Off-label tocilizumab and adjuvant iron chelator effectiveness in a group of severe COVID-19 pneumonia patients: A single center experience

Tocilizumab (TCZ), a monoclonal recombinant antibody against IL-6 receptor, is currently used in managing the cytokine release syndrome (CRS) that occurred in coronavirus disease 2019 (COVID-19) selected cases. The primary objective of our study was to establish the effectiveness of TCZ in patients with severe or critical severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pneumonia.We retrospectively analyzed 25 consecutive patients, admitted in the Academic Emergency Hospital Sibiu, Romania from April 1, 2020 until May 25, 2020, all with confirmed SARS-CoV-2 infection and severe pneumonia. All patients were treated off-label with TCZ, beside their standard care. Adjuvant iron chelator was associated in 11 patients.Six female and 19 male patients admitted in our hospital all with confirmed SARS-CoV-2 infection and severe pneumonia as defined by Chinese Centers for Disease Control and Prevention were enrolled in this study. Seventeen of the 25 enrolled patients (68%) were seriously ill requiring noninvasive ventilation or oxygen mask, and 8 cases (32%) were critically ill requiring invasive mechanical ventilation. All patients received TCZ, and also received hydroxychloroquine, and lopinavir/ritonavir 200/50 mg for 10 days. Adjuvant iron chelator (deferasirox – marketed as Exjade) was associated in 11 patients who had ferritin serum levels above 1000 ng/mL. No side effects were encountered during infusions or after TCZ. We observed a rapid increase in arterial oxygen saturation for 20 of the 25 cases (80%) with a favorable evolution toward healing. Survivors were younger than 60 years old (80%), had less comorbidities (10% no comorbidities, 70% with 1 or 2 comorbidities), lower serum ferritin levels (30% under 1000 ng/mL), and 50% had no serum glucose elevation. Our patients with CRS had no response to corticosteroid therapy. Five out of the 25 patients had an unfavorable evolution to death. The off-label use of TCZ in patients with severe or critically ill form of SARS-CoV-2 infection had good results in our study.Off-label use of TCZ in severe and critical cases of COVID-19 pneumonia is effective in managing the “cytokine storm.” Better outcomes were noted in younger patients. Associated adjuvant iron chelators may contribute to a good outcome and needs to be confirmed in larger studies.     

Combination therapy of Tocilizumab and steroid for management of COVID-19 associated cytokine release syndrome: A single center experience from Pune,Western India

Cytokine release syndrome (CRS) or cytokine storm is thought to be the cause of inflammatory lung damage, worsening pneumonia and death in patients with COVID-19. Steroids (Methylprednislone or Dexamethasone) and Tocilizumab (TCZ), an interleukin-6 receptor antagonist, are approved for treatment of CRS in India. The aim of this study was to evaluate the efficacy and safety of combination therapy of TCZ and steroid in COVID-19 associated CRS.This retrospective cohort study was conducted at Noble hospital and Research Centre (NHRC), Pune, India between April 2 and November 2, 2020. All patients administered TCZ and steroids during this period were included. The primary endpoint was incidence of all cause mortality. Secondary outcomes studied were need for mechanical ventilation and incidence of systemic and infectious complications. Baseline and time dependent risk factors significantly associated with death were identified by Relative risk estimation.Out of 2831 admitted patients, 515 (24.3% females) were administered TCZ and steroids. There were 135 deaths (26.2%), while 380 patients (73.8%) had clinical improvement. Mechanical ventilation was required in 242 (47%) patients. Of these, 44.2% (107/242) recovered and were weaned off the ventilator. Thirty seven percent patients were managed in wards and did not need intensive care unit (ICU) admission. Infectious complications like hospital acquired pneumonia, blood stream bacterial and fungal infections were observed in 2.13%, 2.13% and 0.06% patients respectively. Age ≥ 60 years (P = .014), presence of co-morbidities like hypertension (P = .011), IL-6 ≥ 100 pg/ml (P = .002), D-dimer ≥ 1000 ng/ml (P < .0001), CT severity index ≥ 18 (P < .0001) and systemic complications like lung fibrosis (P = .019), cardiac arrhythmia (P < .0001), hypotension (P < .0001) and encephalopathy (P < .0001) were associated with increased risk of death.Combination therapy of TCZ and steroids is likely to be safe and effective in management of COVID-19 associated cytokine release syndrome. Efficacy of this anti-inflammatory combination therapy needs to be validated in randomized controlled trials.     

