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Item Rhinorrhea and increased chloride secretion through the CFTR chloride channel-a systematic review(2023) Eisenhut, MAbstract Purpose: Allergic and non-allergic rhinorrhea in the forms of acute or chronic rhinosinusitis can mean a watery nasal discharge that is disabling. Primary objective was to review the evidence supporting the hypothesis that rhinorrhea is due to increased chloride secretion through the CFTR chloride channel. Methods: The structure of the evidence review followed the EQUATOR Reporting Guidelines. Databases searched from inception to February 2022 included Pubmed, EMBASE and the Cochrane library using keywords "Rhinorrhea", "chloride", "chloride channel", "CFTR" and "randomized controlled trial". Quality assessment was according to the Oxford Centre for Evidence-based Medicine. Results: 49 articles were included. They included randomized controlled trials out of which subsets of data with the outcome of rhinorrhea on 6038 participants were analysed and in vitro and animal studies. The review revealed that drugs, which activate CFTR are associated with rhinorrhea. Viruses, which cause rhinorrhea like rhinovirus were found to activate CFTR. The chloride concentration in nasal fluid showed an increase in patients with viral upper respiratory tract infection. Increased hydrostatic tissue pressure, which is an activator of CFTR was observed in allergic upper airway inflammation. In this condition exhaled breath condensate chlorine concentration was found to be significantly increased. Drugs, which can reduce CFTR function including steroids, anti-histamines, sympathomimetic and anticholinergic drugs reduced rhinorrhea in randomized controlled trials. Conclusions: A model of CFTR activation-mediated rhinorrhea explains the effectiveness of anticholinergic, sympathomimetic, anti-histamine and steroid drugs in reducing rhinorrhea and opens up avenues for further improvement of treatment by already known specific CFTR inhibitors. Keywords: Chloride channel; Cystic fibrosis transmembrane conductance regulator; Hydrostatic interstitial tissue pressure; Rhinorrhea; Transudate; Vasodilatation. © 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature. PubMed Disclaimer Similar articles Potentiators (specific therapies for class III and IV mutations) for cystic fibrosis. Skilton M, Krishan A, Patel S, Sinha IP, Southern KW. Cochrane Database Syst Rev. 2019 Jan 7;1(1):CD009841. doi: 10.1002/14651858.CD009841.pub3. PMID: 30616300 Free PMC article. Resveratrol ameliorates abnormalities of fluid and electrolyte secretion in a hypoxia-Induced model of acquired CFTR deficiency. Woodworth BA. Laryngoscope. 2015 Oct;125 Suppl 7(0 7):S1-S13. doi: 10.1002/lary.25335. Epub 2015 May 6. PMID: 25946147 Free PMC article. Potentiators (specific therapies for class III and IV mutations) for cystic fibrosis. Patel S, Sinha IP, Dwan K, Echevarria C, Schechter M, Southern KW. Cochrane Database Syst Rev. 2015 Mar 26;(3):CD009841. doi: 10.1002/14651858.CD009841.pub2. Update in: Cochrane Database Syst Rev. 2019 Jan 07;1:CD009841. doi: 10.1002/14651858.CD009841.pub3. PMID: 25811419 Review. Resveratrol enhances airway surface liquid depth in sinonasal epithelium by increasing cystic fibrosis transmembrane conductance regulator open probability. Zhang S, Blount AC, McNicholas CM, Skinner DF, Chestnut M, Kappes JC, Sorscher EJ, Woodworth BA. PLoS One. 2013 Nov 25;8(11):e81589. doi: 10.1371/journal.pone.0081589. eCollection 2013. PMID: 24282612 Free PMC article. CFTR chloride channel drug discovery--inhibitors as antidiarrheals and activators for therapy of cystic fibrosis. Verkman AS, Lukacs GL, Galietta LJ. Curr Pharm Des. 2006;12(18):2235-47. doi: 10.2174/138161206777585148. PMID: 16787252 Review. See all similar articles References Eccles R (2005) Understanding the symptoms of the common cold and influenza. Lancet Infect Dis 5(11):718–725 - PubMed - PMC - DOI Pfaar O, Raap U, Holz M, Hörmann K, Klimek L (2009) Pathophysiology of itching and sneezing in allergic rhinitis. Swiss Med Wkly 139(3–4):35–40 - PubMed Saint-Criq V, Gray MA (2017) Role of CFTR in epithelial physiology. Cell Mol Life Sci 74(1):93–115 - PubMed - DOI Vitzthum C, Clauss WG (1848) Fronius M (2015) Mechanosensitive activation of CFTR by increased cell volume and hydrostatic pressure but not shear stress. Biochim Biophys Acta 11 Pt A:2942–2951 Solymosi EA, Kaestle-Gembardt SM, Vadász I, Wang L, Neye N, Chupin CJ et al (2013) Chloride transport-driven alveolar fluid secretion is a major contributor to cardiogenic lung edema. Proc Natl Acad Sci U S A 110(25):E2308-23163 - PubMed - PMC - DOI Show all 49 references Publication types Systematic Review Review MeSH terms Animals Chloride Channels* Chlorides Cystic Fibrosis Transmembrane Conductance Regulator* Nasal Mucosa / metabolism Randomized Controlled Trials as Topic Sympathomimetics Substances Chloride Channels Cystic Fibrosis Transmembrane Conductance Regulator Chlorides Sympathomimetics Related information Gene Gene (GeneRIF) MedGen Protein (RefSeq) PubChem Compound (MeSH Keyword) LinkOut - more resources Full Text Sources SpringerItem SARS-CoV-2 vaccine-induced immune thrombotic thrombocytopenia: A comprehensive review, release 2 (immunologic perspective)(2023) Tizaoui, Kalthoum; Zidi, Ines; Rahmati, Masoud; Koyanagi, Ai; Kronbichler, Andreas; Eisenhut, Michael; Shin, Jae Il; Smith, LeeAbstract Thromboembolism remains an extremely rare side effect of COVID-19 vaccination, and the benefits of vaccination against COVID-19 continue to outweigh the risks of side effects. The scientific community should have confidence in the safety of the SARS-CoV-2 vaccines when considering solutions to unwanted side effects. This study explores the intricate immunological pathways associated with vaccine-induced immune thrombotic thrombocytopenia (VITT), focusing on the COVID-19 vaccine. The development of VITT is linked to thrombosis, where viral proteins and free DNA in the vaccine bind to platelet factor 4, generating a neo-antigen that induces the production of antibodies promoting platelet activation and clotting. The study sheds light on the complex immunological responses contributing to VITT and its distinction from related syndromes. Keywords: COVID-19; SARS-CoV-2; vaccine; vaccine-induced immune thrombotic thrombocytopenia; public health; virology 1. Introduction Vaccines, like infections, activate the immune system which could eventually trigger the development of an autoimmune disorder like ITP (immune thrombocytopenic purpura) or TTP (thrombotic thrombocytopenic purpura) or Guillain–Barre syndrome.