Response to Tocilizumab in Severe COVID-19

Background: Since the COVID-19 pandemic began in December 2019 no specific therapy for managing severe complications of infection has emerged, although this is under intensive investigation. Progressive pneumonia and multi-organ complications are managed with supportive care and COVID-19 has a mortality of >50% when ventilatory support is needed.Methods: We implemented a compassionate use protocol for tocilizumab, a humanised monoclonal anti-Il-6 receptor antibody. Patients with severe COVID-19 requiring oxygen or ventilation, and complicated by hyperinflammation and the cytokine release syndrome (CRS) received tocilizumab (8 mg/kg up to a maximum of 800 mg, with the option of a second dose given after 12-24 hours). CRS was defined as having at least three of: D-dimer above the upper limit of normal (ULN), rising C-reactive protein (CRP), ferritin >1000 ng/mL and lactate dehydrogenase (LDH) greater than the ULN.Oral consent for prescription of an off-label medicine was obtained from patients, their next of kin or representative, whenever possible. The treatment protocol adhered to the Monitored Emergency Use of Unregistered and Investigational Interventions of the WHO.Findings: Of seventeen patients with severe COVID-19 seen between 3-12th April 2020, eleven patients (seven ventilated and four receiving high flow oxygen) were treated with tocilizumab. Treatment normalised temperatures within 48 hours and was associated with a significant fall in CRP from 311 (138-332) (median, IQR mg/L) to 110 (58-184) (p = 0·001). For the group, oxygen requirements fell by 60±32% (95% CI 38-81) over 1 week (p<0·001). Two of seven patients on intensive care died, five have been extubated and two discharged. All four ward patients have also been discharged.Interpretation: Following tocilizumab treatment, we observed improvement in clinical and laboratory abnormalities in this small series. Compassionate use of tocilizumab can provide valuable information to support clinical trials in patients with severe COVID-19.

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Improved Recovery and Survival with Trimethoprim or Cotrimoxazole in Patients with Severe COVID-19: A Retrospective Analysis

10.47363/jvrr/2020(1)118 ◽

2020 ◽

pp. 1-6

Author(s):

Veronica A.Varney ◽

◽

Thomas John ◽

Thomas Samuel ◽

◽

...

Keyword(s):

Ventilatory Support ◽

Hospital Length ◽

Hospital Length Of Stay ◽

Protein Levels ◽

Reactive Protein ◽

Life Threatening Illness ◽

Formyl Peptide ◽

Life Threatening ◽

Immunological Effects ◽

Oxygen Requirements

Background: COVID-19 may become a life-threatening illness as a result of acute respiratory distress syndrome with the mainstay of management supportive, although dexamethasone and serum from recovered patients look helpful in reducing mortality in oxygen dependant patients. Methods: We retrospectively analysed data from 22 patients with severe COVID-19 treated with trimethoprim (TMP) or cotrimoxazole (CTX) added to standard therapy antibiotics (ST) and compared this with anonymized data from 22 patients with COVID-19 of similar severity receiving ST alone. Results: Patients receiving additional TMP or CTX showed clinical improvement within 48 hours with reduced fever (p= 0.001), C-reactive protein levels (p=0.002) and oxygen requirements (SpO2/FiO2, p<0.001). Mortality was reduced (to 5% versus 32% for ST, p=0.022) and the need for ventilatory support (3 versus 16 patients on ST, p<0.001) and hospital length of stay (mean: 9 days versus 22 days on ST p<0.001). Discussion: This benefit may be due to combined antimicrobial and immunological effects of TMP and CTX. Both drugs block stimulation of the formyl peptide receptors (FPR’s) on the surface of circulating neutrophils and monocytes. When stimulated, FPR’s cause homing of neutrophils to the lung and trigger the release of Reactive Oxygen Series driving cytokine production and therefore a possible cytokine storm. Stressed neutrophils can extrude their nuclear content as ‘external nets’ (NETosis) to trap infectious agents, these nets can block the pulmonary alveolar bed giving severe hypoxia and death as seen in post mortems from COVID-19 patients. Blocking of neutrophil FPR’s by these drugs may be the mechanism by which they protect the lung in COVID-19.

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Compassionate Use of Tocilizumab for Treatment of SARS-CoV-2 Pneumonia

Clinical Infectious Diseases ◽

10.1093/cid/ciaa812 ◽

2020 ◽

Cited By ~ 15

Author(s):

Stanley C Jordan ◽

Phillip Zakowski ◽

Hai P Tran ◽

Ethan A Smith ◽

Cyril Gaultier ◽

...

