key: cord-0825566-05xouhcc
authors: Piemonti, Lorenzo; Landoni, Giovanni
title: COVID‐19 and islet transplantation: different twins
date: 2020-05-13
journal: Am J Transplant
DOI: 10.1111/ajt.16001
sha: 63beee0505e2d7f197603d15abda547febdf453d
doc_id: 825566
cord_uid: 05xouhcc

For those who work in the field of islet transplantation, the micro vascular COVID‐19 lung vessels obstructive thrombo‐inflammatory syndrome (recently referred to as MicroCLOTS) is familiar, as one cannot fail to recognize the presence of similarities with the instant blood mediated inflammatory reaction (IBMIR) occurring in the liver hours and days after islet infusion. Evidences in both MicroCLOTS and IBMIR suggest the involvement of the coagulation cascade and complement system activation, and proinflammatory chemokines/cytokines release. Identification and targeting of pathway(s) playing a role as “master regulator(s)” in the post‐islet transplant detrimental inflammatory events could be potentially useful to suggest innovative COVID‐19 treatments and vice versa. All the scientific organizations across the world are fighting the COVID‐19 pandemic. Islet transplantation, and more generally the transplantation scientific community, could contribute suggesting strategies for innovative approaches. At the same time, in the near future, clinical trials in COVID‐19 patients will produce an enormous quantity of clinical and translational data on the control of inflammation, and complement/microthrombosis activation. These data will represent a legacy to be transformed into innovation in the transplant field. It will be our contribution to change a dramatic event into advancement for the transplant field, and ultimately for our patients.

reaction and by micro vascular pulmonary thrombosis (3) . This implies that part of the tissue damage in patients with SARS-CoV-2 infection is likely due to the activation of the complement cascade and innate immune reaction. The first pathophysiologic steps that are hypothesized are cellular damage induced by the viral replication with release of proinflammatory alarmins, activation of resident macrophages, activation of the complement cascade through the lectin pathways or locally formed immune complexes (4, 5) . These events not only directly cause damage, but further recruit leucocytes responsible of a massive release of proinflammatory cytokines and additional severe vascular endothelial cell damage associated with micro vascular thrombosis (6) . The name of microvascular COVID-19 lung vessels obstructive thromboinflammatory syndrome (MicroCLOTS) was recently proposed to define these pathophysiologic chain of events (5) . According to this model, preliminary studies have shown that SARS-CoV-2 infection triggers a cytokine storm, which, in turn, increases the levels of a variety of cytokine/chemokine (7) (8) (9) . Increased circulating levels of inflammation biomarkers were found in patients with COVID-19 pneumonia, including C-reactive protein (CRP), ferroprotein, erythrocyte sedimentation rate (ESR) and interleukin-6 (IL-6) (10) . Furthermore, patients in ICU had documented higher cytokine levels of interleukin-2 (IL-2), interleukin-7 (IL-7), interleukin-10 (IL-10), granulocyte colony-stimulating factor (GSCF), interferon gamma-induced protein 10 (IP-10), chemokine (C-C motif) ligand 2 (CCL2), Chemokine (C-C motif) ligand 3 (CCL3), and tumour necrosis factor α (TNFα) than those of non-ICU COVID-19 patients (7) . A pattern of tissue damage consistent with complement-mediated micro vascular injury was described in the lung and/or skin of individuals who died with severe COVID-19 (11) . SARS-CoV-2 nucleocapsid protein (N protein) was found to bind the mannan-binding lectin serine protease 2 (MASP-2), the key serine protease in the lectin pathway of complement activation, resulting in aberrant complement 5 activation (4). Either suppressing complement activation or blocking the N protein:MASP-2 interaction were shown to be able to alleviate lung injury in vitro and in vivo.