[1] In thrombosis, viral proteins and free DNA in the vaccine bind to platelet factor 4 (PF4) to generate a neo-antigen that subsequently leads to the development of antibodies promoting platelets activation and clotting.[1] Platelets function as immune cells in conjunction with white blood cells, targeting invading pathogens and inducing immune reactions. Intercellular communications among these immune cells are partly mediated by platelet polyphosphate (polyP), which was originally recognised as a thrombotic and haemostatic biomolecule.[2] Platelets are activated by Immunoglobulin G (IgG) through FcγRIIA (also known as CD32a).[2] PF4-polyphosphates-Ig immune complexes bind to FcγRIIA on the surface of platelets and thus cross-link these receptors, inducing platelet activation and perpetuating over time a platelet activation/consumption and prothrombotic state even without the presence of heparin.[3] Polyphosphates contained in the dense granules of platelets are able to induce autoactivation of Factor XII and trigger the contact phase-dependent coagulation cascade.[4] Thromboembolic events are probably caused by impaired binding of clotting factor X to the viral capsid. The unprotected capsid then stimulates an immune response leading to platelet activation, increased thrombogenicity, and formation of an antibody complex with PF4. Impaired factor X binding may be due to an undiagnosed mutation in affected individuals.[5] 2. Potential molecular mechanisms resulting in VITT After secretion, PF4 may bind other ligands with higher affinity, such as endothelial-derived perlecan heparan sulphate side chains.[5] It is thought that the polyanions allow conformational changes in PF4 exposing antigenic determinants for anti-PF4 IgG antibodies.[6] It is possible that antibodies are induced by continued viral infection, and that the adenoviral vector itself activates platelets and provides an early trigger for PF4 secretion. These strong antibodies, if released in sufficient titers, are able to aggregate PF4 in a ligand-independent manner.[7] After vaccination and consequent possible viraemia, ChAdOx1 nCov-19 particles, can directly reach different cell types, including platelets and endothelial cells, causing severe thrombocytopenia.[7] Greinacher et al. observed a strong activation of platelets by ChAdOx1 nCov-19.[8] Positively charged structures on the AdV surface that bind negatively charged glycosaminoglycans, might elicit antibodies cross-reacting with PF4, which would explain that both PF4 and the AdV components of the vaccine enhance platelet activation.[8] It remains to be determined whether the antibodies found are auto-antibodies against PF4 induced by the strong inflammatory stimulus of vaccination or vaccine-induced antibodies that cross-react with PF4 and platelets.[8] Pang and collaborators proposed five potential anionic substances of the ChAdOx1-S vaccine that can combine with PF4 and trigger VITT, including (1) the proteins on the surface of adenovirus, e.g., negative charged glycoprotein; (2) the adjuvant components of the vaccine, e.g., Tween 80; (3) the DNA of adenovirus; (4) the S protein antigen expressed by the vaccine; and (5) the negatively charged impurity proteins expressed by the vaccine, e.g., adenovirus skeleton proteins. After analyzing each case, they considered that the most likely trigger was a negatively charged impurity proteins expressed by the vaccine. Accordingly, the susceptible individuals of VITT after ChAdOx1-S vaccination may be those expressing negatively charged impurity proteins that could be detected in the sera of VITT patients by quantitative proteomics, or by isolating and purifying the cations of the impurity proteins and testing their PF4 binding capacity.[9] Recently, Kanack and collaborators revealed the difference between the development of platelet-activating anti-PF4 antibodies and the thrombotic thrombocytopenia syndrome seen after ChAdOx1 nCoV-19 and Ad26.COV2.S vaccination and Heparin induced thrombocytopenia (HIT) [9], indicating that clonally restricted anti-PF4 antibodies mediate vaccine-induced immune thrombotic thrombocytopenia (VITT) while polyclonal anti-PF4 antibodies mediate HIT. In VITT, the strong immune response may result in the activation of a single or few pre-existing anti-PF4 reactive clones, and development of clonally restricted anti-PF4 antibodies with a similar pathophysiology to spontaneous HIT.[9] 3. Immunologic responses Anti-PF4/polyanion IgG-mediated thrombus formation in patients with VITT is accompanied by a massive innate immune activation, and particularly the fulminant activation of neutrophils including NETosis (Fig. 1). Intravascular administration of AdV-S induces both innate and adaptive immune responses characterized by increased levels of cytokines and chemokines. Thus, intravascular application of AdV-based vaccines induced inflammatory responses, as well as interaction with platelets, endothelial cells, and the coagulation cascade.[10] Thus, AdV-S vaccine such as ChAdOx1 nCoV-19 may contribute to thrombocyte activation.[9] A post-mortem study of VITT showed large venous vessels involvement in thrombotic occlusions in the microcirculation of multiple organs as well as increased inflammatory infiltrates, suggesting a progression of an inflammatory process that culminates in microvascular injury of multiple organs by iatrogenic activation of the innate immune system along with the complement system.[11] ChAdOx1 leads to an inflammatory response with increased levels of interleukin (IL)-6.[12] In hospitalised patients with COVID-19, prothrombotic antibodies that activate neutrophils, platelets, and endothelium have been identified.