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Id Subject Object Predicate Lexical cue
T1 0-25 Sentence denotes Covid-19 and autoimmunity
T2 27-42 Sentence denotes 1 Introduction
T3 43-495 Sentence denotes Though the exact etiology of autoimmune diseases still remains unknown, there are various factors which are believed to contribute to the emergence of an autoimmune disease in a host including the genetic predisposition, the environmental triggers such as bacterial infections, including the gut microbiota, viral fungal and parasitic infections, as well as physical and environmental agents, hormonal factors and the hosts immune system dysregulation.
T4 496-621 Sentence denotes All these factors interplay was coined by Shoenfeld et al., many years ago “The Mosaic of Autoimmunity” [[1], [2], [3], [4]].
T5 622-749 Sentence denotes The most prominent pathogenic viruses which have been proposed in the triggering and initiation of autoimmune diseases include:
T6 750-920 Sentence denotes Parvovirus B19, Epstein-Barr-virus (EBV), Cytomegalovirus (CMV), Herpes virus-6, HTLV-1, Hepatitis A and C virus, and Rubella virus [[5], [6], [7], [8], [9], [10], [11]].
T7 921-1316 Sentence denotes These viruses have been implicated in the initiation of chronic inflammatory or autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome, primary billiary cholangitis, multiple sclerosis, polymoysitis, uveitis, Henoch Schonlein Puprpura, Systemic Juvenile Idiopathic arthritis, systemic sclerosis, Hashimoto thyroiditis and autoimmune hepatitis [12,13].
T8 1317-1681 Sentence denotes Suggested mechanisms of induction of the autoimmunity include both molecular mimicry [14] as well as “bystander activation” whereby the infection may lead to activation of antigen presenting cells that may in turn activate pre-primed auto-reactive T-cells, thus leading to the production of pro-inflammatory mediators, which in turn may lead to tissue damage [15].
T9 1682-1790 Sentence denotes Alternative suggested mechanisms include epitope spreading as well as presentation of cryptic antigens [16].
T10 1791-1901 Sentence denotes Corona viruses represent a major group of viruses mostly affecting human beings through zoonotic transmission.
T11 1902-2134 Sentence denotes In the past two decades, this is the third instance of the emergence of a novel coronavirus, after the severe acute respiratory syndrome (SARS) in 2003 and the Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012 [17,18].
T12 2135-2265 Sentence denotes In December 2019 a novel outbreak of a new strain of coronavirus infection emerged in Wuhan, China the SARS-CoV-2 or the Covid-19.
T13 2266-2520 Sentence denotes The disease which was declared as a pandemic in early March 2020, is characterized by fever, dry cough, myalgia and or extreme fatigue, may be asymptomatic or with minimal flu-like constitutional symptoms leading to a favorable outcome in many instances.
T14 2521-2922 Sentence denotes However, some of the patients encounter a severe pneumonia with sepsis leading to an acute respiratory distress syndrome (ARDS) with respiratory failure requiring mechanical ventilation, and at times accompanied by hyperferritinemia and multiple organ involvement including hematological, gastrointestinal, neurological and cardiovascular complications leading to death [[19], [20], [21], [22], [23]].
T15 2923-3207 Sentence denotes The ARDS described in up to 20% of Covid-19 cases, is reminiscent of the cytokine release syndrome-induced ARDS and secondary hemophagocytic lymphohistiocytosis (sHLH) observed in patients with SARS-CoV and MERS-CoV as well as in leukemia patients receiving engineered T cell therapy.
T16 3208-3389 Sentence denotes These cases with Covid-19 are those who develop through the excessive cytokine release and the uncontrolled immune activation, the multiorgan failure with a grave prognosis [24,25].
T17 3391-3479 Sentence denotes 2 Autoimmune diseases / syndromes potentially associated with Covid-19 described so far
T18 3480-3857 Sentence denotes It has been suggested that the shared pathogenetic mechanisms and clinical-radiological aspects between the hyper-inflammatory diseases and Covid-19 may suggest that SARS-CoV-2 could act as a triggering factor for the development of a rapid autoimmune and/or autoinflammatory dysregulation, leading to the severe interstitial pneumonia, in genetic predisposed individuals [26].
T19 3858-4058 Sentence denotes Furthermore, in an online pre-published study from Germany the authors studied prospectively a group of 22 patients for the possible role of autoimmunity in SARS-CoV-2 -associated respiratory failure.
T20 4059-4389 Sentence denotes Based on serological, radiological and histomorphological similarities between Covid-19-associated ARDS and acute exacerbation of connective tissue disease induced interstitial lung disease, the authors suggest that SARS-CoV-2 infection might trigger or simulate a form of organ specific autoimmunity in predisposed patients [27].
