speeds up clinical improvement in patients with a baseline concentration of IL-6 > 100 pg/mL, particularly if they need oxygen supplementation owing to the lower value of SpO2 ≤ 90%.

Download Full-text

0907 Implementation Of Pathway For Severe Obstructive Sleep Apnea Management In Children

SLEEP ◽

10.1093/sleep/zsaa056.903 ◽

2020 ◽

Vol 43 (Supplement_1) ◽

pp. A345-A345

Author(s):

S Gehring ◽

L Auricchio ◽

S Kidwell ◽

K Oppy ◽

S Smallwood ◽

...

Keyword(s):

Obstructive Sleep Apnea ◽

Sleep Apnea ◽

Health Care Providers ◽

Therapeutic Option ◽

Sleep Medicine ◽

Close Monitoring ◽

Severe Obstructive Sleep Apnea ◽

Care Providers ◽

Oxygen Supplementation ◽

Obstructive Sleep

Abstract Introduction Obstructive Sleep Apnea (OSA) is associated with neuro-cognitive, cardiovascular and metabolic morbidity in children. Adeno-tonsillectomy is the first line of treatment for OSA with PAP therapy and Oxygen supplementation being alternative therapeutic options in select cases. Severe Obstructive Sleep Apnea is a known risk factor for postoperative respiratory complications after adenotonsillectomy. Therefore, inpatient adenotonsillectomy with close monitoring is recommended for this group of children. Challenges to safe and timely care for this high risk group of children can be overcome with effective coordination of care between different locations and health care providers. Methods All children seeking treatment at Dayton Children’s Division of Sleep Medicine were managed through a pathway developed by a multi-disciplinary team involving sleep medicine, otolaryngology and clinical logistics. Severe OSA was defined as AHI ≥15 events/hr (children <2 year old), AHI ≥15 events/hr with three or more Oxygen desaturations <80% (children ≥2 to <6 years old), AHI ≥ 30 events/hr with three or more Oxygen desaturations <80% (Children ≥6 to 18 years old). Results A total of 78 children were diagnosed with severe OSA in 2019. All children were successfully triaged to appropriate therapeutic option (Adenonotonsillectomy, PAP, O2) within 24 hours of diagnosis. Urgent adenotonsillectomy was performed on the same day in 4 children and within 2 weeks on 12 children. There was no postoperative respiratory complication after urgent adenotonsillectomy. Thirteen children had adenotonsillectomy after 2 weeks. PAP therapy was started in 28 children (34%). Therapy was initiated on the same day in 10 children and the next day on one child. Oxygen supplementation was started in 21 children (27%). Conclusion A multidisciplinary collaborative approach can result in delivery of timely and safe care for severe OSA in children. Support NA

Download Full-text

Immunomodulating functions of recombinant ovine interferon tau: potential for therapy in mulitple sclerosis and autoimmune disorders

Multiple Sclerosis Journal ◽

10.1177/135245859800400204 ◽

1998 ◽

Vol 4 (2) ◽

pp. 63-69 ◽

Cited By ~ 10

Author(s):

O A Khan ◽

H Jiang ◽

P S Subramaniam ◽

H M Johnson ◽

S S Dhib-Jalbut

Keyword(s):

Therapeutic Option ◽

High Dose ◽

Interferon Tau ◽

Unique Type ◽

Immune Mediated ◽

High Concentrations ◽

Ifn Treatment ◽

High Doses ◽

Mulitple Sclerosis

The interferons (IFN) are a family of complex proteins possessing antiviral, antiproliferative, and immunomodulatory activities. Two type 1 recombinant human IFN have been recently approved for the treatment of multiple sclerosis (MS). However, use of high dose type 1 IFN treatment in MS patients has been limited by dose-related toxicity. Ovine IFNt is a unique type 1 interferon discovered for its role in the animal reproductive cycle. It differs from other type 1 IFNs in that it is remarkably less toxic even at high concentrations, is able to cross species barriers, and is not inducible by viral infection. Ovine IFNt has been shown to be very effective in the treatment of animal models of MS. In this study, we examined the toxicity of OvIFNt on human T-cells at high doses and its immunregulatory properties at equivalent doses. Our experiments confirmed the remarkably non-toxic nature of OvIFNt on human cells at high concentrations as well as immunomodulating properties consistent with other type 1 IFNs including an antilymphoproliferative effect and inhibition of IFNg-induced HLA class II expression. These results suggest that OvIFNt could be developed into a potentially less toxic therapeutic option for immune-mediated disorders including MS.