[12] lc-3-0-17-g1Fig. 1. Potential mechanisms of VITT. VITT, vaccine induced thrombosis with thrombocytopenia; TTS, thrombosis with thrombocytopenia syndrome; HIT, heparin induced thrombocytopenia.Download Original Figure Immune assays and immune cell phenotyping by flow cytometry analyses and immunoprecipitation with anti-PF4 antibody in plasma samples followed by mass spectrometry revealed circulating inflammatory markers.[13] Precipitated immune complexes indicated that multiple innate immune pathways trigger platelet and leucocyte activation. In plasma samples, levels of innate immune response cytokines and markers of systemic inflammation increased, alongside extensive degranulation of neutrophils, formation of neutrophil extracellular traps (NETs), IgG deposits, increased levels of circulating H3Cit, dsDNA, and myeloperoxidase (MPO)–DNA complex. Indirect signs of NET formation in peripheral blood of patients are found including H3Cit, dsDNA, and MPO–DNA complex as opposed to healthy controls and vaccinated healthcare workers without signs of thrombus formation, and tissue and endothelial damage.[13] The study highlighted that the role of innate immune responses in VITT includes an unusual fulminant focal neutrophil activation in cell-rich thrombi as well as systemic activation of leucocytes and circulating cytokines, free nucleic acids, and acute phase reactants. Increased levels of the alarmins S100A8 and S100A9 were observed both in circulation and in the sinus thrombus.[13] NETs, consisting of neutrophil-derived chromatin associated with pro-coagulant proteins and antimicrobial proteins, such as MPO or neutrophil elastase are present abundantly in thrombotic events. COVID-19 is characterised by a high prevalence of thrombotic complications.[13] PF4 can bind and aggregate DNA (as a polyanion) and amplify toll-like receptor 9 (TLR9) signalling by organising fragmented DNA into liquid-crystalline integrated circuis with inter-DNA spacings optimal for TLR9 amplification. This suggests a positive feedback loop that would be further stabilised by anti-PF4 IgG. Thus, it is likely that the FccRIIA, complement C5a receptor 1, and TLR9 signalling converged in a massive activation of neutrophils in the patients.[13] In VITT, this might be caused by platelets’ direct activation by the ChAdOx1 nCoV-19 adenoviral vector vaccine degranulation and PF4/glycosaminoglycan secretion, exchange of glycosaminoglycan with an unknown polyanion, generation of IgG against PF4/polyanion. The chemokine PF4/polyanion activates leucocytes via the CXCR3-B splice variant of CXCR3 and CCR1.[14] Following the formation of PF4—adenovirus complexes, T cell, especially within the CD4+ subset, responses against prior adenovirus infections may provide help to B cells in the generation of anti-PF4 response.[15] The strong proinflammatory T cell responses induced by vaccination could also induce the anti-PF4 antibody response in VITT, as IL-10–producing regulatory T cells have been demonstrated to suppress PF4/heparin-specific antibody responses during HIT in mice.[16] It has been shown that SARS-CoV-2infections itself can also induce a diverse array of functional auto-antibodies in the host.[16] Future studies should profile autoantibody production resulting from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and the proposed autoantibodies resulting from vaccination to establish any possible links between the presence of autoantibodies and thromboembolic events. 4. Therapeutic approach based on immunology 4.1 Intravenous Immunoglobulin (IVIg) To address proper treatment, it is important to diagnose VITT and to exclude other potential causative factors resembling the disease. Based on its resemblance with HIT, several therapeutics have been proposed to manage VITT, but results are uncertain and research is still ongoing. PCR testing has shown negative SARS-CoV-2 infection in many but not all patients with VITT. Therefore, whether VITT is an atypical form of COVID-19 requires further studies.[17] Management of VITT generally includes heparin avoidance, use of alternative (non-heparin) anticoagulants, and intravenous immunoglobulin. The antibodies involved in thrombocytopenia after AdV-S vaccination occurred without any prior heparin therapy, and their effect on platelet activation was rather blocked by heparin.[17] In VITT, heparin should be avoided as it is difficult to exclude cross-reactivity between pre-existing antibodies and PF4/H complexes.[18] An important treatment for both HIT and for VITT is IVIgs, a known inhibitor of FcγRIIA.[18] A body of evidence from non-randomised trials and retrospective studies suggests that IVIg may be an effective treatment of VITT, although sometimes not effective as a single agent. Recent articles reported successful treatment of VITT using IVIg, which prevents platelet activation by anti-PF4 antibodies. IVIg treatment parallels emerging experience in the treatment of severe autoimmune HIT in which high-dose IVIg has resulted in rapid increases in platelet count and de-escalation of hypercoagulability.[18] Thus, IVIg is proposed as a therapeutic agent for VITT due to its success in treating autoimmune HIT. 4.2 Low-molecular-weight heparin (LMWH) Three cerebral venous sinus thrombosis cases reported by Wolf et al. were managed by heparinisation and endovascular recanalization of the venous sinuses.[18] Under treatment with LMWH, platelet counts normalised within several days, and the patients survived and underwent rehabilitation.[18] In the HEP-COVID randomised clinical trial, therapeutic LMWH dose reduced the composite of thromboembolism and death compared with standard heparin thromboprophylaxis without increasing the frequency of major bleeding among hospitalised patients with COVID-19.[19] The type of anticoagulant may play a role, as a therapeutic dose of LMWH may exert pleiotropic effects such as anti-inflammatory, immunomodulatory, and antiviral effects, in addition to its antithrombotic properties, whereas small-molecule direct oral anticoagulants may lack these properties.[20] 4.3 Mix of treatments VITT is a novel disease with diverse clinical features, and multiple therapeutic modalities. Non-heparin anticoagulants and immunoglobulins may help treat VITT/TTS.