T21 4390-4661 Sentence denotes In a similar retrospective study from China of 21 patients with critical SARS-CoV-2 pneumonia, the authors showed a prevalence of between 20 and 50% of autoimmune disease related autoantibodies, suggesting the rational for immunosupression in such cases of Covid-19 [28].
T22 4663-4725 Sentence denotes 3 Immune thrombocytopenic purpura – ITP secondary to COVID-19
T23 4726-4961 Sentence denotes Immune thrombocytopaenic purpura (ITP) is an autoimmune systemic disease manifested by the presence of low blood platelets count (<10 [5]/μl) and the production of autoantibodies against glycoproteins expressed on the platelet surface.
T24 4962-5142 Sentence denotes The clinical course is often acute, and life-threatening events may occur especially in children, with 52% of pediatric patients recovering either spontaneously or after treatment.
T25 5143-5256 Sentence denotes A chronic ITP evolution is observed in 64% of adults, of whom 12% will develop an overlapping autoimmune disease.
T26 5257-5423 Sentence denotes Several microbial infections as well as viruses including CMV, EBV parvovirus, rubella, measles or HIV can potentially trigger ITP through molecular mimicry [29,30]..
T27 5424-5700 Sentence denotes The association between ITP and Covid-19 has been suggested in a single case report of a 65-year-old female patient with a background history of hypertension, autoimmune hypothyroidism, and positive swab for Covid-19 who presented with fever, dry cough and signs of pneumonia.
T28 5701-5851 Sentence denotes Laboratory studies were within normal limits and she was treated by intra-venous amoxicillin–clavulanic acid, low-molecular weight heparin and oxygen.
T29 5852-6038 Sentence denotes The normal platelet count on admission had gradually dropped to 66,000 and later to 8000 per cubic millimeter on day seven accompanied by classical lower-extremity purpura and epistaxis.
T30 6039-6090 Sentence denotes Both heparin and the antibiotics were discontinued.
T31 6091-6317 Sentence denotes She was treated by two rounds of IVIG while the platelets had drooped even further to 1000 per cubic millimeter followed by the onset of right frontal headache, with a CT of the head demonstrating subarachnoid microhemorrhage.
T32 6318-6409 Sentence denotes A platelet transfusion was administered with concurrent starting of 100 mg of prednisolone.
T33 6410-6590 Sentence denotes On day 10, the headache had resolved with no new neurologic findings, and the platelet count had gradually increased to 139,000 on day 13 with a complete resolution of the purpura.
T34 6591-6797 Sentence denotes The temporal sequence in this case suggests, but does not prove, that the ITP was triggered by the Covid-19 especially in view of the history of autoimmune hypothyroidism which is often associated with ITP.
T35 6798-7000 Sentence denotes There are however other potential causes for the thrombocytopenia in this case such as the treatment with amoxicillin–clavulanic acid as well as the known heparin-induced-thrombocytopenia (HIT) [31,32].
T36 7001-7203 Sentence denotes Another report by Tsao et al. currently online, describes a case of SARS-CoV-2 positive pediatric patient with ITP and raises the awareness of ITP as a possible pediatric presentation of the virus [33].
T37 7205-7259 Sentence denotes 4 Guillian-Barrė syndrome (GBS) secondary to COVID-19
T38 7260-7447 Sentence denotes GBS is a progressive, ascending, symmetrical flaccid limbs paralysis, along with areflexia or hyporeflexia with or without cranial nerve involvement which can progress over days to weeks.
T39 7448-7533 Sentence denotes The disease may be triggered by respiratory or intestinal infections or vaccinations.
T40 7534-7716 Sentence denotes The known triggering infections include Influenza; Chlamydia; CMV; varicella; mumps; rubella; HIV; Polio; Hepatitis E; Borrelia; Mycoplasma pneumonia as well as Campilobacter Jejuni.
T41 7717-7917 Sentence denotes GBS is an immune-mediated disorder with molecular mimicry playing an important role in its autoimmune disorder in which the immune system attacks gangliosides on the peripheral nervous system [34,35].
T42 7918-7995 Sentence denotes There are so far 2 reports of GBS associated with Covid-19 infection [36,37].
T43 7996-8104 Sentence denotes It is yet unclear whether Covid-19 induces the production of antibodies against these specific gangliosides.
T44 8105-8240 Sentence denotes The first is a report of five out of 1200 patients hospitalized between February 28th and March 21st, 2020 in Northern Italy hospitals.
T45 8241-8331 Sentence denotes The onset of neurological symptoms began 7–10 days after the initial respiratory symptoms.
