Immune response to SARS-CoV-2 and mechanisms of immunopathological changes in COVID-19.

Plasma exchange and COVID 19

The coronavirus disease 2019 (COVID-19) pandemic constitutes a global health emergency. Currently, there are no completely effective therapeutic medications for the management of this outbreak. The cytokine storm is a hyperinflammatory medical condition due to excessive and uncontrolled release of pro-inflammatory cytokines in patients suffering from severe COVID-19, leading to the development of acute respiratory distress syndrome (ARDS) and multiple organ dysfunction syndrome (MODS) and even mortality. Understanding the pathophysiology of COVID-19 can be helpful for the treatment of patients. Evidence suggests that the levels of tumor necrosis factor alpha (TNF-α) and interleukin (IL)-1 and IL-6 are dramatically different between mild and severe patients, so they may be important contributors to the cytokine storm. Several serum markers can be predictors for the cytokine storm. This review discusses the cytokines involved in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, focusing on interferons (IFNs) and ILs, and whether they can be used in COVID-19 treatment. Moreover, we highlight several microRNAs that are involved in these cytokines and their role in the cytokine storm caused by COVID-19.

Use of ECMO in Patients With Coronavirus Disease 2019: Does the Evidence Suffice?

COVID-19-related coagulopathy is a known complication of SARS-CoV-2 infection and can lead to intracranial hemorrhage (ICH), one of the most feared complications of extracorporeal membrane oxygenation (ECMO). We sought to evaluate the incidence and etiology of ICH in patients with COVID-19 requiring ECMO. Patients at two academic medical centers with COVID-19 who required venovenous-ECMO support for acute respiratory distress syndrome (ARDS) were evaluated retrospectively. During the study period, 33 patients required ECMO support; 16 (48.5%) were discharged alive, 13 died (39.4%), and 4 (12.1%) had ongoing care. Eleven patients had ICH (33.3%). All ICH events occurred in patients who received intravenous anticoagulation. The ICH group had higher C-reactive protein (P = 0.04), procalcitonin levels (P = 0.02), and IL-6 levels (P = 0.05), lower blood pH before and after ECMO (P < 0.01), and higher activated partial thromboplastin times throughout the hospital stay (P < 0.0001). ICH-free survival was lower in COVID-19 patients than in patients on ECMO for ARDS caused by other viruses (49% vs. 79%, P = 0.02). In conclusion, patients with COVID-19 can be successfully bridged to recovery using ECMO but may suffer higher rates of ICH compared to those with other viral respiratory infections.

The coronavirus disease 2019 (COVID‐19) pandemic, a viral illness caused by the severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2), 1 has produced at the time of this writing nearly 33 million cases of infection, with over a million deaths in 235 countries, 2 causing an unprecedented burden on healthcare systems and a severe global socioeconomic crisis. As the pandemic spreads, knowledge on the disease course, as well as potential risk factors and predictors of severity is increasing daily, and initial data from randomised controlled studies have allowed care providers to refine therapeutic strategies. Nonetheless, mortality is markedly elevated among those presenting with severe disease, long‐term sequelae among survivors are unknown, and vaccine‐based therapies currently remain at early stages of development. Most reported cases are asymptomatic or present with mild symptoms; however, 7–26% of hospitalised patients experience severe disease, often requiring admission to intensive care units (ICUs), with progressive multiple organ dysfunction and high mortality. 3 , 4 , 5 Such differences in clinical outcomes have led physicians to initiate diverse pharmacological therapies at various stages of the disease, generating challenges as to the most appropriate therapeutic choice for COVID‐19. In this context, the use of dexamethasone has significantly reduced mortality rates in critically ill patients requiring supplemental oxygen or mechanical ventilation, 6 and remdesivir has demonstrated clinical benefit in hospitalised patients, but with unknown survival benefit to date 7 ; additional effective treatment options are therefore urgently needed. In an initial attempt to provide a uniform and widely reproducible methodology to guide systematic treatment strategies, a three‐stage classification of COVID‐19 has been proposed. 8 The Stage I or ‘early infection’ occurs at the initial establishment of disease with high viral replication, and commonly presents with a range of complaints that can include mild and often non‐specific influenza‐like signs and symptoms. Stage II is the ‘pulmonary phase’, with preferential viral‐mediated injury of the lung parenchyma and this is characterised by shortness of breath, hypoxia and pulmonary infiltrates with some degree of lung inflammation. Stage III is characterised by an exaggerated host immune‐inflammatory response to the virus, leading to acute respiratory distress syndrome (ARDS) and multi‐organ failure (MOF).