[21] Anticoagulation alone or in combination with eculizumab or IVIg resolved the pathology in three patients.[21] Treatment with fondaparinux, IVIg, and prednisone led to a marked improvement of VITT. Treatments including IVIg, methylprednisolone and direct oral anticoagulant improved VITT gradually.[22] Patients with VITT were treated successfully with IVIg, non-heparin anticoagulants and corticosteroids. Although it is difficult to assess response to treatment in patients with VITT-associated cerebral venous thrombosis in a purely observational study, both non-heparin anticoagulants and IVIg were associated with better outcomes.[23] Both high-dose IVIg (2g/kg body weight over 2 to 5 days) and the potent thrombin inhibitor argatroban are potent agents to block the two fundamental steps triggering TTS: platelet activation (FcγRIIA ligation by PF4-polyanions-IgG complex) and activation of the coagulation cascade (FXII activation by polyphosphates).[23] In severe cases such as severe thrombocytopenia and thrombosis, plasma exchange may be considered along with high-dose IVIg in addition to anticoagulant treatment. 5. Potential alternatives for VITT treatment Greinacher et al. tested another potential therapeutic, the spleen tyrosine kinase (SYK) inhibitor fostamatinib that is currently used for the treatment of chronic immune thrombocytopenia.[24] The FcγRIIA-dependent signalling mechanism leading to platelet activation in VITT identified by Greinacher et al. provides strong rationale to consider SYK inhibition in the limited therapeutic armamentarium treating VITT and perhaps other forms of autoantibody-mediated thrombosis.[24] Fostamatinib inhibits activation of the Fc receptor by antigen/antibody complexes, and reduced NETosis and platelet activation in ex-vivo COVID-19 studies.[25] Orally administered fostamatinib reduced adverse events and showed a trend toward clinical benefit.[26] Vayne and collaborators developed a chimeric IgG1 anti-PF4 antibody, 1E12, which strongly mimics “autoimmune” HIT antibodies in terms of specificity and cellular effects, and could be used as a model antibody to study the pathophysiology of VITT.[26] They evaluated the capability of DG-1E12, a deglycosylated form of 1E12 unable to bind Fc receptor, to inhibit cellular activation induced by VITT antibodies. DG-1E12 may allow the development of a new drug neutralising the pathogenic effect of autoimmune anti-PF4 antibodies, such as those associated with VITT. Afkhami et al. used adenoviral vectors of human and chimpanzee origin, and evaluated Ad-vectored trivalent COVID-19 vaccines expressing spike-1, nucleocapsid, and RNA-dependent RNA polymerase antigens in murine models.[27] Single-dose intranasal immunization, particularly with chimpanzee adenoviral vectored vaccine, is superior to intramuscular immunization in induction of the tripartite protective immunity consisting of local and systemic antibody responses, mucosal tissue-resident memory T cells and mucosal trained innate immunity. They further showed that intranasal immunisation provides protection against the ancestral SARS-CoV-2. Respiratory mucosal delivery of Ad-vectored multivalent vaccine represents an effective next-generation COVID-19 vaccine strategy to induce wide-spread mucosal immunity.[27] Immunothrombosis is driven by the complement/tissue factor/neutrophil axis, as well as by activated platelets, which can trigger the release of NETs and release further effectors of immunothrombosis, including PF4/CXCL4 and high-mobility box 1 protein (HMGB1).[28] Many of the central effectors of deregulated immunothrombosis, including activated platelets and platelet-derived extracellular vesicles (pEVs) expressing PF4, soluble PF4, HMGB1, histones, as well as histone-decorated NETs, are positively charged and thus bind to heparin. The authors provide evidence that adsorbents functionalised with endpoint-attached heparin efficiently deplete activated platelets, pEVs, PF4, HMGB1 and histones/nucleosomes. They suggested that elimination of central effectors of immunothrombosis, rather than binding directly to pathogens, could be a clinically relevant strategy for mitigating thrombotic complications of sepsis or COVID-19 using heparin-functionalised adsorbents.[28, 29] 6. Conclusions and perspectives Although scientists around the world have rapidly developed effective vaccines to fight COVID-19, many factors such as the mechanism and risk of VITT remain uncertain. Rare life-threatening thrombotic manifestations appear to occur with all four vaccines, with differences in frequency and mechanism that need further investigation. ChAdOx1 nCoV-19 and in second position, Ad26.COV2-S vaccines showed the most frequent adverse reactions by triggering severe thrombosis. Scientists explained this phenomenon as caused by impurities related to vaccine preparation. VITT is a rare and severe reaction that causes the extreme activation of platelets and coagulation with a high risk of death. Diagnosis should be guided by standardised definitions, and should also take into account early and seemingly atypical presentations. Particularly, identification, quantification and molecular mechanisms of platelets have attracted increasing attention and suggested platelets as new biomarkers for diagnostic and therapeutic strategies in VITT. NETs, cytokines and interleukins are implicated in VITT pathogenesis, indicating intense innate immune activation. Non-heparin anticoagulants along with IVIg show effectiveness to treat VITT. Important next steps in optimising the management of this novel condition will include defining the optimal duration of anticoagulant treatment and determining the long-term outcomes among affected patients. Other alternatives for vaccination and treatment are always possible. Actually, only vaccines administered intramuscularly and designed to only target the spike protein were experienced. However, there is a pressing need to develop next-generation vaccine strategies for broader and long-lasting protection. Respiratory mucosal delivery of adenoviral vectored multivalent vaccine represents an effective next-generation COVID-19 vaccine strategy