Keyword(s):

Adverse Events ◽

Morbidity And Mortality ◽

Cytokine Storm ◽

Compassionate Use ◽

Serious Adverse Events ◽

T Cell Therapy ◽

Reactive Protein ◽

Single Center Study ◽

Oxygen Requirements

Abstract Background Preliminary data from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia patients indicate that a cytokine storm may increase morbidity and mortality. Tocilizumab (anti-IL-6R) is approved by the Food and Drug Administration for treatment of cytokine storm associated with chimeric antigen receptor T-cell therapy. Here we examined compassionate use of tocilizumab in patients with SARS-CoV-2 pneumonia. Methods We report on a single-center study of tocilizumab in hospitalized patients with SARS-CoV-2 pneumonia. All patients had confirmed SARS-CoV-2 pneumonia and oxygen saturations <90% on oxygen support with most intubated. We examined clinical and laboratory parameters including oxygen and vasopressor requirements, cytokine profiles, and C-reactive protein (CRP) levels pre- and post-tocilizumab treatment. Results Twenty-seven SARS-CoV-2 pneumonia patients received one 400 mg dose of tocilizumab. Interleukin (IL)-6 was the predominant cytokine detected at tocilizumab treatment. Significant reductions in temperature and CRP were seen post-tocilizumab. However, 4 patients did not show rapid CRP declines, of whom 3 had poorer outcomes. Oxygen and vasopressor requirements diminished over the first week post-tocilizumab. Twenty-two patients required mechanical ventilation; at last follow-up, 16 were extubated. Adverse events and serious adverse events were minimal, but 2 deaths (7.4%) occurred that were felt unrelated to tocilizumab. Conclusions Compared to published reports on the morbidity and mortality associated with SARS-CoV-2, tocilizumab appears to offer benefits in reducing inflammation, oxygen requirements, vasopressor support, and mortality. The rationale for tocilizumab treatment is supported by detection of IL-6 in pathogenic levels in all patients. Additional doses of tocilizumab may be needed for those showing slow declines in CRP. Proof of efficacy awaits randomized, placebo-controlled clinical trials.

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A retrospective study evaluating efficacy and safety of compassionate use of tocilizumab in 13 patients with severe-to-critically ill COVID-19: analysis of well-responding cases and rapidly-worsening cases after tocilizumab administration

10.1101/2020.06.24.20134288 ◽

2020 ◽

Author(s):

Shoji Hashimoto ◽

Heita Kitajima ◽

Tsuyoshi Arai ◽

Yoshitaka Tamura ◽

Takayuki Nagai ◽

...

Keyword(s):

Critically Ill ◽

Critically Ill Patients ◽

Oxygen Supply ◽

Ventilatory Support ◽

Compassionate Use ◽

C Reactive Protein ◽

Beneficial Effects ◽

Reactive Protein ◽

Methylprednisolone Treatment ◽

Treatment Administration

AbstractWe administered tocilizumab into 13 severe-to-critically ill patients with coronavirus disease 2019 (COVID-19) for compassionate use in combination with potential anti-viral agents in those who required an oxygen supply and showed increased laboratory inflammatory markers such as C-reactive protein (CRP) and ferritin. One injection of tocilizumab led to rapid improvements in clinical features, inflammatory findings, and oxygen supply in seven patients with severe COVID-19 and substantial amelioration in two patients who were critically ill, whereas four patients, who exhibited rapidly worsened respiratory function, required artificial ventilatory support even after tocilizumab treatment. Three of these four patients ultimately recovered from deterioration after methylprednisolone treatment. Administration of tocilizumab did not affect viral elimination nor IgG production specific for the virus. Compared with well-responding patients, rapidly-worsened patients showed a significantly higher ratio of ferritin vs. CRP. These findings suggest that tocilizumab has beneficial effects in severe-to-critically ill patients with COVID-19; however, in some cases, addition of methylprednisolone is required for disease rescue.

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549. Clinical Characteristics and Outcomes of Patients with COVID-19 treated with Convalescent Plasma in Miami, Florida

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa439.743 ◽

2020 ◽

Vol 7 (Supplement_1) ◽

pp. S340-S341

Author(s):

Shweta Anjan ◽

Dimitra Skiada ◽

Miriam Andrea Duque Cuartas ◽

Douglas Salguero ◽

David P Serota ◽

...