Download Full-text

The membrane skeleton of acetylcholine receptor domains in rat myotubes contains antiparallel homodimers of beta-spectrin in filaments quantitatively resembling those of erythrocytes

Journal of Cell Science ◽

10.1242/jcs.108.9.3145 ◽

1995 ◽

Vol 108 (9) ◽

pp. 3145-3154 ◽

Cited By ~ 2

Author(s):

D.W. Pumplin

Keyword(s):

Monoclonal Antibody ◽

Acetylcholine Receptor ◽

Acetylcholine Receptors ◽

Cytoplasmic Membrane ◽

Membrane Surface ◽

Membrane Skeleton ◽

Immunogold Labeling ◽

Platinum Coating ◽

High Concentrations ◽

Receptor Clusters

I used immunogold labeling and quick-freeze, deep-etch, rotary replication to characterize the membrane skeleton at regions with high concentrations of acetylcholine receptor domains in receptor clusters of cultured rat muscle cells. This membrane skeleton consists of a network of filaments closely applied to the cytoplasmic membrane surface. The filaments are specifically decorated by immunogold labeling with a monoclonal antibody, VIIF7, that recognizes an isoform of beta-spectrin colocalizing with acetylcholine receptors. The filaments are 32 +/- 11 nm in length and three to four filaments (average 3.1-3.3) join at each intersection to form the network. These parameters are nearly identical to those reported previously for the membrane skeleton of erythrocytes. Depending on the amount of platinum coating, filament diameters range from 9 to 11 nm in diameter, and are 1.4 nm larger on average than spectrin filaments of erythrocytes replicated at the same time. Filaments are decorated with gold particles close to one end, consistent with the location of the epitope recognized by the monoclonal antibody. Computer modeling shows that all filament intersections in the membrane skeletal network are equally capable of being labeled by the monoclonal antibody. This pattern of labeling is consistent with a network containing antiparallel homodimers of beta-spectrin.

Download Full-text

Intravenous Immunoglobulin as a Therapeutic Option for Mycoplasma pneumoniae Encephalitis

Journal of Child Neurology ◽

10.1177/0883073819854854 ◽

2019 ◽

Vol 34 (11) ◽

pp. 687-691

Author(s):

Mebratu Daba ◽

Peter B. Kang ◽

John Sladky ◽

Sharatchandra S. Bidari ◽

Robert M. Lawrence ◽

...

Keyword(s):

Intravenous Immunoglobulin ◽

Clinical Improvement ◽

Treatment Regimen ◽

Mycoplasma Pneumoniae ◽

Therapeutic Option ◽

Brain Magnetic Resonance Imaging ◽

Therapeutic Interventions ◽

Mri Findings ◽

Prodromal Symptoms ◽

Neurologic Symptoms

Objective: To analyze the outcomes of a cohort of children diagnosed with Mycoplasma pneumoniae encephalitis whose treatment regimens included intravenous immunoglobulin (IVIG). Methods: A retrospective study was performed at a single center between 2011 and 2016 of children diagnosed with Mycoplasma pneumoniae encephalitis whose acute treatment regimen included IVIG. Details of therapeutic interventions and the clinical course were retrieved from medical records via an institutionally approved protocol. The modified Rankin score was used to quantify outcomes. Results: Four children met inclusion criteria, 3 of whom had prodromal symptoms of infection lasting 5 to 7 days before onset of their neurologic symptoms. One patient presented with neurologic symptoms with no clinical prodrome. The initial treatment regimen included systemic corticosteroids, antibiotics, or both. IVIG was administered for a total dose of 2 g/kg divided over 2 to 4 days to all 4 children. All children showed clinical improvement after IVIG. The 3 children with prodromal symptoms showed immediate and dramatic clinical improvement after IVIG therapy. Discussion: The immediate response to immunomodulatory therapy in the patients with prodrome suggests that the neurologic syndrome may be caused at least in part by an autoimmune process. The child who did not respond to IVIG had no prodrome, and also had normal electroencephalographic (EEG) and brain magnetic resonance imaging (MRI) findings. These cases suggest that early administration of IVIG should be considered in patients suspected of having Mycoplasma encephalitis, particularly in those who have had prodromal symptoms.