to induce all-around mucosal immunity. Although VITT is successfully diagnosed and several immunologic mechanisms were identified, many questions remain: What is the protein(s) in the vaccine that binds to PF4? What is the precise neoantigen generated when PF4 and vaccine components interact? Do human proteins in the vaccine provoke an immune response? Is the prothrombotic antibody repertoire in VITT limited to PF4, the vaccine and its components, or is there overlap with autoantibodies found in acute COVID-19, autoimmune disease, and other critical illnesses? With ongoing research, other questions are arising, and answering implicates development of vaccines and therapeutics that use adenovirus- and other virus-based vectors. Thromboembolism remains an extremely rare side effect of COVID-19 vaccination, and the benefits of vaccination against COVID-19 continue to outweigh the risks of side effects. The scientific community should have confidence in the safety of the SARS-CoV-2 vaccines when considering solutions to unwanted side effects. Further analyses based on more detailed reporting of thrombotic adverse events, including patients’ characteristics and comorbidities, may allow for more specific assessment of causality. Capsule Summary The study sheds light on the complex immunological responses contributing to VITT and its distinction from related syndromes. Patient and public involvement No patients were directly involved in designing the research question or in conducting the research. No patients were asked for advice on interpretation or writing up the results. There are no plans to involve patients or the relevant patient community in dissemination at this moment. Transparency statement The leading authors (Dr. JIS) are an honest, accurate, and transparent account of the study being reported. Acknowledgements None Author Contribution All authors made substantial contributions to all of the following: (1) the conception and design of the study, or acquisition of data, and interpretation of data, (2) drafting the article or revising it critically for important intellectual content, (3) final approval of the version to be submitted. Funding None Conflicts of Interest All authors state that they have no actual or potential conflict of interest including any financial, personal, or other relationships with other people or organizations. Provenance and peer review Not commissioned; externally peer reviewed. References 1. Baumann P, Diedrich K. Thromboembolic complications associated with reproductive endocrinologic procedures. Hematol Oncol Clin North Am. 2000; 14(2):431-43 2. Uematsu T, Sato A, Aizawa H, Tsujino T, Watanabe T, Isobe K, et al. Effects of SARS-CoV-2 mRNA vaccines on platelet polyphosphate levels and inflammation: A pilot study. Biomed Rep. 2022; 16(3):21 3. Cines DB, Yarovoi SV, Zaitsev SV, Lebedeva T, Rauova L, Poncz M, et al. Polyphosphate/platelet factor 4 complexes can mediate heparin-independent platelet activation in heparin-induced thrombocytopenia. Blood Adv. 2016; 1(1):62-74 4. Maas C, Renné T. Coagulation factor XII in thrombosis and inflammation. Blood. 2018; 131(17):1903-9 5. Lord MS, Cheng B, Farrugia BL, McCarthy S, Whitelock JM. Platelet factor 4 binds to vascular proteoglycans and controls both growth factor activities and platelet activation. J Biol Chem. 2017; 292(10):4054-63 6. Cai Z, Yarovoi SV, Zhu Z, Rauova L, Hayes V, Lebedeva T, et al. Atomic description of the immune complex involved in heparin-induced thrombocytopenia. Nat Commun. 2015; 6:8277 7. Nguyen TH, Medvedev N, Delcea M, Greinacher A. Anti-platelet factor 4/polyanion antibodies mediate a new mechanism of autoimmunity. Nat Commun. 2017; 8:14945 8. Greinacher A, Thiele T, Warkentin TE, Weisser K, Kyrle PA, Eichinger S. Thrombotic thrombocytopenia after ChAdOx1 nCov-19 Vaccination. N Engl J Med. 2021; 384(22):2092-101 9. Kanack AJ, Bayas A, George G, Abou-Ismail MY, Singh B, Kohlhagen MC, et al. Monoclonal and oligoclonal anti-platelet factor 4 antibodies mediate VITT. Blood. 2022; 140(1):73-7 10. Pomara C, Sessa F, Ciaccio M, Dieli F, Esposito M, Garozzo SF, et al. Post-mortem findings in vaccine-induced thrombotic thombocytopenia. Haematologica. 2021; 106(8):2291-3 11. Willems LH, Nagy M, Ten Cate H, Spronk HMH, Jacobs LMC, Kranendonk J, et al. ChAdOx1 vaccination, blood coagulation, and inflammation: No effect on coagulation but increased interleukin-6. Res Pract Thromb Haemost. 2021; 5(8)e12630 12. Zuo Y, Estes SK, Ali RA, Gandhi AA, Yalavarthi S, Shi H, et al. Prothrombotic autoantibodies in serum from patients hospitalized with COVID-19. Sci Transl Med. 2020; 12(570) 13. Holm S, Kared H, Michelsen AE, Kong XY, Dahl TB, Schultz NH, et al. Immune complexes, innate immunity, and NETosis in ChAdOx1 vaccine-induced thrombocytopenia. Eur Heart J. 2021; 42(39):4064-72 14. Fox JM, Kausar F, Day A, Osborne M, Hussain K, Mueller A, et al. CXCL4/Platelet Factor 4 is an agonist of CCR1 and drives human monocyte migration. Sci Rep. 2018; 8(1):9466 15. Bliss CM, Bowyer G, Anagnostou NA, Havelock T, Snudden CM, Davies H, et al. Assessment of novel vaccination regimens using viral vectored liver stage malaria vaccines encoding ME-TRAP. Sci Rep. 2018; 8(1):3390 16. Zheng Y, Zhu W, Haribhai D, Williams CB, Aster RH, Wen R, et al. Regulatory T cells control PF4/heparin antibody production in mice. J Immunol. 2019; 203(7):1786-92 17. Ladner JT, Henson SN, Boyle AS, Engelbrektson AL, Fink ZW, Rahee F, et al. Epitope-resolved profiling of the SARS-CoV-2 antibody response identifies cross-reactivity with endemic human coronaviruses. Cell Rep Med. 2021; 2(1):100189 18. Thaler J, Ay C, Gleixner KV, Hauswirth AW, Cacioppo F, Grafeneder J, et al. Successful treatment of vaccine-induced prothrombotic immune thrombocytopenia (VIPIT). J Thromb Haemost. 2021; 19(7):1819-22 19. Spyropoulos AC, Goldin M, Giannis D, Diab W, Wang J, Khanijo S, et al. Efficacy and safety of therapeutic-dose heparin vs standard prophylactic or intermediate-dose heparins for thromboprophylaxis in high-risk hospitalized patients with COVID-19: The HEP-COVID randomized clinical trial. JAMA Intern Med. 2021; 181(12):1612-20 20. Gozzo L, Viale P, Longo L, Vitale DC, Drago F. The potential role of heparin in patients with COVID-19: Beyond the anticoagulant effect. A review. Front Pharmacol. 