Efficacy of Tocilizumab Therapy in Different Subtypes of COVID-19 Cytokine Storm Syndrome

Background: Cytokine storm in COVID-19 is heterogenous. There are at least three subtypes: cytokine release syndrome (CRS), macrophage activation syndrome (MAS), and sepsis. Methods: A retrospective study comprising 276 patients with SARS-CoV-2 pneumonia. All patients were tested for ferritin, interleukin-6, D-Dimer, fibrinogen, calcitonin, and C-reactive protein. According to the diagnostic criteria, three groups of patients with different subtypes of cytokine storm syndrome were identified: MAS, CRS or sepsis. In the MAS and CRS groups, treatment results were assessed depending on whether or not tocilizumab was used. Results: MAS was diagnosed in 9.1% of the patients examined, CRS in 81.8%, and sepsis in 9.1%. Median serum ferritin in patients with MAS was significantly higher (5894 vs. 984 vs. 957 ng/mL, p < 0.001) than in those with CRS or sepsis. Hypofibrinogenemia and pancytopenia were also observed in MAS patients. In CRS patients, a higher mortality rate was observed among those who received tocilizumab, 21 vs. 10 patients (p = 0.043), RR = 2.1 (95% CI 1.0–4.3). In MAS patients, tocilizumab decreased the mortality, 13 vs. 6 patients (p = 0.013), RR = 0.50 (95% CI 0.25–0.99). Conclusions: Tocilizumab therapy in patients with COVID-19 and CRS was associated with increased mortality, while in MAS patients, it contributed to reduced mortality.     

Lung recovery with prolonged ECMO following fibrotic COVID-19 acute respiratory distress syndrome

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has been associated with acute respiratory distress syndrome (ARDS) and in some cases with pulmonary fibrosis. There is limited information regarding the long-term outcomes of patients who develop severe COVID-19 infection and subsequent pulmonary fibrosis. We present a patient with severe ARDS due to COVID-19 who required prolonged extra-corporeal oxygenation support and eventually recovered significant lung function. This case is unique because the patient survived one of the longest reported runs on extra-corporeal membrane oxygenation without requiring lung transplantation. Further, our patient developed severe parenchymal and airway distortion but ultimately resolved pulmonary fibrosis many months into the hospitalization. In addition to our detailed case discussion, we will provide a focused review on pulmonary fibrosis post COVID-19.     

Efficacy and safety of tocilizumab in severe COVID-19 patients: a single-centre retrospective cohort study

BackgroundTocilizumab (TCZ), a humanized monoclonal antibody targeting the interleukin-6 (IL-6) receptor, has been proposed for the treatment of COVID-19 patients; however, limited data are available on the safety and efficacy.MethodsWe performed a retrospective study on severe COVID-19 patients with hyper-inflammatory features admitted outside intensive care units (ICUs). Patients treated with intravenous TCZ in addition to standard of care were compared to patients treated with standard of care alone. Safety and efficacy were assessed over a 28-day follow-up.Results65 patients were included. Among them, 32 were treated with TCZ. At baseline, all patients were on high-flow supplemental oxygen and most (78% of TCZ patients and 61% of standard treatment patients) were on non-invasive ventilation. During the 28-day follow-up, 69% of TCZ patients experienced a clinical improvement compared to 61% of standard treatment patients (p = 0.61). Mortality was 15% in the tocilizumab group and 33% in standard treatment group (p = 0.15). In TCZ group, at multivariate analysis, older age was a predictor of death, whereas higher baseline PaO2:FiO2 was a predictor of clinical improvement at day 28. The rate of infection and pulmonary thrombosis was similar between the two groups.ConclusionsAt day 28, clinical improvement and mortality were not statistically different between tocilizumab and standard treatment patients in our cohort. Bacterial or fungal infections were recorded in 13% of tocilizumab patients and in 12% of standard treatment patients. Confirmation of efficacy and safety will require ongoing controlled trials.     

Pancreatitis in a Patient with Severe Coronavirus Disease Pneumonia Treated with Veno-venous Extracorporeal Membrane Oxygenation

Severe coronavirus disease (COVID-19) can induce serious complications, including acute respiratory distress syndrome, septic shock, and acute kidney injury. However, few reports have associated COVID-19 with pancreatitis. We herein report the case of a 55-year-old patient who developed acute pancreatitis associated with severe COVID-19 pneumonia and was successfully treated with veno-venous extracorporeal membrane oxygenation (ECMO). Elevated pancreatic enzymes levels and computed tomography findings led to the diagnosis of acute pancreatitis due to COVID-19. Although we found that severe COVID-19 pneumonia can lead to pancreatitis, the underlying pathophysiology remains unknown.     

