3m 1708 pdf

In this way, the chemokines produced by activated monocytes and macrophages lead to the recruitment of neutrophils, monocytes, and T cells into the lungs The damage caused by neutrophils, monocytes, and T cells results in lung-parenchyma changes, such as diffuse alveolar damage, which leads to ARDS In summary, the excessive cytokines and chemokines caused by lethal coronavirus infection involve mainly antigen-presenting cells APCs such as macrophages and T cells.

However, cytokines secreted by immune cells are produced to eliminate viral infection, and deficiency of such cytokines may be harmful to the body. Critical illness as one of the following conditions: respiratory failure and requiring mechanical ventilation; shock; complication of other organ failures, and needs intensive care. The most common symptoms of COVID were fever, cough, shortness of breath, fatigue, and myalgia 5 , 7 , 39 , 40 , and severe cases tend to be older with more basic diseases and suffer from dyspnea, more complications 5 , The lung lesions increase and the scope expands as the disease progresses, and ground-glass opacity coexisted with consolidation or striated shadow.

Some severe patients showed diffuse lesions in both lungs. Up to date, the inflammatory disorders insufficient in chemokines in COVID have been reported in many clinical studies. The results of the other immune cells, the B cell and natural killer NK cell, have more inconsistency in recent researches. IL-6 was observed increased in all studies, and only one study show IL was not elevated. Only Huang et al. The exhaustion markers return to normal in patients who have recovered or are convalescent 47 , Furthermore, Xiong et al.

These results could provide some reasons for the cause of patients' lymphopenia. Another team of Chen and his colleagues studied the mechanisms for lymphopenia As a consequence, it recruits neutrophils and induces uncontrollable host inflammatory response. For example, all the viruses can cause lymphopenia and influenza-like symptoms in the early stage.

Tocilizumab TCZ is a recombinant humanized anti-human IL-6 receptor monoclonal antibody, preventing IL-6 binding to its receptor to exert the immunosuppression promoted by IL Michot et al.

Similarly, some case reports showed TCZ is an efficacy and safety approach in COVID, even patients with other diseases combined, such as multiple myeloma, end-stage renal disease, and sickle cell disease 52 — A prospective open-label, multicenter single-arm study manifests the pilot results of the off-label application of TCZ in severe patients with COVID It is worth mentioning that a cautionary case report by Radbel et al.

Unfortunately, both patients progressed to severe HLH, and one developed to viral myocarditis. All the cytokines produced by immune cells are responsible for viral clearance. Suppression of cytokine release at an early stage of disease as treatment is controversial. The timing and the doses of the intervention still need to be inspected clearly.

It still needs more large samples and high-quality studies to evaluate the exact efficacy and safety in COVID The ongoing trials of potential treatments and other treatments focus on inflammatory disorders in COVID are available in Supplementary Table 1. Glucocorticoid therapy is used widely among critically ill patients with other coronavirus infections e. Glucocorticoids exhibit pharmacologic effects at any therapeutically relevant dose through classic genomic mechanisms.

Glucocorticoids reduce the proliferation, activation, differentiation, and survival of T cells and macrophages Glucocorticoids proffer inhibitory actions on the transcription and action of various cytokines. However, it is controversial whether corticosteroids are beneficial in the treatment of severe COVID patients.

A comment and a meta-analysis, which mainly bases on the evidence of SARS and MERS 64 , 65 , stated that corticosteroid would increase mortality and delayed clearance of viral in coronavirus infection diseases. Thus, the corticosteroids should not be administrated for the treatment of SARS-Cov-2 induced lung injury or shock. Newly published studies also indicate that the use of corticosteroids is not beneficial for COVID patients not severe cases , and high-dose corticosteroids are associated with mortality 44 , 66 , Inspecting the studies included and analyzed by the meta-analysis, only one study 68 described the numbers of patients with corticosteroids and non-corticosteroids treatment in the severe group and non-severe group.

Another comment 69 , which was written by front-line physicians from China, showed corticosteroids might have some benefit for critically ill patients with COVID It might be overuse to administrate corticosteroids to counteract a wide range of cytokines. The dose, duration, and timing of corticosteroid therapy will be crucial if administrated to COVID patients.

As stated above, lymphocytes exhaustion is one of the characteristics of COVID, and PD-1 checkpoint-inhibitor might some help in reversing the anergy of lymphocytes.