Keyword(s):

Treatment Options ◽

Disease Outbreaks ◽

Nasopharyngeal Swab ◽

Rt Pcr ◽

Health Crisis ◽

Infectious Disease Outbreaks ◽

Reactive Protein ◽

High Acuity ◽

Us Fda ◽

Oxygen Requirements

Abstract Background The Coronavirus disease of 2019 (COVID-19) global health crisis caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in unprecedented mortality, impacted society, and strained healthcare systems, yet sufficient data regarding treatment options are lacking. Convalescent plasma, used since 1895 for infectious disease outbreaks, offers promise as a treatment option for COVID-19. Methods This is a retrospective study of patients diagnosed by a nasopharyngeal swab SARS-CoV-2 reverse transcriptase–polymerase chain reaction (RT-PCR), who received convalescent plasma between April to June 2020 at two large hospitals in Miami, Florida, as part of the US FDA Expanded Access Program for COVID-19 convalescent plasma (CCP). Results A total of 23 patients received CCP, 13 (57%) had severe COVID-19 disease, while 8 (35%) had critical or critical with multiorgan dysfunction. Median time of follow up was 26 (range, 7–79) days. Overall, 11 (48%) survived to discharge, 6 (26%) died, while 6 (26%) are currently hospitalized. All deaths reported were due to septic shock from secondary infections. 15 (65%) showed improvement in oxygen requirements 7 days post CCP transfusion. Measured inflammatory markers, c-reactive protein, lactate dehydrogenase, ferritin and d-dimer improved 7 days post transfusion in 13 (57%) patients. No adverse events due to the transfusion were reported. 10 (43.4%) patients had a negative SARS-CoV-2 RT-PCR at a median of 14.5 (range, 4–31) days after receiving convalescent plasma. Conclusion Administration of convalescent plasma was found to be safe, with favorable outcomes in this small cohort of relatively high acuity patients. Larger studies including control arms are needed to establish the efficacy of convalescent plasma on clinical and virologic outcomes for patients with COVID-19. Table Disclosures All Authors: No reported disclosures

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Safety of intravenous anakinra in COVID-19 with evidence of hyperinflammation, a case series

Rheumatology Advances in Practice ◽

10.1093/rap/rkaa040 ◽

2020 ◽

Vol 4 (2) ◽

Cited By ~ 1

Author(s):

Kristina E N Clark ◽

Oliver Collas ◽

Helen Lachmann ◽

Animesh Singh ◽

Jim Buckley ◽

...

Keyword(s):

Bacterial Infections ◽

Severe Disease ◽

Ventilatory Support ◽

Case Series ◽

Rapid Improvement ◽

Intensive Care Admission ◽

Beneficial Effects ◽

Life Threatening ◽

Oxygen Requirements ◽

Subsequent Improvement

Abstract Objectives Anakinra is a selective IL-1 inhibitor, which has been used in the context of secondary haemophagocytic lymphohistiocytosis. Although usually given in the s.c. form, previous anecdotal reports have emphasized its utility when given i.v. Our aim is to report our experience on the beneficial effects of anakinra i.v. in patients with SARS-CoV-2 and evidence of hyperinflammation. Methods We report four patients with severe COVID-19 infection requiring intensive care admission and ventilatory support. Results All four patients showed evidence of deterioration, with hyperferritinaemia and increasing oxygen requirements and with superadded bacterial infections. Upon commencement of anakinra i.v., there was subsequent improvement in the patients clinically, with reduction in ventilatory support and inotropic support, and biochemically, with rapid improvement in inflammatory markers. Conclusion Anakinra is safe to use i.v. in patients with COVID-19 and evidence of superadded bacterial infection. Although its utility has not been confirmed in a randomized trial, current research in the COVID-19 pandemic aims to establish the utility of immunosuppression, including IL-1 blockade, on the outcomes of patients with moderate to severe disease. Our case series supports its use in patients with severe, life-threatening COVID-19 and evidence of hyperinflammation.

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Practice Variation in Spontaneous Breathing Trial Performance and Reporting

Canadian Respiratory Journal ◽

10.1155/2016/9848942 ◽

2016 ◽

Vol 2016 ◽

pp. 1-10 ◽

Cited By ~ 8

Author(s):

Stephanie Godard ◽

Christophe Herry ◽

Paul Westergaard ◽

Nathan Scales ◽

Samuel M. Brown ◽

...