Management of a patient presenting with anterior STEMI with concomitant COVID-19 infection early in the course of the U.S. pandemic

The coronavirus disease-2019 (COVID-19) is a viral illness with heterogenous clinical manifestations, ranging from mild symptoms to severe acute respiratory distress syndrome and shock caused by the severe acute respiratory syndrome coronavirus-2. The global healthcare community is rapidly learning more about the effects of COVID-19 on the cardiovascular system, as well as the strategies for management of infected patients with cardiovascular disease. There is minimal literature available surrounding the relationship between COVID-19 infection and acute coronary syndrome. We describe the case of a woman who presented with an acute anterior ST-elevation myocardial infarction managed by primary percutaneous coronary intervention, who subsequently developed severe COVID-19 infection and ultimately succumbed to multisystem organ failure.     

Severe coronary spasm in a COVID-19 patient

Myocardial injury is frequently detected in coronavirus disease 2019 (COVID-19) patients. However, up to one-third of COVID-19 patients showing ST-segment elevation on the electrocardiogram have angiographically normal coronary arteries. We present a case of an acute coronary syndrome due to a coronary spasm in a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) patient. This pathophysiological mechanism was clearly demonstrated by intracoronary imaging techniques (optical coherence tomography) and invasive vasospasm test.     

Acute upper limb ischemia in a patient with COVID-19

Patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection mainly present with upper and lower respiratory tract symptoms, with complications related to cytokine storm syndrome and acute respiratory distress syndrome. It has also been described to predispose to venous and arterial thromboembolism; however, limited published data is available regarding thrombosis in coronavirus disease 2019 (COVID-19). Here we are presenting a case of arterial thrombosis in a patient with COVID-19 and a systematic review on coagulopathy associated with COVID-19.     

Tocilizumab in the treatment of myocardial infarction

Tocilizumab (TCZ) is an important biologic response modifier that rheumatologists routinely employ in the treatment of several systemic autoimmune diseases. TCZ binds to interleukin (IL)-6 receptors, inhibits cellular activation, and mitigates inflammation by IL-6. In mid-2017, TCZ was approved by the US Food and Drug Administration for its first nonrheumatologic condition, the treatment of chimeric antigen receptor (CAR) T cell-induced severe or life-threatening cytokine release syndrome in patients 2 years of age or older. With this approval and with the increasing use of TCZ off-label for other non-rheumatologic conditions such as Castleman’s Disease and its variant TAFRO syndrome, where else might TCZ be successfully utilized as treatment? Recently interesting data has been published regarding possible use of TCZ in the treatment of myocardial infarction. This review focuses on the role of IL-6 and its receptor in myocardial inflammation and association with adverse clinical outcomes. Discussed are one animal study and two human trials that have been published studying the effect of TCZ in patients with acute myocardial infarction. Finally, this review summarizes the current data and makes recommendations for future clinical trial development in what hopefully will be a promising application of TCZ for a serious nonrheumatologic condition.     

Acute pancreatitis and nosocomial COVID-19: Cause specific host responses may determine lung injury

BackgroundCoronavirus disease 2019 (COVID-19) presents with myriad extra-pulmonary manifestation and a high mortality in patients with comorbidities. Its effect on patients with pre-existing acute pancreatitis is not known.MethodsWe hereby, present 3 cases with severe acute pancreatitis with persistent respiratory failure who acquired nosocomial COVID-19 during their hospital stay after recovery from respiratory failure. Their clinical course is highlighted which reflects on pathophysiology of organ dysfunction in these 2 disease states.ResultsNone of the 3 patients with severe acute pancreatitis who developed nosocomial COVID-19 redeveloped respiratory failure due to COVID-19 despite having recently recovered from pancreatitis induced acute hypoxemic respiratory failure. Only one patient developed SARS-CoV2 induced moderate pneumonia.ConclusionThese cases highlight that host responses and mechanisms of lung injury might be different in severe acute pancreatitis and COVID-19.     

SARS-CoV-2 leading to acute pancreatitis: an unusual presentation

During SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2) pandemic, the etiologic agent of COVID-19, several studies described the involvement of other tissues besides the respiratory tract, such as the gastrointestinal tract. Angiotensin-converting enzyme-2, the functional virus host cell receptor expressed by organs and tissues, seems to have an important role in the pathophysiology and presentation of this disease. In pancreas, this receptor is expressed in both exocrine glands and islets, being a potential target for the virus and subsequent pancreatic injury. There are few articles reporting pancreatic injury in COVID-19 patients but most of them do not report acute pancreatitis. Diagnosing acute pancreatitis secondary to SARS-CoV-2 infection is challenging due to the need to rule out other etiologies as well the notable heterogeneous presentations. Herein we report the case of a patient with COVID-19 who developed severe acute pancreatitis.     