Download Full-text

Thrombospondin stimulates motility of human neutrophils.

The Journal of Cell Biology ◽

10.1083/jcb.111.6.3077 ◽

1990 ◽

Vol 111 (6) ◽

pp. 3077-3086 ◽

Cited By ~ 51

Author(s):

P J Mansfield ◽

L A Boxer ◽

S J Suchard

Keyword(s):

Monoclonal Antibody ◽

Cell Types ◽

Human Neutrophils ◽

Heparin Binding ◽

Directed Movement ◽

Surface Receptors ◽

Chemotactic Peptides ◽

Heparin Binding Domain ◽

High Concentrations ◽

Priming Activity

Polymorphonuclear leukocytes (PMNs) migrate to sites of inflammation or injury in response to chemoattractants released at those sites. The presence of extracellular matrix (ECM) proteins at these sites may influence PMN accumulation at blood vessel walls and enhance their ability to move through tissue. Thrombospondin (TSP), a 450-kD ECM protein whose major proteolytic fragments are a COOH-terminal 140-kD fragment and an NH2-terminal heparin-binding domain (HBD), is secreted by platelets, endothelial cells, and smooth muscle cells. TSP binds specifically to PMN surface receptors and has been shown, in other cell types, to promote directed movement. TSP in solution at low concentrations (30-50 nM) "primed" PMNs for f-Met-Leu-Phe (fMLP)-mediated chemotaxis, increasing the response two- to fourfold. A monoclonal antibody against the HBD of TSP totally abolished this priming effect suggesting that the priming activity resides in the HBD of TSP. Purified HBD retains the priming activity of TSP thereby corroborating the antibody data. TSP alone, in solution at high concentrations (0.5-3.0 microM), stimulated chemotaxis of PMNs and required both the HBD and the 140-kD fragment of TSP. In contrast to TSP in solution, TSP bound to nitrocellulose filters in the range of 20-70 pmol stimulated random locomotion of PMNs. The number of PMNs migrating in response to bound TSP was approximately two orders of magnitude greater than the number of cells that exhibited chemotaxis in response to soluble TSP or fMLP. Monoclonal antibody C6.7, which recognizes an epitope near the carboxyl terminus of TSP, blocked migration stimulated by bound TSP, suggesting that the activity resides in this domain. Using proteolytic fragments, we demonstrated that bound 140-kD fragment, but not HBD, promoted migration of PMNs. Therefore, TSP released at injury sites, alone or in synergy with chemotactic peptides like fMLP, could play a role in directing PMN movement.

Download Full-text

Plant-Produced Anti-Enterovirus 71 (EV71) Monoclonal Antibody Efficiently Protects Mice Against EV71 Infection

Plants ◽

10.3390/plants8120560 ◽

2019 ◽

Vol 8 (12) ◽

pp. 560 ◽

Cited By ~ 5

Author(s):

Kaewta Rattanapisit ◽

Zhang Chao ◽

Konlavat Siriwattananon ◽

Zhong Huang ◽

Waranyoo Phoolcharoen

Keyword(s):

Monoclonal Antibody ◽

Therapeutic Option ◽

Enterovirus 71 ◽

Cost Effective ◽

Ev71 Infection ◽

Asia Pacific ◽

Variable Regions ◽

Hand Foot Mouth Disease ◽

Protection Against Infection

Enterovirus 71 (EV71) is the main causative agent of severe hand-foot-mouth disease. EV71 affects countries mainly in the Asia-Pacific region, which makes it unattractive for pharmaceutical companies to develop drugs or vaccine to combat EV71 infection. However, development of these drugs and vaccines is vital to protect younger generations. This study aims to develop a specific monoclonal antibody (mAb) to EV71 using a plant platform, which is a cost-effective and scalable production technology. A previous report showed that D5, a murine anti-EV71 mAb, binds to VP1 protein of EV71, potently neutralizes EV71 in vitro, and effectively protects mice against EV71 infection. Herein, plant-produced chimeric D5 (cD5) mAb, variable regions of murine D5 antibody linked with constant regions of human IgG1, was transiently expressed in Nicotiana benthamiana using geminiviral vectors. The antibody was expressed at high levels within six days of infiltration. Plant-produced cD5 retained its in vitro high-affinity binding and neutralizing activity against EV71. Furthermore, a single dose (10 µg/g body weight) of plant-produced cD5 mAb offered 100% protection against infection in mice after a lethal EV71 challenge. Therefore, our results showed that plant-produced anti-EV71 mAb is an effective, safe, and affordable therapeutic option against EV71 infection.