T46 8332-8467 Sentence denotes Four out of the 5 patients had lower-limb weakness and paresthesia and one was with facial diplegia followed by ataxia and paresthesia.
T47 8468-8578 Sentence denotes Generalized, flaccid tetraparesis or tetraplegia evolved over a period of 36 h to 4 days in 4 of the patients.
T48 8579-8625 Sentence denotes Three of them required mechanical ventilation.
T49 8626-8687 Sentence denotes Anti-ganglioside antibodies were either negative or not done.
T50 8688-8781 Sentence denotes All patients received IVIG (1 of then required 2 cycles) and one had started plasma exchange.
T51 8782-8986 Sentence denotes The second report from Iran describes a 65 year old male patient admitted to hospital because of acute progressive symmetric ascending quadriparesis, two weeks after a history of cough, fever and dyspnea.
T52 8987-9020 Sentence denotes Covid-19 was diagnosed by RT-PCR.
T53 9021-9106 Sentence denotes The patient was treated by hydroxychloroquine, Lopinavir/Ritonavir, and Azithromycin.
T54 9107-9132 Sentence denotes GBS was confirmed by EMG.
T55 9133-9176 Sentence denotes The patient was treated by IVIG for 5 days.
T56 9177-9354 Sentence denotes Another early report of a single GBS patient came from China during the SARS-CoV-2 epidemic, although there is some concern regarding the causality in this particular case [38].
T57 9356-9409 Sentence denotes 5 Miller Fisher syndrome (MFS) secondary to COVID-19
T58 9410-9558 Sentence denotes MFS is a rare, acquired disease that is considered to be a mild variant of Guillain-Barré syndrome, and is observed in about 5% of all cases of GBS.
T59 9559-9632 Sentence denotes It is characterized by a triad of ataxia, areflexia, and ophthalmoplegia.
T60 9633-9695 Sentence denotes Acute onset of external ophthalmoplegia is a cardinal feature.
T61 9696-9763 Sentence denotes Ataxia tends to be out of proportion to the degree of sensory loss.
T62 9764-9845 Sentence denotes Patients may also have mild limb weakness, ptosis, facial palsy, or bulbar palsy.
T63 9846-9923 Sentence denotes Occasionally generalized muscle weakness and respiratory failure may develop.
T64 9924-10015 Sentence denotes Patients have reduced or absent sensory nerve action potentials and absent tibial H reflex.
T65 10016-10070 Sentence denotes Like GBS, symptoms may be preceded by a viral illness.
T66 10071-10208 Sentence denotes The majority of individuals with MFS have unique antibodies that characterize the disorder, which are Anti-GQ1b and anti-GD1b antibodies.
T67 10209-10395 Sentence denotes Dense concentrations of GQ1b ganglioside are found in the oculomotor, trochlear, and abducens nerves, which may explain the relationship between anti-GQ1b antibodies and ophthalmoplegia.
T68 10396-10501 Sentence denotes Treatment for MFS is identical to treatment for GBS: intravenous immunoglobulin (IVIG) or plasmapheresis.
T69 10502-10642 Sentence denotes A group from Spain reported of two patients infected with SARS-CoV-2 who acutely presented with MFS and polyneuritis cranialis respectively.
T70 10643-10706 Sentence denotes Both patients presented with the typical neurological symptoms.
T71 10707-10853 Sentence denotes One of the two patients was found to be positive for anti-GD1b-IgG antibodies and was treated with IVIG and the second patient with acetaminophen.
T72 10854-10987 Sentence denotes Two weeks later, both patients made a complete neurological recovery, except for residual anosmia and ageusia in the first case [39].
T73 10989-11056 Sentence denotes 6 Antiphospholipid antibodies and thrombosis secondary to COVID-19
T74 11057-11185 Sentence denotes Deep vein thrombosis, pulmonary embolism and stroke have been observed in patients affected by severe forms of COVID-19 [40,41].
T75 11186-11277 Sentence denotes These vascular events, particularly strokes, were mostly recorded in elderly patients [41].
T76 11278-11368 Sentence denotes However, 5 cases of stroke were recently reported in relatively young patients (age range:
T77 11369-11474 Sentence denotes 33–49 years), in association with prolonged activated partial-thromboplastin time (aPTT) in 2 cases [42].
T78 11475-11738 Sentence denotes Vascular manifestations of COVID-19 comprise either venous or arterial thrombosis or stroke in subjects under the age of 50, sometimes with a severe phenotype that can resemble the “catastrophic” clinical picture associated with antiphospholipid antibodies (aPL).