Keyword(s):

Spontaneous Breathing ◽

Spontaneous Breathing Trial ◽

Ventilatory Support ◽

Standard Of Care ◽

Practice Variation ◽

Ventilator Support ◽

Physiological Variables ◽

Physiologic Parameters ◽

Spontaneous Breathing Trials ◽

Oxygen Requirements

Background. Spontaneous breathing trials (SBTs) are standard of care in assessing extubation readiness; however, there are no universally accepted guidelines regarding their precise performance and reporting.Objective. To investigate variability in SBT practice across centres.Methods. Data from 680 patients undergoing 931 SBTs from eight North American centres from the Weaning and Variability Evaluation (WAVE) observational study were examined. SBT performance was analyzed with respect to ventilatory support, oxygen requirements, and sedation level using the Richmond Agitation Scale Score (RASS). The incidence of use of clinical extubation criteria and changes in physiologic parameters during an SBT were assessed.Results. The majority (80% and 78%) of SBTs used 5 cmH2O of ventilator support, although there was variability. A significant range in oxygenation was observed. RASS scores were variable, with RASS 0 ranging from 29% to 86% and 22% of SBTs performed in sedated patients (RASS < −2). Clinical extubation criteria were heterogeneous among centres. On average, there was no change in physiological variables during SBTs.Conclusion. The present study highlights variation in SBT performance and documentation across and within sites. With their impact on the accuracy of outcome prediction, these results support efforts to further clarify and standardize optimal SBT technique.

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Hemoadsorption for management of Patients on Veno-venous ECMO Support for Severe COVID-19 Acute Respiratory Distress Syndrome

10.22541/au.161888021.17404769/v1 ◽

2021 ◽

Author(s):

Travis Geraci ◽

Zachary Kon ◽

Nader Moazami ◽

Stephanie Chang ◽

Julius Carillo ◽

...

Keyword(s):

Clinical Effect ◽

Hospital Length ◽

Hospital Length Of Stay ◽

C Reactive Protein ◽

Ecmo Circuit ◽

Reactive Protein ◽

Small Series ◽

Cytokine Levels ◽

Median Hospital ◽

Vv Ecmo

Background and aim of the study: Patients with severe coronavirus disease 2019 (COVID-19) develop a profound cytokine-mediated pro-inflammatory response. This study reports outcomes in 10 patients with COVID-19 supported on veno-venous extracorporeal membrane oxygenation (VV-ECMO) who were selected for the emergency use of a hemoadsorption column integrated in the ECMO circuit. Materials and Methods: Pre and post treatment, clinical data and inflammatory markers were assessed to determine the safety and feasibility of using this system, and to evaluate the clinical effect. Results: During hemoadsorption, median levels of interleukin (IL)-2R, IL-6, and IL-10 decreased by 54%, 86%, and 64% respectively. Reductions in other markers were observed for LDH (-49%), ferritin (-46%), D-dimer (-7%), C-reactive protein (-55%), procalcitonin (-76%) and lactate (-44%). Vasoactive-inotrope scores decreased significantly over the treatment interval (-80%). The median hospital length of stay was 53 days (36-85) and at 90-days post cannulation, survival was 90% which was similar to a group of patients without the use of hemoadsorption. Conclusions: Addition of hemoadsorption to VV-ECMO in patients with severe COVID-19 is feasible and reduces measured cytokine levels. However, in this small series, the precise impact on the overall clinical course and survival benefit still remains unknown.

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Combating a Case of COVID Pneumonia with ARDS – a Physiotherapist’s Standpoint

Journal of Pharmaceutical Research International ◽

10.9734/jpri/2021/v33i57b34074 ◽

2021 ◽

pp. 412-417

Author(s):

Chaithanya Ratheesh ◽

Aishwarya Nair

Keyword(s):

Case Report ◽

Ventilatory Support ◽

Treatment Protocol ◽

Respiratory Illness ◽

Supplemental Oxygen ◽

Multiple Organ ◽

Vital Role ◽

Correct Identification ◽

Physiotherapy Treatment ◽

Organ Systems

Introduction: Coronavirus disease (COVID-19) is an infectious disease caused by the SARS-CoV-2 virus, affecting multiple organ systems. The disease usually presents as mild to moderate respiratory illness but in many cases has progressed to development of pneumonia and ARDS ultimately requiring ventilatory support and prolonged ICU stay. Prolonged immobilization itself is a harbinger of various complications drastically altering a patient’s functional status. Physiotherapy plays a vital role in the management of COVID-19 symptoms as well as in the prevention of complications. Case Study: This case report describes the progress of a 44-year old female patient diagnosed with COVID-19 presenting with subsequent pneumonia and ARDS. The patient was started with medical management and supplemental oxygen therapy. In combination to the above-mentioned protocols, physiotherapy treatment was also initiated. After 2 weeks of rehabilitation and drug therapy, the patient displayed improved respiratory function at room air and was able to independently ambulate with minimal breathing difficulty. Discussion: This case report aims to highlight the importance of early intervention of physiotherapy in COVID-19 patients. The scope of physiotherapy treatment in patients with COVID-19 pneumonia is vast. The treatment protocol adapted for this patient are in tune with the various research articles analysed to ensure evidence-based care. This will enable the healthcare professionals to ensure timely referral and early initiation of Physiotherapy treatment. Conclusion: As per the findings and results of this case report, it is evident that the patient benefited from the timely advent of physiotherapy intervention. The key factor was the correct identification of the problematic areas and accurate prioritization based on the clinical presentation and investigation findings