The Cross-Talk between Thrombosis and Inflammatory Storm in Acute and Long-COVID-19: Therapeutic Targets and Clinical Cases

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) commonly complicates with coagulopathy. A syndrome called Long-COVID-19 is emerging recently in COVID-19 survivors, characterized, in addition to the persistence of symptoms typical of the acute phase, by alterations in inflammatory and coagulation parameters due to endothelial damage. The related disseminated intravascular coagulation (DIC) can be associated with high death rates in COVID-19 patients. It is possible to find a prothrombotic state also in Long-COVID-19. Early administration of anticoagulants in COVID-19 was suggested in order to improve patient outcomes, although exact criteria for their application were not well-established. Low-molecular-weight heparin (LMWH) was commonly adopted for counteracting DIC and venous thromboembolism (VTE), due to its pharmacodynamics and anti-inflammatory properties. However, the efficacy of anticoagulant therapy for COVID-19-associated DIC is still a matter of debate. Thrombin and Factor Xa (FXa) are well-known components of the coagulation cascade. The FXa is known to strongly promote inflammation as the consequence of increased cytokine expression. Endothelial cells and mononuclear leucocytes release cytokines, growth factors, and adhesion molecules due to thrombin activation. On the other hand, cytokines can activate coagulation. The cross-talk between coagulation and inflammation is mediated via protease-activated receptors (PARs). These receptors might become potential targets to be considered for counteracting the clinical expressions of COVID-19. SARS-CoV-2 is effectively able to activate local and circulating coagulation factors, thus inducing the generation of disseminated coagula. LMWH may be considered as the new frontier in the treatment of COVID-19 and Long-COVID-19. Indeed, direct oral anticoagulants (DOACs) may be an alternative option for both early and later treatment of COVID-19 patients due to their ability to inhibit PARs. The aim of this report was to evaluate the role of anticoagulants—and DOACs in particular in COVID-19 and Long-COVID-19 patients. We report the case of a COVID-19 patient who, after administration of enoxaparin developed DIC secondary to virosis and positivity for platelet factor 4 (PF4) and a case of Long-COVID with high residual cardiovascular risk and persistence of blood chemistry of inflammation and procoagulative state.     

SARS-CoV-2 and the pancreas: What do we know about acute pancreatitis in COVID-19 positive patients?

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can cause pancreatic damage, both directly to the pancreas via angiotensin-converting enzyme 2 receptors (the transmembrane proteins required for SARS-CoV-2 entry, which are highly expressed by pancreatic cells) and indirectly through locoregional vasculitis and thrombosis. Despite that, there is no clear evidence that SARS-CoV-2 is an etiological agent of acute pancreatitis. Acute pancreatitis in coronavirus disease 2019 (COVID-19) positive patients often recognizes biliary or alcoholic etiology. The prevalence of acute pancreatitis in COVID-19 positive patients is not exactly known. However, COVID-19 positive patients with acute pancreatitis have a higher mortality and an increased risk of intensive care unit admission and necrosis compared to COVID-19 negative patients. Acute respiratory distress syndrome is the most frequent cause of death in COVID-19 positive patients and concomitant acute pancreatitis. In this article, we reported recent evidence on the correlation between COVID-19 infection and acute pancreatitis.     

No evidence of tocilizumab treatment efficacy for severe to critical SARS-CoV2 infected patients: Results from a retrospective controlled multicenter study

To assess tocilizumab (TCZ) efficacy associated to standard of care (SOC) compared to SOC alone in severe coronavirus associated disease 2019 (COVID-19) patients. In a matched case-control study from 3 French Hospital COVID-19 Departments, 27 patients with severe COVID-19 treated with TCZ and SOC were matched for baseline epidemiological and clinical features and compared to 27 severe COVID-19 patients treated with SOC alone. Baseline characteristics of the study population were comparable between groups. Eleven patients (20%) died. TCZ was not associated with clinical improvement as compared to SOC regarding oxygen-free status (44% vs 63%) and death (18.5% vs 22%), despite a higher decrease of the C-reactive protein at Day 7 (10.7 vs 52 mg/L; P < 10⁻³). Compared to the 43 patients alive at the end-of follow-up, patients who died were older (78 vs 64 years; P < 10⁻³), with 82% of them older than 72 years vs only 23% of live patients (P < 10⁻³). Age (OR = 1.15; 95%CI = 1.04–1.3; P = .008) and age over 72 years (OR) = 14.85; 95%CI = 2.7–80; P = .002) were independently associated with mortality. TCZ in addition to SOC for severe COVID-19 patients did not reduce mortality, subsequent need for invasive mechanical ventilation nor did it shorten the time of oxygen support, despite better control of the inflammatory response. More powerful and randomized controlled trials are warranted to determine if TCZ is effective in the management of COVID-19.     