2020; 11:1307 21. Ihnatko M, Truchla I, Ihnatková L, Prohászka Z, Lazúrová I. Case report: A case of COVID vaccine-induced thrombotic thrombocytopenia manifested as pulmonary embolism and hemorrhagia. A First Reported Case From Slovakia. Front Med (Lausanne). 2021; 8:789972 22. Hsiao PJ, Wu KL, Chen YC, Chen YL, Wang RL, Wu KA, et al. The role of anti-platelet factor 4 antibodies and platelet activation tests in patients with vaccine-induced immune thrombotic thrombocytopenia: Brief report on a comparison of the laboratory diagnosis and literature review. Clin Chim Acta. 2022; 529:42-5 23. Cattaneo M. Thrombosis with Thrombocytopenia Syndrome associated with viral vector COVID-19 vaccines. Eur J Intern Med. 2021; 89:22-4 24. Strich JR, Kanthi Y. VITT(al) insights into vaccine-related clots. Blood. 2021; 138(22):2159-60 25. Strich JR, Tian X, Samour M, King CS, Shlobin O, Reger R, et al. Fostamatinib for the treatment of hospitalized adults With coronavirus disease 2019: A randomized trial. Clin Infect Dis. 2022; 75(1):e491-e8 26. Vayne C, Palankar R, Billy S, Handtke S, Thiele T, Pouplard C, et al. The deglycosylated form of 1E12, a monoclonal anti-PF4 IgG, strongly inhibits antibody-triggered cellular activation in vaccine-induced thrombotic thrombocytopenia, and is a potential new treatment for Vιττ. Blood. 2021; 138:582 27. Afkhami S, D’Agostino MR, Zhang A, Stacey HD, Marzok A, Kang A, et al. Respiratory mucosal delivery of next-generation COVID-19 vaccine provides robust protection against both ancestral and variant strains of SARS-CoV-2. Cell. 2022; 185(5):896-915.e19 28. Ebeyer-Masotta M, Eichhorn T, Weiss R, Semak V, Lauková L, Fischer MB, et al. heparin-functionalized adsorbents eliminate central effectors of immunothrombosis, including platelet factor 4, high-mobility group box 1 protein and histones. Int J Mol Sci. 2022; 23(3) 29. Hwang J, Park SH, Lee SW, Lee SB, Lee MH, Jeong GH, et al. Predictors of mortality in thrombotic thrombocytopenia after adenoviral COVID-19 vaccination: the FAPIC score. Eur Heart J. 2021; 42(39):4053-63Item Immune checkpoints and cancer immunotherapies: insights into newly potential receptors and ligands(2023) Kamali , A.N; Bautista , J.M; Eisenhut , M; Hamedifar, HAbstract Checkpoint markers and immune checkpoint inhibitors have been increasingly identified and developed as potential immunotherapeutic targets in various human cancers. Despite valuable efforts to discover novel immune checkpoints and their ligands, the precise roles of their therapeutic functions, as well as the broad identification of their counterpart receptors, remain to be addressed. In this context, it has been suggested that various putative checkpoint receptors can be induced upon activation. In the tumor microenvironment, T cells, as crucial immune response against malignant diseases as well as other immune central effector cells, such as natural killer cells, are regulated via co-stimulatory or co-inhibitory signals from immune or tumor cells. Studies have shown that exposure of T cells to tumor antigens upregulates the expression of inhibitory checkpoint receptors, leading to T-cell dysfunction or exhaustion. Although targeting immune checkpoint regulators has shown relative clinical efficacy in some tumor types, most trials in the field of cancer immunotherapies have revealed unsatisfactory results due to de novo or adaptive resistance in cancer patients. To overcome these obstacles, combinational therapies with newly discovered inhibitory molecules or combined blockage of several checkpoints provide a rationale for further research. Moreover, precise identification of their receptors counterparts at crucial checkpoints is likely to promise effective therapies. In this review, we examine the prospects for the application of newly emerging checkpoints, such as T-cell immunoglobulin and mucin domain 3, lymphocyte activation gene-3, T-cell immunoreceptor with Ig and ITIM domains (TIGIT), V-domain Ig suppressor of T-cell activation (VISTA), new B7 family proteins, and B- and T-cell lymphocyte attenuator, in association with immunotherapy of malignancies. In addition, their clinical and biological significance is discussed, including their expression in various human cancers, along with their roles in T-cell-mediated immune responses. Keywords: cancers; checkpoints inhibitors and immunotherapy; immune checkpoints. © The Author(s), 2023. PubMed Disclaimer Conflict of interest statement The authors declare that there is no conflict of interest. Figures Figure 1. Figure 1. A summarized overview of mechanisms… Similar articles Multiple myeloma and the potential of new checkpoint inhibitors for immunotherapy. Kamali AN, Hamedifar H, Eisenhut M, Bautista JM. Ther Adv Vaccines Immunother. 2024 Oct 9;12:25151355241288453. doi: 10.1177/25151355241288453. eCollection 2024. PMID: 39399301 Free PMC article. Review. Immune checkpoints and cancer development: Therapeutic implications and future directions. Mehdizadeh S, Bayatipoor H, Pashangzadeh S, Jafarpour R, Shojaei Z, Motallebnezhad M. Pathol Res Pract. 2021 Jul;223:153485. doi: 10.1016/j.prp.2021.153485. Epub 2021 May 15. PMID: 34022684 Review. Clinical Insights Into Novel Immune Checkpoint Inhibitors. Lee JB, Ha SJ, Kim HR. Front Pharmacol. 2021 May 6;12:681320. doi: 10.3389/fphar.2021.681320. eCollection 2021. PMID: 34025438 Free PMC article. Review. Novel immune checkpoint targets: moving beyond PD-1 and CTLA-4. Qin S, Xu L, Yi M, Yu S, Wu K, Luo S. Mol Cancer. 2019 Nov 6;18(1):155. doi: 10.1186/s12943-019-1091-2. PMID: 31690319 Free PMC article. Review. Manipulation of the Immune System for Cancer Defeat: A Focus on the T Cell Inhibitory Checkpoint Molecules. D'Arrigo P, Tufano M, Rea A, Vigorito V, Novizio N, Russo S, Romano MF, Romano S. Curr Med Chem. 2020;27(15):2402-2448. doi: 10.2174/0929867325666181106114421. PMID: 30398102 Review. See all similar articles Cited by Multiple myeloma and the potential of new checkpoint inhibitors for immunotherapy. Kamali AN, Hamedifar H, Eisenhut M, Bautista JM. Ther Adv Vaccines Immunother. 