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JAK Inhibition with Ruxolitinib in Patients with COVID-19 and Severe Pneumonia: Multicenter Clinical Experience from a Compassionate Use Program in Italy

Journal of Clinical Medicine ◽

10.3390/jcm10163752 ◽

2021 ◽

Vol 10 (16) ◽

pp. 3752

Author(s):

Alessandro Maria Vannucchi ◽

Andrea Mortara ◽

Andrea D’Alessio ◽

Mara Morelli ◽

Alberto Tedeschi ◽

...

Keyword(s):

Clinical Status ◽

Severe Pneumonia ◽

Ambient Air ◽

Positive Outcome ◽

Compassionate Use ◽

Duration Of Treatment ◽

Reactive Protein ◽

Inflammatory Drugs ◽

Grade 3

Jak inhibitors are potent anti-inflammatory drugs that have the potential to dampen the hyperactive inflammatory response associated with severe COVID-19. We reviewed the clinical outcomes of 218 patients with COVID-19 hospitalized for severe pneumonia and treated with ruxolitinib through a compassionate use program. Data on the duration of treatment; outcomes at 4, 7, 14, and 28 days; oxygen support requirements; clinical status; and laboratory parameters were retrospectively collected. Overall, according to the physician evaluation, 66.5% of patients showed improvement at follow-up; of these, 83.5% showed improvement by day 7. Oxygen support status also showed improvement, and by day 7, 21.6% of patients were on ambient air, compared with 1.4% at baseline, which increased to 48.2% by day 28. Significant decreases in C-reactive protein and increases in the lymphocyte total count were already observed by day 4, which seemed to correlate with a positive outcome. At the end of the observation period, 87.2% of patients were alive. No unexpected safety findings were observed, and grade 3/4 adverse events were reported in 6.9% of patients.

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COVID-19: general overview, pharmacological options and ventilatory support strategies

Multidisciplinary Respiratory Medicine ◽

10.4081/mrm.2020.708 ◽

2020 ◽

Vol 15 ◽

Author(s):

Francesco Menzella ◽

Andrea Matucci ◽

Alessandra Vultaggio ◽

Chiara Barbieri ◽

Mirella Biava ◽

...

Keyword(s):

Randomized Clinical Trials ◽

Treatment Options ◽

Pulmonary Inflammation ◽

Invasive Mechanical Ventilation ◽

Ventilatory Support ◽

Current Treatment ◽

World Health ◽

Effective Vaccine ◽

High Flow Oxygen ◽

The World

The novel coronavirus called “Severe Acute Respiratory Syndrome Coronavirus 2” (SARS-CoV-2) caused an outbreak in December 2019, starting from the Chinese city of Wuhan, in the Hubei province, and rapidly spreading to the rest of the world. Consequently, the World Health Organization (WHO) declared that the coronavirus disease of 2019 (COVID-19) can be characterized as a pandemic. During COVID-19 several immunological alterations have been observed: in plasma of severe patients, inflammatory cytokines are at a much higher concentration (“cytokine storm”). These aspects are associated with pulmonary inflammation and parenchymal infiltrates with an extensive lung tissue damage in COVID-19 patients. To date, clinical evidence and guidelines based on reliable data and randomized clinical trials (RCTs) for the treatment of COVID-19 are lacking. In the absence of definitive management protocols, many treatments are currently being evaluated worldwide. Some of these options were soon abandoned due to ineffectiveness, while others showed promising results. As for ventilatory strategies, at the moment there are still no consistent data published about the different approaches and how they may influence disease progression. What will probably represent the real solution to this pandemic is the identification of a safe and effective vaccine, for which enormous efforts and investments are being put in place. This review will summarize the state-of-the-art of COVID-19 current treatment options and those potentially available in the future, as well as high flow oxygen therapy and non-invasive mechanical ventilation approaches.

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