Download Full-text

The Epidemiology and Clinical Associations of Stroke in Patients with Acute Myeloid Leukemia: A Review of 10,972 Admissions from the 2012 National Inpatient Sample

Blood ◽

10.1182/blood.v126.23.1314.1314 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1314-1314

Author(s):

Taeha Kim ◽

Joseph Shatzel ◽

Harley Friedman ◽

Frederick Lansigan

Keyword(s):

Mechanical Ventilation ◽

Renal Failure ◽

Acute Renal Failure ◽

Length Of Stay ◽

Myeloid Leukemia ◽

Hospitalized Patients ◽

National Database ◽

National Inpatient Sample ◽

Inpatient Mortality ◽

Clinical Associations

Abstract Background: Patients withacute myeloid leukemia (AML) are at increased risk for both hemorrhage and thrombosis, including in the central nervous system. There is limited data on the incidence, clinical association and mortality associated with cerebrovascular accident (CVA) in hospitalized patients with active AML. The aim of this study is to evaluate the epidemiology and mortality of hospitalized patients with AML who suffered concurrent stroke from a large national database. Methods: Using the 2012 National Inpatient Sample (NIS), admissions with an International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) codes for AML without remission and AML in relapse (205.00 and 205.02, respectively) were extracted, and correlated with age, gender, length of stay and mortality. All CVA (ICD-9-CM 434.91) data were extracted as well for comparison of mortality, length of stay (LOS). Results: Of the 7,296,968 unweighted admissions in the 2012 NIS, 9384 involved AML patients who had not yet achieved remission, and 1600 involved relapsed AML (Prevalence of 0.12% and 0.021% respectively). Of the combined group of admitted patients with active AML (N=10,984), 65 patients (0.59%) had a concomitant CVA (either hemorrhagic or ischemic, of whom 56 (0.51%) had active disease and 9 (0.08%) had relapsed disease). Compared to all other active AML patients, those who developed stroke were older (Mean age 66 y/o vs 58 y/o P=0.003), had longer LOS (20 days vs 12 days P= 0.53), were predominantly female (55% vs 45%; p=0.078) and had significantly higher inpatient mortality rates (36.9% vs 10.5%; OR 3.5; 95%CI 2.2, 5.5; P<0.0001). AML patients with CVA had significantly higher inpatient mortality then all admitted patients with stroke (36.9% vs 6.7%; OR 5.5; 95%CI 3.5, 8.8; P<0.0001). Multivariate logistic regression attempting to find significant clinical associations in AML patients who develop stroke, after controlling for confounding variables, found that acute renal failure with tubular necrosis(OR 4.47; 95%CI 1.8, 11.2; P=0.0013), hypernatremia (OR 3.85; 95%CI 1.6, 9.1; P=0.002), urinary tract infection (OR 3.28; CI95% 1.8, 6.1; P=0.0002) and secondary thrombocytopenia (OR 2.92; 95%CI 1.5, 5.7; P=0.0018) were all significantly predictive, as were mechanical ventilation >96 hours (OR 4.92; CI95% 1.02, 23.6; P=0.047) and continuous positive airway pressure ventilation (OR 3.03; CI95% 1.11, 8.26; P=0.031). Disseminated intravascular coagulation (DIC) and leukocytosis were more prevalent in AML patients with CVA compare to all AML patients, but the difference did not reach statistical significance. Conclusions: CVA in patients with active AML was strongly associated with older age and higher mortality, and appeared to be a relatively rare event, occurring in only 0.59% of patients. There was no statistically significant difference in LOS or gender distribution between those who developed CVA and those who did not amont active AML patients. As compared to all CVA patients, active AML patients with CVA had 5-fold higher risk of mortality. Significant acute renal failure, hypernatremia and thrombocytopenia appear to portend a higher risk of stroke in patients with active AML. It is unclear if UTI, and the need for mechanical ventilation is a predictor of stroke, as much as they may be a ramification of it. While more common in AML patients with CVA vs AML patients without CVA, we did not find DIC or hyperleukocytosis to be significantly predictive. Disclosures No relevant conflicts of interest to declare.

Download Full-text