Platelet-leukocyte crosstalk in COVID-19: How might the reciprocal links between thrombotic events and inflammatory state affect treatment strategies and disease prognosis?

Immune mechanisms of pulmonary intravascular coagulopathy in COVID-19 pneumonia.

Peer Reviewed

he prevalence of coronavirus disease 2019 (COVID-19) has posed a great threat to people's health worldwide, bringing a great challenges to the public healthcare systems. A recent study has confirmed that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses severe acute respiratory syndrome coronavirus (SARS-CoV) receptor angiotensin-converting enzyme 2 (ACE2) for host cell entry. 1 ACE2 expression was previously found to correlate with susceptibility to SARS-CoV infection in vitro.

Treatment of Stage 3 COVID-19 With Transcutaneous Auricular Vagus Nerve Stimulation Drastically Reduces Interleukin-6 Blood Levels: A Report on Two Cases

Citation:McSharry D, Malhotra A. Potential influences of obstructive sleep apnea and obesity on COVID-19 severity. J Clin Sleep Med. 2020;16(9):1645.

Toll-like receptors and COVID-19: a two-faced story with an exciting ending.

Acute respiratory distress syndrome (ARDS) is an end-point for multiple heterogeneous disease processes. Most current treatment strategies have focused on minimizing the harm placed on the patient by mechanical ventilation (Table 1). Today, the mainstay of treatment for ARDS has been reduced to treating the underlying condition and maintaining lung protective mechanical ventilation. Unfortunately, even with these protective measures, there is still ventilator-induced lung injury. Ventilator-induced lung injury is a well described, multifactorial phenomenon experienced by the patient during ventilation that encompasses barotrauma, volutrauma, atelectrauma, biotrauma, and newly described energy trauma.1,5,9,10 Table 1. - The History and Management of ARDS1–11 1967: ARDS was first described by Ashbaugh et al.1 1975: Suter et al. found that the optimum PEEP for optimizing oxygen delivery was the PEEP that achieved the best compliance.1 1975: Kirby et al. described a high PEEP strategy to minimize shunting.1 1979: NIH did the first trial looking at ECMO for ARDS.1 1981: Lemaire et al. found that the minimal PEEP for the patient should be 2 cm H2O above the lower inflection point.1 1987: Gattinoni et al. described the concept of "baby lung" and that the lungs were not stiff, but the size of the usable lung was that of a child's lung.2 1990: Hickling et al. described lung rest with low tidal volume ventilation.1 1994: NIH-NHLBI ARDSNet was created.3 1999: Ranieri et al. published a paper showing reduced inflammatory markers when using lung protective strategies.4 1999: Slutsky described the four accepted ventilator-induced lung injuries.5 2000: ARMA trial was published which showed that 6 ml/kg is better than 12 ml/kg.6 2009: CESAR trial showed improved outcomes in patients who went to an ECMO center.7 2011: The Berlin definition of ARDS was described.8 2015: Amato et al. described ΔP. A ΔP ≤ 15 cm H2O reduced mortality.9 2016: Energy trauma, based on ΔP, was described as a new type of VILI.10 2019: Rozencwajg et al.8 described ultra-lung protection ventilation on ECMO was shown to reduce biotrauma.11 ΔP, driving pressure; ARDS, acute respiratory distress syndrome; ARDSNet, Acute Respiratory Distress Syndrome Network; ARMA, lower tidal volume ventilation in ALI/ARDS; CESAR, efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure; ECMO, extracorporeal membrane oxygenation; NHLBI, National Heart, Lung, and Blood Institute; NIH, National Institute of Health; PEEP, positive end-expiratory pressure; VILI, ventilator-induced lung injury. Over the past 2 decades, extracorporeal membrane oxygenation (ECMO) has gained popularity as a life-sustaining modality for patients who cannot be adequately oxygenated or ventilated using more conventional means. Using ECMO, in conjunction with ultraprotective lung ventilation (UPLV), has been shown to reduce barotrauma, volutrauma, atelectrauma, and energy trauma.11 Additionally, the ability to reduce the fraction of inspired oxygen on ECMO decreases oxygen free radicals. This reduction, and the reduction in injurious ventilator settings, reduces inflammation and cytokine production which decreases biotrauma.11–13 Despite these advantages of ECMO, several problems remain. Notably, while ECMO/UPLV can reduce the iatrogenic inflammation from mechanical ventilation, it does not address the underlying inflammatory insult of the disease. Furthermore, the ECMO circuit itself is a pro-inflammatory. The artificial surface of