2024 Oct 9;12:25151355241288453. doi: 10.1177/25151355241288453. eCollection 2024. PMID: 39399301 Free PMC article. Review. Immune Checkpoints and Graves' Disease, Thyroid Eye Disease, and Orbital Myopathy: A Comprehensive Review. Souri Z, Pakdel F. J Ophthalmic Vis Res. 2024 Sep 16;19(3):368-380. doi: 10.18502/jovr.v19i3.15047. eCollection 2024 Jul-Sep. PMID: 39359534 Free PMC article. Review. Hyperoside Inhibits RNF8-mediated Nuclear Translocation of β-catenin to Repress PD-L1 Expression and Prostate Cancer. Chen J, Zhao Y, Wang X, Zang L, Yin D, Tan S. Anticancer Agents Med Chem. 2024;24(6):464-476. doi: 10.2174/0118715206289246240110044931. PMID: 38305391 References Pardoll D. Cancer and the immune system: basic concepts and targets for intervention. Semin Oncol 2015; 42: 523–538. - PMC - PubMed Castello A, Rossi S, Toschi L, et al.. Soluble PD-L1 in NSCLC patients treated with checkpoint inhibitors and its correlation with metabolic parameters. Cancers (Basel) 2020; 12: 1–8. - PMC - PubMed Dong MP, Enomoto M, Thuy LTT, et al.. Clinical significance of circulating soluble immune checkpoint proteins in sorafenib-treated patients with advanced hepatocellular carcinoma. Sci Rep 2020; 10: 3392. - PMC - PubMed Inomata M, Kado T, Okazawa S, et al.. Peripheral PD1-positive CD4 T-lymphocyte count can predict progression-free survival in patients with non-small cell lung cancer receiving immune checkpoint inhibitor. Anticancer Res 2019; 39: 6887–6893. - PubMed Ishikawa M, Nakayama K, Nakamura K, et al.. High PD-1 expression level is associated with an unfavorable prognosis in patients with cervical adenocarcinoma. Arch Gynecol Obstet 2020; 302: 209–218. - PMC - PubMed Show all 199 references Publication types Review Related information MedGen LinkOut - more resources Full Text Sources Atypon Europe PubMed Central PubMed Central Research Materials NCI CPTC Antibody Characterization ProgramItem Evolution of CD4 T-Cell Count With Age in a Cohort of Young People Growing Up With Perinatally Acquired Human Immunodeficiency Virus(2024) Castro , H; Sabin, C; Collins, I.J; Okhai, H; Schou Sandgaard , K; Prime, K; Foster , C; Le Prevost , M; Crichton, S; Klein, N; Judd , AAbstract Background: Recent studies have shown a decrease in CD4 count during adolescence in young people with perinatally acquired human immunodeficiency virus (HIV, PHIV). Methods: Young people with PHIV in the United Kingdom, followed in the Collaborative HIV Paediatric Study who started antiretroviral therapy (ART) from 2000 onward were included. Changes in CD4 count over time from age 10 to 20 years were analyzed using mixed-effects models, and were compared to published CD4 data for the gerneral population. Potential predictors were examined and included demographics, age at ART start, nadir CD4 z score (age-adjusted) in childhood, and time-updated viral load. Results: Of 1258 young people with PHIV included, 669 (53%) were female, median age at ART initiation was 8.3 years, and the median nadir CD4 z score was -4.0. Mean CD4 count was higher in young people with PHIV who started ART before age 10 years and had a nadir CD4 z score ≥-4; these young people with PHIV had a decline in CD4 count after age 10 that was comparable to that of the general population. Mean CD4 count was lower in young people with PHIV who had started ART before age 10 and had a nadir CD4 z score <-4; for this group, the decline in CD4 count after age 10 was steeper over time. Conclusions: In children, in addition to starting ART at an early age, optimizing ART to maintain a higher CD4 z score during childhood may be important to maximizing immune reconstitution later in life. Keywords: CD4 T cell; HIV; adult; child; perinatal. © The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. PubMed Disclaimer Conflict of interest statement Potential conflicts of interest. C. S. reports funding for membership on data and safety and monitoring boards advisory boards and for preparation of educational materials from Gilead Sciences, ViiV Healthcare, and MSD and a role as vice-chair (until the end of 2022) for the British HIV Association. C. F. reports research grants from ViiV Healthcare and Gilead Sciences. H. O. reports consulting fees to author from Gilead Sciences. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. Figures Graphical Abstract Graphical Abstract This graphical abstract is also… Figure 1. Figure 1. Predicted mean CD4 counts over… Figure 2. Figure 2. Predicted mean CD4 counts over… Similar articles Time-varying age- and CD4-stratified rates of mortality and WHO stage 3 and stage 4 events in children, adolescents and youth 0 to 24 years living with perinatally acquired HIV, before and after antiretroviral therapy initiation in the paediatric IeDEA Global Cohort Consortium. Desmonde S, Neilan AM, Musick B, Patten G, Chokephaibulkit K, Edmonds A, Duda SN, Malateste K, Wools-Kaloustian K, Ciaranello AL, Davies MA, Leroy V; IeDEA. J Int AIDS Soc. 2020 Oct;23(10):e25617. doi: 10.1002/jia2.25617. PMID: 33034417 Free PMC article. Rapid CD4 decline prior to antiretroviral therapy predicts subsequent failure to reconstitute despite HIV viral suppression. Darraj M, Shafer LA, Chan S, Kasper K, Keynan Y. J Infect Public Health. 2018 Mar-Apr;11(2):265-269. doi: 10.1016/j.jiph.2017.08.001. Epub 2017 Aug 18. PMID: 28826735 Neurocognitive and quality of life study in perinatally HIV-infected young people and their peers. NeuroCoRISpeS study. García-Navarro C, Martín-Bejarano M, Jimenez de Ory S, Zamora B, Ruiz-Saez B, Velo C, Cuéllar-Flores I, Garcia Lopez-Hortelano M, Guillen-Martin S, Navarro-Gómez ML, Ramos JT, González-Tomé MI; Pediatric National AIDS Research Network of Spain (CORISPE). Enferm Infecc Microbiol Clin (Engl Ed). 