Increased PD-L1 expression in monocytes is associated with mortality in patients with septic shock A meta-analysis of checkpoint inhibitors showed that such therapy increased the chance of survival They revealed that giving a checkpoint inhibitor did not result in unexpected safety findings or indicate a cytokine storm 75 , Those results suggest that lethal COVID, along with H7N9, may be related to defective activation and exhaustion of T cells, which also suggest that checkpoint-inhibitor administration may reverse this status.

Cytokine adsorption involves using a method, such as extracorporeal membrane oxygenation ECMO , to filter harmful substances directly. Moreover, hemodynamic stabilization, respiratory improvement, and a decline in capillary leakage can be achieved in combination therapy A similar therapy involves dialysis.

The mainly water-soluble mediators are removed from plasma, and the hemofilters can have additional adsorptive properties Neutralizing excessive cytokines with hemoadsorption devices might be relatively effective. The disadvantage is like corticosteroids: a wide range of cytokines would be adsorbed. Thus, it would lead to the a lack of cytokines, which are at reasonable or even insufficient levels.

We suggest treating the cytokine storm in COVID should base on the laboratory results of cytokines and chemokines. Meanwhile, adjusting the parameters of the devices e. IVIG can elicit passive immunity, anti-inflammatory, and immunomodulatory effects that can improve treatment effects and increase survival in severe infection. An IgG molecule binds to a specific target antigen through the humoral and cellular arms of the immune system.

Ma and colleagues detailed a severe case of glandular fever treated with IVIG A multicenter, double-blind, randomized controlled trial for cases with severe influenza A H1N1 infection demonstrated that IVIG reduced the serum concentration of cytokines, viral load, and reduced mortality A meta-analysis of 17 studies 1, participants found IgM-enriched polyclonal and standard Ig molecules decreased mortality in adults with severe sepsis or septic shock.

However, a meta-analysis did not reveal a benefit in adult mortality with polyclonal IVIG using high-quality trials only A meta-analysis included the studies up to 5 April 86 and showed that four clinical trials and three observational studies are eligible for the study. The study also indicates high dosage HCQ might not be suitable for critically ill patients because of its potential safety hazards. Several studies 88 — 93 have shown that the add-on of TCM to Western medicine can shorten the duration of hospitalization, alleviate symptoms, reduce mortality including for critically ill patients , and reduce the prevalence of adverse reactions in SARS.

However, the quality of the studies must be improved. The administration of TCM in a standard manner worldwide is complicated because of the different decoctions used and the matching of herbs.

Artemisinin can be obtained from Artemisia annua , and one kind of antimalarial agents. Hou and colleagues showed that extracts from artemisinin-family drugs could regulate cells from the innate and adaptive immune system, and lead to anti-inflammatory and immunomodulatory actions The scope of application for artemisinin-family medicines includes infectious disease and autoimmune diseases, and artemisinin-family shows a difference in immune regulation compared with hydroxychloroquine 98 — Artesunate is a derivative of artemisinin and can lessen the pathologic changes and neutrophil infiltration in the lungs of ALI patients, and decrease sepsis-induced mortality Hu and colleagues explored a new and efficacious approach for ALI Besides, kidney impairment in hospitalized COVID patients is associated with a high risk of in-hospital death Cheng et al.

TLR2 mainly locates outside the cell membrane of macrophages, DCs, and granulocytes, and recognizes bacteria The mitogen-activated protein kinase MAPK signaling pathway plays a vital part in the development, differentiation, proliferation, transformation, and apoptosis of cells In another LPS-induced macrophage model, artemisinin has a property of prohibiting STAT1 activation, and it leads to the reduction of NO an inflammatory-cascade inducer in macrophages Artesunate therapy has been shown to improve the survival of mice infected with the herpes simplex virus.

These cytokines are produced primarily by APCs and Th1 cells. Previous studies have suggested that the artesunate can regulate Th cells in virus infections. RA is an autoimmune disease manifested by dysfunction of various immune cells e.

Fan et al. T reg can be anti-inflammatory, secrete anti-inflammatory cytokines e. Artemisinin-family drugs have shown efficacy and safety in treating malaria. One study reported 32 patients with severe malaria caused by Plasmodium falciparum. Ten patients suffered renal failure, eight had cerebral malaria, and 14 had other causes of severe malaria. After artesunate treatment, concentrations of IL-6, and soluble IL-6 receptor in plasma were normalized within 24 h In recent years, artemisinin-family drugs have been shown to be beneficial against infection caused by the human cytomegalovirus, hepatitis-B virus, Ebola virus, and human immunodeficiency virus Shapira and co-workers reported the first case of the Treatment of HCMV infection with artesunate Germi and collaborators reported that the artesunate led to an effective response in three cases with mild HCMV infection but was not efficacious in two patients with severe HCMV infection.