the circuit initiates several inflammatory cascades which contribute to biotrauma, end-organ damage, and coagulopathies.12,13 The coronavirus disease 2019 (COVID-19) epidemic has brought biotrauma to the forefront as a major contributor to mortality in ARDS. Coronavirus disease 2019 is extremely pro-inflammatory and can spiral into cytokine storm, which carries a high mortality rate. Cytokines are released when the body recognizes an infection and are responsible for the immune response mounted to fight off the invading organism. Cytokines are responsible for their own regulation which allows it to help specify the pathogen, limit itself to an appropriate response level, and downregulate during the resolution phase. Cytokine storms occur when the immune system either does not regulate its response, leading to inappropriately elevated levels, or does not appropriately enter the resolution phase, leading to prolonged inflammation. When there is an inappropriate response or prolonged response, the result is collateral damage to the body. It is unclear the exact mechanism of how COVID-19 infections cause cytokine storm, but the end result is supratherapeutic cytokine levels. When the cytokine levels reach hyperactive response level, it causes a more systemic response by activating the release and mobilization of neutrophils and monocytes to the infected site. This response inappropriately activates the coagulation, fibrinolytic, and complement cascades out of proportion to the infection causing shock, thromboembolic disease, and organ failure, especially lung damage. Interleukin (IL)–6 and tumor necrosis factor (TNF)–α are two of the pro-inflammatory cytokines most associated with cytokine storm and the resulting biotrauma leading to lung injury. Increased IL-2 levels are associated with capillary leak which causes the breakdown of cell bridges and increases the vascular permeability leading to pulmonary edema, kidney injury, and third-spacing. Capillary leak, with the addition of inflammatory vasodilation, is a major cause of the severe hypotension/shock also seen in these critically ill patients. Interleukin-10 is an anti-inflammatory cytokine and part of the Compensatory Anti-inflammatory Response Syndrome.14 Interleukin-10 downregulates the immune response and helps to keep the inflammatory response at an appropriate level. In cytokine storm, the IL-10 levels are also inappropriately elevated since it is trying to decrease the response.15 In 2007, Kellum et al.14 looked at the inflammatory markers in patients with pneumonia and sepsis. Cytokine levels were the highest in patients with the worst outcomes. The highest risk of death was in patients with high levels of both pro-inflammatory (IL-6) and anti-inflammatory markers (IL-10).16 Medications to target the cytokine cascades have always been of interest in research. If there was a way to prevent this inappropriate response, it could prevent the capillary leak, organ failure, and shock. Unfortunately, medications that target a specific part of a cascade have not been shown to be successful. Recombinant activated protein C was trialed to replete the reduced levels seen in septic shock. Initial studies were promising, but it was found to increase bleeding and not improve outcomes after further studies. Anti–TNF-α medications were also studied in patients with septic shock. The results are more controversial with heterogeneous studies but may have a positive role in patients in shock or with elevated IL-6 levels.17 Due to the poor results using medications, a variety of methods for extracorporeal blood purification have been explored to reduce the amount of circulating inflammatory markers in the body. Many modalities have been described in sepsis and ARDS, including continuous venovenous hemofiltration (CVVH), hemoperfusion, and plasma exchange. CVVH in ARDS was studied in the 2000s, and success with plasma exchange with H1N1 ARDS in 2009 was also described in a case series.18,19 The efficacy of these modalities has been controversial with conflicting trial results.20,21 In patients infected with COVID-19, immunomodulation has again become a major target for research and intervention. Currently, the standard of care for immunomodulator use is steroids and IL-6 inhibitors. Corticosteroids reduce the inflammatory response by binding to intracellular receptors that inhibit transcription factors, phospholipase A2, and cyclooxygenase 2, all of which reduce the production of pro-inflammatory cytokines. Dexamethasone was shown to reduce mortality in COVID-19 patients.22 Tocilizumab is an IL-6 receptor antibody that prevents