Concordantly, complement hyper-activation was also observed in COVID-19 patients, and a promising suppressive effect was observed when the deteriorating patients were treated with anti-C5a monoclonal antibody (4). Moreover, significantly increased levels of D-dimer and fibrinogen/fibrin degradation products have been associated with poor prognosis of COVID-19(12). In fact, some patients with severe COVID-19 infection can develop a coagulopathy meeting criteria for Disseminated Intravascular Coagulation (DIC) with fulminant activation of

This article is protected by copyright. All rights reserved coagulation and consumption of coagulation factors (13) . Concordantly, the autoptic analysis of lung tissues of patients with COVID-19 showed the presence of fibrin thrombi of small arterial vessels (diameter < 1mm) in 33 out of 38 cases, half of them with >25% of tissue involvement (14) . For those who work in the field of islet transplantation this cascade of events is quite familiar, as one cannot fail to recognize the presence of an impressive similarity with the immunological/inflammatory reaction after the islet infusion in the portal vein (15) . Early innate inflammatory reaction strongly affects islet engraftment and survival after intraportal infusion.

This early immune response is triggered by ischemia-reperfusion injury and instant blood mediated inflammatory reaction (IBMIR) occurring hours and days after islet infusion (16) .

Evidence in both mouse model and in human counterpart suggests the involvement of coagulation (17) , complement system (18) , and proinflammatory chemokines/cytokines (19) , as in the case of MicroCLOTS (Table 1) Table- at the time of hospital admission to halt or decrease progression of respiratory insufficiency and prevent the need for intensive care support (20) . Considering other treatments under evaluation to avoid IBMIR in islet transplantation (although not yet commercially available) the CXCR2 inhibitor reparixin appears of interest (21, 22) . In fact, numerous studies have confirmed a key role

This article is protected by copyright. All rights reserved of CXCR1/CXCR2 receptor as potential therapeutic target in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) (23, 24) . Neutrophil infiltration of the lung is controlled by a complex network of chemokines that are released by a variety of cell types. Alveolar macrophages are a major source of chemokines in the alveolar space and produce IL-8, growthregulated oncogene (GRO)-related peptides and CXCL5 (also known as epithelial neutrophilactivating protein [ENA]-78) (25, 26) . High concentrations of IL-8 in bronco alveolar lavage fluid from ARDS patients are associated with increased neutrophil influx into the airspace (27) . Some studies have shown that IL-8 in BAL fluid is bound to IL-8 autoantibodies (anti-IL-8/IL-8 complexes) and BAL fluid concentrations of these complexes exhibits chemotactic and proinflammatory activity and correlate with the development and outcome of ALI (28) . In rodents, the most relevant chemokines for neutrophil recruitment into the lung are keratinocyte-derived chemokine (KC, also named CXCL1) or cytokine-induced neutrophil chemoattractant (CINC; the rat homolog to KC) and macrophage inflammatory protein-2 (MIP-2, also named CXCL2).

Similar to IL-8, CXCL1, CXCL2, lipopolysaccharide-induced CXC chemokine (LIX, also named CXCL5) and lungkine (CXCL15) bind to CXCR2. Inhibition or knockout of CXCR2 receptor diminishes neutrophil influx into the lung (29) . In contrast to the multiple CXC chemokines only two CXC chemokine receptors, CXCR1 and CXCR2 have been shown to mediate the response to CXC chemokines in human neutrophils. Whereas human CXCR1 binds to CXCL6 and CXCL8 Table 2 ). From a hematochemical standpoint, during treatment with reparixin we observed an improvement or at least stabilization of the inflammatory markers (C-reactive protein, procalcitonin, ferritin) and of the tissue damage markers (lactate dehydrogenase, aspartate and alanine aminotransferase). Based on this experience, we are now approved by the Italian Medicines Agency (AIFA) to conduct an adaptive

This article is protected by copyright. All rights reserved phase 2/3, randomized, controlled multicentre study on the efficacy and safety of reparixin for the treatment of hospitalized patients with COVID-19 pneumonia.