IL, a cytokine with anti-inflammatory properties, could be secreted by virtually all immune cells, including macrophages, DCs, NK cells, T cells, and B cells Images Donate icon An illustration of a heart shape Donate Ellipses icon An illustration of text ellipses.

Belsen Trial Item Preview. EMBED for wordpress. Want more? Advanced embedding details, examples, and help! The underlying pathophysiology varies with the type of virus involved. However, in some cases, it is difficult to exclude other causes of AP, including certain medications. And 4 Doxycycline, lisinopril, estrogens and steroids are associated with AP development, and constituted the chronic medications of some of the patients included in the case reports.

Furthermore, idiopathic AP IAP is an exclusion diagnosis, which indicates that no etiology has been determined after a complete diagnostic evaluation, including a detailed history, laboratory serum tests, and adequate imaging.

Numerous studies have suggested that microlithiasis and sludge may be the cause of a large subset of previously diagnosed IAP and endoscopic ultrasound imaging and magnetic resonance cholangiopancreatography can detect biliary etiology in one-third of patients diagnosed with IAP[ 23 ].

In a case series, published by Elhence et al [ 24 ], three cases of severe AP with respiratory failure systemic complication of AP tested positive for COVID several days after the diagnosis of AP 34 to 91 d from admission. These patients did not develop severe respiratory complications due to the novel coronavirus. A marked inflammatory response early in the course of AP can lead to organ failure and the development of a compensatory anti-inflammatory response syndrome, a state of immune exhaustion[ 9 ], preventing a strong inflammatory response to SARS-CoV It has also been postulated that the immune response in AP, determined by individual genetic factors, can also modulate the inflammatory response to SARS-CoV-2 and that COVID may be associated with a milder course in most of these cases, especially in younger patients.

However, careful monitoring is advised as many COVID patients may pose specific and unpredictable challenges. These sequelae are also recognized as indirect signs of pancreatic lesion in COVID patients, which have a higher incidence than previously considered and can develop even in milder cases. Wang and colleagues[ 27 ], in a retrospective analysis, indicated that 6 of 9 patients with COVID pneumonia and pancreatic injury developed blood glucose abnormalities and Gadiparthi et al [ 28 ] reported an AP case with new-onset type 2 diabetes.

Exocrine insufficiency was not mentioned in the included cases, and to the best of our knowledge, no other pancreas-related sequelae are currently reported in the literature. Further studies and follow-up of patients with presumed COVIDinduced AP are needed to evaluate the incidence and prognosis of these sequelae. The paucity of published literature associated with short follow-up periods and some inconsistent findings, have rendered prognostic evaluation in this subset of patients difficult to determine.

This review had some limitations. The case reports included in our review have a risk of bias, as certain clinical information was not included and none of the case reports were written according to CARE guidelines[ 29 ].

The etiologic work-up of some of these patients was also incomplete when considering current guidelines, and the attribution of SARS-CoV-2 as the causative agent of AP in some causes may be abusive. Adherence to AP guidelines, namely diagnosis and etiological work-up, and careful monitoring of patients are of utmost importance to ensure the most adequate orientation and avoid convenience diagnosis.

Prediction of disease course, assessment of disease severity in the background of COVID and overall outcome when these two entities coexist are some of the most pertinent open research questions.

To explore current literature and provide a concise overview of the current evidence as well as possible mechanisms of pancreatic injury in coronavirus disease COVID patients. To provide an overview of current evidence on AP in COVID patients and to promote and enhance future studies on this special subset of patients.

Available studies on AP in COVID patients present important limitations and mechanisms of pancreatic injury are debatable and not completely understood. Conflict-of-interest statement: The authors declare no conflicts of interest. Manuscript source: Invited manuscript.

Peer-review started: January 10, First decision: February 14, Article in press: June 1, Specialty type: Gastroenterology and hepatology.

Grade A Excellent : A. Grade B Very good : B, B. National Center for Biotechnology Information , U. World J Gastrointest Surg. Published online Jun Author information Article notes Copyright and License information Disclaimer. Published by Baishideng Publishing Group Inc. All rights reserved. This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. This article has been cited by other articles in PMC.

RESULTS A literature review revealed a growing body of evidence on SARS-CoVinduced pancreatic lesions including the mechanisms of direct virus-mediated injury, systemic inflammatory response and circulating pro-inflammatory interleukins, virus-induced lipotoxicity, and drug-induced injury.

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