Imaging for Cardiovascular Complications of COVID-19: Cardiac Manifestations in Context

After the first confirmed case in 2019, COVID-19 rapidly spread worldwide and overwhelmed the medical community. In the intervening time, we have learned about COVID-19’s clinical manifestations and have developed effective therapies and preventative vaccines. Severe COVID-19 infection is associated with many cardiovascular disorders in the acute phase, and patients recovered from illness can also manifest long-term sequelae, including long COVID syndrome. Furthermore, severe acute respiratory syndrome–related coronavirus-2 messenger RNA (mRNA) vaccination can trigger rare cases of myopericarditis. We have gained significant knowledge of the acute and long-term cardiovascular complications of COVID-19– and mRNA vaccine–associated myocarditis through clinical and investigative studies using cardiac imaging. In this review, we describe how cardiovascular imaging can be used to understand the cardiovascular complications and cardiac injury associated with acute COVID-19 infection, review the imaging findings in patients recovered from illness, and discuss the role and limitations of cardiac imaging in COVID-19 mRNA vaccine–associated myocarditis.     

Using 18F-FDG PET/CT to rule out Richter transformation as cause of deterioration in a patient with chronic lymphatic leukemia and severe COVID-19: A case report

Rationale:This case report demonstrates the use of flourine-18 fluorodeoxyglucose (¹⁸F-FDG) positron emission tomography (PET)/computed tomography (CT) to rule out Richter transformation (RT) as the cause of clinical deterioration in a patient with chronic lymphatic leukemia (CLL) and severe COVID-19. ¹⁸F-FDG PET/CT can be used to establish the diagnosis of RT in patients with CLL, but the use of ¹⁸F-FDG PET/CT to exclude RT as the cause of clinical deterioration in patients with CLL and severe COVID-19 has not previously been described.Patient concerns:A 61-year-old male with CLL and COVID-19 developed increased dyspnea, malaise and fever during hospitalization for treatment of severe and prolonged COVID-19.Diagnoses:¹⁸F-FDG PET/CT ruled out RT and revealed progression of opacities in both lungs consistent with exacerbation of severe acute respiratory syndrome coronavirus 2 pneumonia.Interventions:¹⁸F-FDG PET/CT imaging.Outcomes:The patient was discharged at day 52 without the need of supplemental oxygen, with normalized infection marks and continued care for CLL with venetoclax.Lessons:¹⁸F-FDG PET/CT ruled out RT as the cause of deteriorations in a patient with CLL and severe COVID-19, enabling directed care of exacerbation of severe acute respiratory syndrome coronavirus 2 pneumonia.     

Long COVID-19: A Primer for Cardiovascular Health Professionals,on Behalf of the CCS Rapid Response Team

It is now widely recognized that COVID-19 illness can be associated with significant intermediate and potentially longer-term physical limitations. The term, “long COVID-19” is used to define any patient with persistent symptoms after acute COVID-19 infection (ie, after 4 weeks). It is postulated that cardiac injury might be linked to symptoms that persist after resolution of acute infection, as part of this syndrome. The Canadian Cardiovascular Society Rapid Response Team has generated this document to provide guidance to health care providers on the optimal management of patients with suspected cardiac complications of long COVID-19.     

Using JAK inhibitor to treat cytokine release syndrome developed after chimeric antigen receptor T cell therapy for patients with refractory acute lymphoblastic leukemia: A case report

Rationale:Significant concerns about the adverse effects following chimeric antigen receptor T cell (CAR-T) therapy are still remained including cytokine release syndrome (CRS). In rare circumstances, CRS may be refractory to tocilizumab and/or corticosteroids, a new treatment is needed for the management of CRS.Patient concerns:We present a case of a 20-year-old male patient with acute lymphoblastic leukemia developed CRS after CD19/CD22 bispecific CAR-T treatment.Diagnosis:The patient was diagnosed with BCR-ABL(P210) positive B-ALL and developed CRS after CD19/CD22 bispecific CAR-T treatment.Interventions:Tocilizumab and methylprednisolone were administered, unfortunately the patient''s symptoms of CRS were still not resolved. Another methylprednisolone and ruxolitinib were administered.Outcomes:The persistent fever and hypotension of this patient achieved a rapid clinical remission within hours after ruxolitinib administration.Lessons:Ruxolitinib can be used as an alternative therapeutic approach for severe and refractory CRS without impairing CAR-T amplification and anti-tumor effect.