Safety of anti-inflammatory therapies in patients with COVID-19 pneumonia is a matter of discussion. In contrast to islet transplantation COVID-19 is an infectious disease, often in elderly patients and patients with comorbidities. There is concern that anti-inflammatory biologics and immunosuppressants might compromise viral clearance and increase the risk of bacterial or fungal super-infections. However, this concern does not seem to be confirmed by the first available evidence and there are data suggesting that the low degree of immunocompetence in patient did not induce serious complications and that it could even have offered an advantage in the prevention of sever forms (31, 32) . Preliminary analysis shows that patients with inflammatory bowel disease or rheumatoid arthritis who are already on anti-TNF treatment do not be at increased risk of respiratory or life-threatening complications from SARS-CoV-2 compared with the general population (33, 34) . Moreover, anti-inflammatory treatments in animal model with severe viral pneumonia induce beneficial effects without compromising viral clearance (35) and

decreasing the susceptibility to secondary bacterial superinfection (36) . However, concerns about safety are important when considering therapies for a new and still partially unknown disease. The possibility of a late detrimental impact of anti-inflammatory treatment in COVID-19 cannot be excluded since after respiratory viral infection, superinfections with other organisms could occur at the most severe end of the disease spectrum. In order to have an optimal risk-benefit balance, it is therefore important to identify the most suitable patient and the best time for intervention with anti-inflammatory approaches. In our experience, the first criterion is related to the ARDS severity. ARDS patients are classified as mild (200 mmHg < PaO2/FiO2 ratio ≤300 mmHg), moderate (200 mmHg < PaO2/FiO2 ratio ≤300 mmHg) or severe (PaO2/FiO2 ratio ≤100 mmHg).

Early treatment with anti-inflammatory drugs should be limited to hospitalized patients with mildmoderate ARDS, while the indication for treatment in patients with severe ARDS requiring mechanical ventilation must be considered with extreme caution. The second criterion is the presence of an hyper-inflammatory state documented by the following: lactate dehydrogenase (LDH) > normal range, C-reactive protein (CRP) ≥ 100mg/L or IL-6 ≥ 40pg/mL, serum ferritin ≥ 900ng/mL, serum crosslinked fibrin (XDP) >20mcg/mL. The third criterion is the absence of uncontrolled bacterial/fungal infection, of severe comorbidities and conditions at high risk of immediate infectious complications (such as diverticulitis).

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We have a lot to learn on the treatment of IBMIR from the results that will be obtained in the COVID-19 treatment trials. In fact, the COVID-19 pandemic is pushing the clinical test of many potentially useful treatments. Among these, the treatment with anti-IL-6 is of great interest. IL-6 is a soluble mediator that has roles both as a pro-inflammatory cytokine and as anti-inflammatory cytokine, including various biological effects on inflammation, immune response, and haematopoiesis. Preliminary data suggest that the treatment with humanized anti-human inteleukine-6 receptor antibodies tocilizumab or sarilumab is associated with an improvement in respiratory and laboratory parameters and could be a safe option in hospitalized adult patients with The role of anti-IL-6 therapy in islet transplantation is still controversial. In the pig to Non-Human Primate (NHP) islet xenotransplantation model, the anti-IL-6 tocilizumab can delay revascularization of the transplanted islets, although this effect had no significant correlation to the overall islet graft survival (39) , and in some reports IL-6 was shown to protect pancreatic islets from inflammatory cytokine-induced cell death and functional impairment, both in vitro and in vivo (40) . On the other hand, IL-6 has been reported to amplify activation of coagulation through

This article is protected by copyright. All rights reserved up-regulation of tissue factor on innate immune cells and resulted as one of the most relevant factor released after intraportal islet infusion (22) . The result of the effect of IL-6 blockade on MicroCLOTS will likely support considering the use of this molecule in the field of islet transplantation. Similarly, the Janus kinase inhibitor efficacy is likely to be of great interest. In fact, the JAK3 inhibitor tofacitinib was recently suggested as a possible replacement for tacrolimus in a highly translatable NHP islet transplantation model, and good results in COVID-19 treatment would accelerate its incorporation in human allogeneic islet transplantation protocols (41) .

In conclusion, all the scientific organizations across the world are fighting the COVID-19 pandemic. Islet transplantation, and more generally the transplantation scientific community, could contribute to this fight suggesting strategies for innovative approaches. At the same time, in the near future an enormous quantity of clinical and translational data will be available on the control of inflammation, complement activation and microtrombosis activation. These data will represent a legacy that it will be our responsibility to transform into innovation in the transplant field. It will be our contribution to change a dramatic event into advancement for the transplant community, and ultimately for our patients.