IL-6 binding to the receptor which reduces the inflammatory response. Tocilizumab was initially shown in case reports and retrospective trials to reduce the need for mechanical ventilation and improve mortality. However, a recent prospective randomized controlled trial failed to repeat these results.23,24 Given the theoretical benefits, but mixed real-world efficacy of immunomodulation, the novel method of a selective cytopheretic device (SCD) presented by Yessayan et al.25 is intriguing. The device approaches the inflammatory cascade upstream of typical cytokine scavenging or inhibition methods by binding the most active neutrophils and monocytes. Through an unclear mechanism, the circulating neutrophils and monocytes are reduced to a less inflammatory state decreasing cytokine production. In this two-patient study, there was a clear reduction in inflammatory cytokine markers and improvement in the patient's respiratory status after initiation of SCD. Other studies looking at the SCD in acute kidney injury have shown improvements and no side effects attributable to the device itself.26 One concern to consider is that looking at limited data can lead to misleading results. The inability to repeat a beneficial response to immunomodulation interventions has been seen over and over again. This study of two patients was limited and therefore has a high risk that similar results of improvement will not be seen when expanded to larger trials. At our institution, we have currently managed nine COVID-19 patients on venovenous ECMO with results similar to the national average (Extracorporeal Life Support Organization Registry as of December 9, 2020: 989/1,846 [53%] discharged alive). We have had four survive to discharge, three were unable to be weaned, and two who are currently still on ECMO. When looking at our IL-6 data, the average level was 167 pg/mL, and we also saw a large distribution (37–519 pg/mL). We did have one patient with a level greater than 3,000 pg/mL that did not get tocilizumab. This level was a significant outlier and was not included in the average. Using the inclusion criteria of the SCD study, we would have had two patients qualify for the device, both which had prolonged courses and did not survive. Looking at these initial SCD results, this treatment option would be something we would want to have moving forward. The limitations of needing an elevated IL-6 level and having not received Tocilizumab decreases the use of the SCD. Only 22% of our patients would have qualified for the study, which leaves a large population of critically ill patients excluded. As mentioned in the article, six patients with COVID-19 and ARDS were screened and did not have an IL-6 level elevated enough to meet criteria, and four of these patients were on ECMO at the time of screening. I think future trials would need to look at decreasing the limitations on SCD use to either mechanically ventilated COVID-19 patients with severe ARDS or any mechanically ventilated patients with elevated IL-6 levels. With such a small percentage of ECMO patients qualifying, small to medium centers for ECMO may not have enough patients meet the qualifications to be in a trial. Finally, the use of steroids as an anti-inflammatory was not mentioned in the article. Dexamethasone was shown to decrease 28 day mortality in patients with COVID-19 who were receiving mechanical ventilation or supplemental oxygen.20 With steroids now being used early-on as an anti-inflammatory drug, it remains to be seen how the SCD would work as a supplement to steroid use and if it would reach statistical significance. Additionally, another consideration for future trials is that tocilizumab use is increasing, and if it prevents the use of SCD treatment, it could limit patient recruitment. In conclusion, beyond treatment of the viral associated cytokine storms, the implications of being able to reduce inflammation and lung injury associated with ARDS and ECMO cannulation are intriguing. This has the potential to be the missing piece needed to address the nonventilator biotrauma that current management strategies for ARDS do not address. More trials need to be conducted to study the impact of the SCD for COVID-19 patients. Future trials are needed to look at the effectiveness of SCD in other patient populations. There is high potential for the SCD to be another treatment tool for ARDS, especially in COVID-19, and look forward to further studies.

The role of a cytokine storm in severe coronavirus disease 2019 in pregnancy

The Right Ventricle in COVID-19 Lung Injury: Proposed Mechanisms, Management, and Research Gaps