2020 Nov;38(9):417-424. doi: 10.1016/j.eimc.2020.01.004. Epub 2020 Feb 26. PMID: 32113706 English, Spanish. Effectiveness of antiretroviral therapy in HIV-infected children under 2 years of age. Penazzato M, Prendergast A, Tierney J, Cotton M, Gibb D. Cochrane Database Syst Rev. 2012 Jul 11;(7):CD004772. doi: 10.1002/14651858.CD004772.pub3. Update in: Cochrane Database Syst Rev. 2014 May 22;(5):CD004772. doi: 10.1002/14651858.CD004772.pub4. PMID: 22786492 Review. [Recommendations from the GESIDA/Spanish AIDS Plan regarding antiretroviral treatment in adults with human immunodeficiency virus infection (update February 2009)]. Panel de expertos de Gesida y Plan Nacional sobre el Sida. Enferm Infecc Microbiol Clin. 2009 Apr;27(4):222-35. doi: 10.1016/j.eimc.2008.11.002. Epub 2009 Feb 26. PMID: 19246124 Spanish. See all similar articles Cited by Adults with perinatally acquired HIV in low- and middle-income settings: time for a generational shift in HIV care and global guidance. Sohn AH, Davies MA. J Int AIDS Soc. 2024 Jul;27(7):e26338. doi: 10.1002/jia2.26338. PMID: 39034739 Free PMC article. No abstract available. References UNICEF data . Available at: https://data.unicef.org/topic/hivaids/adolescents-young-people/. Accessed 1 December 2022. Slogrove AL, Schomaker M, Davies M-A, et al. The epidemiology of adolescents living with perinatally acquired HIV: a cross-region global cohort analysis. PLoS Med 2018; 15:e1002514. - PMC - PubMed Chappell E, Lyall H, Riordan A, et al. The cascade of care for children and adolescents with HIV in the UK and Ireland, 2010 to 2016. J Int AIDS Soc 2019; 22:e25379. - PMC - PubMed Weijsenfeld AM, Smit C, Wit FWNM, et al. Long-term virological treatment outcomes in adolescents and young adults with perinatally and non-perinatally acquired human immunodeficiency virus. Open Forum Infect Dis 2022; 9:ofac561. - PMC - PubMed Ritchwood TD, Malo V, Jones C, et al. Healthcare retention and clinical outcomes among adolescents living with HIV after transition from pediatric to adult care: a systematic review. BMC Public Health 2020; 20:1195. - PMC - PubMed Show all 37 references Publication types Research Support, Non-U.S. Gov't MeSH terms Adolescent Anti-HIV Agents* / therapeutic use CD4 Lymphocyte Count CD4-Positive T-Lymphocytes Child Female HIV HIV Infections* / drug therapy HIV Infections* / epidemiology Humans Male Viral Load Young Adult Substances Anti-HIV Agents Related information MedGen Grants and funding MR/M004236/1/MRC_/Medical Research Council/United Kingdom LinkOut - more resources Full Text Sources Europe PubMed Central Ovid Technologies, Inc. PubMed Central Silverchair Information Systems Medical MedlinePlus Health Information Research Materials NCI CPTC Antibody Characterization ProgramItem .Clinical value of the red blood cell distribution width to albumin ratio in the assessment of prognosis in critically ill patients with sepsis: a retrospective analysis.(2024) Ma, C; Liang, G; Wang, B; Eisenhut , M; Urrechaga, E; Wiedermann , C.J; Andaluz-Ojeda , D; O'Rourke, J; Zhang, Z; Jin , X; Zhong, XAbstract Background: Red blood cell (RBC) distribution width (RDW) to albumin ratio is a novel biomarker and its prognostic effect on critically ill patients with sepsis has not been extensively investigated. The objective of this study was to identify the prognostic value of the RDW to albumin ratio in these patients. Methods: Data were extracted from the Medical Information Mart for Intensive Care III (MIMIC-III) database. A Cox proportional hazards model and restricted cubic spline model were used to determine the association of RDW to albumin ratio with mortality. Receiver operating characteristic (ROC) curves and Kaplan-Meier survival curves were applied, and the area under the curve (AUC) was used to compare the predictive value. Results: A total of 3,969 eligible patients were enrolled. The median RDW to albumin ratio was significantly higher in non-survivors than in survivors at 30 and 90 days. Patients were divided into groups according to the RDW to albumin ratio, and the risk of 30- and 90-day mortality markedly increased in the group with a higher ratio. The relationship between the RDW to albumin ratio as a continuous variable and 30-day mortality also showed an upward trend in the restricted cubic spline. The AUC of the RDW to albumin ratio was 0.633 in discriminating 30-day mortality which was similar to that of the lactate to albumin ratio (AUC =0.617; P=0.133) and higher than that of the neutrophil percentage to albumin ratio (AUC =0.559; P<0.001). Conclusions: The RDW to albumin ratio is a promising biomarker for assessing the prognosis of critically ill patients with sepsis. Its predictive value in determining mortality was found to be similar to that of the lactate to albumin ratio and superior to that of the neutrophil percentage to albumin ratio. Keywords: Sepsis; albumin; prognosis; red blood cell distribution width (RDW). 2024 Journal of Thoracic Disease. All rights reserved. PubMed Disclaimer Conflict of interest statement Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-1696/coif). C.J.W. reports fees for speaking and/or consulting from Biotest, CSL Behring, and Grifols. The other authors have no conflicts of interest to declare. Figures Figure 1 Figure 1 Flowchart of patients enrolled from… Figure 2 Figure 2 Comparison of RDW to albumin… Figure 3 Figure 3 The association between RDW to… Figure 4 Figure 4 Adjusted HR and 95% CI… Figure 5 Figure 5 Prognostic value of indicators for… Figure 6 Figure 6 Kaplan-Meier survival curve at 30… References Machado FR, Cavalcanti AB, Bozza FA, et al. The epidemiology of sepsis in Brazilian intensive care units (the Sepsis PREvalence Assessment Database, SPREAD): an observational study. Lancet Infect Dis 2017;17:1180-9. 10.1016/S1473-3099(17)30322-5 - DOI - PubMed Xie J, Wang H, Kang Y, et al. The Epidemiology of Sepsis in Chinese ICUs: A National Cross-Sectional Survey. Crit Care Med 2020;48:e209-18. 10.1097/CCM.0000000000004155 - DOI - PubMed Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016;315:801-10. 10.1001/jama.2016.0287 - DOI - PMC - PubMed Duncan CF, Youngstein T, Kirrane MD, et al. Diagnostic Challenges in Sepsis. Curr Infect Dis Rep 2021;23:22. 10.1007/s11908-021-00765-y - DOI - PMC - PubMed Zheng YJ, Zhu XJ, Chen YW, et al. Establishment of a novel risk score for in-hospital mortality in adult sepsis patients. Ann Transl Med 2022;10:781. 10.21037/atm-21-2900 - DOI - PMC - PubMed Show all 41 references Related information MedGen LinkOut - more resources Full Text Sources AME Publishing Company Europe PubMed Central PubMed Central