This article is protected by copyright. All rights reserved 

This article is protected by copyright. All rights reserved 

A Novel Coronavirus from Patients with Pneumonia in China

Covid-19 Does Not Lead to a "Typical" Acute Respiratory Distress Syndrome

Advances in COVID-19: the virus, the pathogenesis, and evidence-based control and therapeutic strategies

Highly pathogenic coronavirus N protein aggravates lung injury by MASP-2-mediated complement over-activation

Microvascular COVID-19 lung vessels obstructive thromboinflammatory syndrome (MicroCLOTS): an atypical acute respiratory distress syndrome working hypothesis

Thromboinflammation and the hypercoagulability of COVID-19

Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

The pathogenesis and treatment of the `Cytokine Storm' in COVID-19

Exuberant elevation of IP-10, MCP-3 and IL-1ra during SARS-CoV-2 infection is associated with disease severity and fatal outcome

Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study

Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: A report of five cases

Accepted Article with COVID-19 in Wuhan, China: a retrospective cohort study

Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia

Pulmonary post-mortem findings in a large series of COVID-19 cases from Northern Italy

Anti-inflammatory strategies to enhance islet engraftment and survival

Control of instant blood-mediated inflammatory reaction to improve islets of Langerhans engraftment

Evaluate Safety and Efficacy of Low Molecular Weight Sulfated Dextran in Islet Transplantation

The role and regulation of complement activation as part of the thromboinflammation elicited in cell therapies

Intrahepatic Islet Transplantation: A Comparative Study in Preclinical Models

Trials of anti-tumour necrosis factor therapy for COVID-19 are urgently needed

Targeting CXCR1/2 Does Not Improve Insulin Secretion After Pancreatic Islet Transplantation: A Phase 3, Double-Blind, Randomized, Placebo-Controlled Trial in Type 1 Diabetes

CXCR1/2 inhibition enhances pancreatic islet survival after transplantation

Chemokines in acute respiratory distress syndrome

Imbalance in the expression of CXC chemokines correlates with bronchoalveolar lavage fluid angiogenic activity and procollagen levels in acute respiratory distress syndrome

Neutrophil emigration in the skin, lungs, and peritoneum: different requirements for CD11/CD18 revealed by CD18-deficient mice

Role of protein synthesis and CD11/CD18 adhesion complex in neutrophil emigration into the lung

Increased interleukin-8 concentrations in the pulmonary edema fluid of patients with acute respiratory distress syndrome from sepsis

Proinflammatory activity of anti-IL-8

IL-8 complexes in alveolar edema fluid from patients with acute lung injury

Therapeutic inhibition of CXCR2 by Reparixin attenuates acute lung injury in mice

The functional significance behind expressing two IL-8 receptor types on PMN

COVID-19: consider cytokine storm syndromes and immunosuppression

COVID-19 in long-term liver transplant patients: preliminary experience from an Italian transplant centre in Lombardy

Clinical course of COVID-19 in a series of patients with chronic arthritis treated with immunosuppressive targeted therapies

Outcomes of COVID-19 in 79 patients with IBD in Italy: an IG-IBD study

Inhibition of tumor necrosis factor reduces the severity of virus-specific lung immunopathology

Lowering the threshold of lung innate immune cell activation alters susceptibility to secondary bacterial superinfection

Accepted Article off-label use of tocilizumab in severe patients with COVID-19

Effective treatment of severe COVID-19 patients with tocilizumab

Delayed revascularization of islets after transplantation by IL-6 blockade in pig to non-human primate islet xenotransplantation model

IL-6 protects pancreatic islet beta cells from proinflammatory cytokines-induced cell death and functional impairment in vitro and in vivo

JAK3 inhibitor-based immunosuppression in allogeneic islet transplantation in cynomolgus monkeys

We thank Dr Marina Scavini for the careful revision of the manuscript. We dedicate this work to all health professionals in the world who lost their lives caring for COVID-19 patients.Authors' contribution: GL and LP equally contributed to the writing of the manuscript.Conflicts of Interest: The authors of this manuscript have no conflicts to describe as defined by the American Journal of Transplantation.

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Accepted Article