T79 11739-12171 Sentence denotes In patients with systemic autoimmune diseases such as Systemic Lupus Erythematosus (SLE), aPL represent the major cause of thrombosis (either arterial or venous or microangiopathic) and pregnancy morbidity. aPL are pathogenic autoantibodies that can cause the same vascular and obstetric manifestations also in subjects without any other autoimmune disease, suffering from the so called Primary Antiphospholipid Syndrome (APS) [43].
T80 12172-12412 Sentence denotes The more severe form of APS (the “catastrophic” APS, CAPS) is characterized by a rapidly occurring multiorgan thrombotic damage with histopathological evidence of microangiopathy [44], recalling pictures described in patients with COVID-19.
T81 12413-12521 Sentence denotes CAPS is usually preceded by a precipitating factor, which is an infection in the majority of the cases [45].
T82 12522-12777 Sentence denotes The link between infection and aPL was first observed when patients with different autoimmune conditions were found to be positive for the serological test of syphilis, whose antigen was described as a mixture of phospholipids, including cardiolipin [46].
T83 12778-13041 Sentence denotes Nowadays, the detection of aPL is performed by anticardiolipin (aCL) and anti-beta2glicoprotein I (anti-b2GPI) immunoassays and by the functional coagulation test lupus anticoagulant (LA), according to the international consensus APS classification criteria [47].
T84 13042-13168 Sentence denotes Three cases of COVID-19 patients with severe thrombotic events associated with aCL and anti-b2GPI were recently reported [48].
T85 13169-13379 Sentence denotes Specifically, aCL of IgA isotype and anti-b2GPI of IgG and IgA isotype were detected, raising the hypothesis that the mucosal damage induced by SARS-CoV-2 could preferentially stimulate the IgA immune response.
T86 13380-13428 Sentence denotes LA was found to be negative in these 3 patients.
T87 13429-13598 Sentence denotes On the other hand, LA was found to be positive in 25 out of 56 (44.6%) consecutive COVID-19 patients, while IgG/IgM aCL and/or anti-b2GPI were positive only in 5 (8.9%).
T88 13599-13670 Sentence denotes No specific relation with thrombosis was mentioned in this cohort [49].
T89 13671-13788 Sentence denotes In addition, LA was studied in patients with prolonged aPTT, a finding that has been frequently reported in COVID-19.
T90 13789-13915 Sentence denotes More than 90% of patients with prolonged aPTT, with or without clinical evidence of thrombosis, resulted positive for LA [50].
T91 13916-14032 Sentence denotes Another study investigated patients with acute respiratory distress syndrome and COVID-19 from intensive care units.
T92 14033-14224 Sentence denotes In this study, 50 out of 59 (84.7%) tested patients had LA positive, strongly associated with high D-dimers and thrombosis, particularly if the test was performed early in the disease course.
T93 14225-14294 Sentence denotes In this series only one patient had positive aCL of IgM isotype [51].
T94 14295-14394 Sentence denotes Therefore, we can assume that aPL can be frequently detected in patients with SARS-CoV-2 infection.
T95 14395-14442 Sentence denotes Certainly, this finding is not surprising [52].
T96 14443-14709 Sentence denotes In fact, the occurrence of transient aPL was described in patients affected by several viral infections such as human immunodeficiency virus (HIV), varicella zoster, hepatitis C virus, cytomegalovirus (CMV), Epstein–Barr virus (EBV), adenovirus, parvovirus B19 [53].
T97 14710-14901 Sentence denotes In addition, aPL were also detected in patients with infections of different origin (bacterial, parasitic, etc) and an infection was often reported just before the clinical onset of APS [54].
T98 14902-15140 Sentence denotes These observations suggest the possible existence of molecular mimicry due to similarity between the peptide regions identified in the b2GPI molecule (and recognized by anti-b2GPI) and membrane proteins of several virus and bacteria [55].
T99 15141-15332 Sentence denotes Animals immunized with different viruses or bacteria (or proteins derived from them) developed anti-b2GPI antibodies that in some cases were associated with the occurrence of thrombosis [56].
T100 15333-15485 Sentence denotes The different pathogenic potential of antibodies can be attributed to the fine specificity that they acquire after immunization with different antigens.
T101 15486-15777 Sentence denotes It is in fact known that antibodies directed to domain 1 of the b2GPI molecule are associated with an increased risk of thrombosis (in systemic autoimmune diseases and APS) [57] while antibodies directed to other parts of the molecule, such as domain 4/5, can be regarded as “innocent” [58].
T102 15778-16044 Sentence denotes On the other hand, the features of the host can also be important, since genetic background is recognized as one of the determinant factors in the induction of autoimmunity and can be the driver which turns aPL from being transient to persistent and pathogenic [59].
T103 16045-16225 Sentence denotes The above considerations widely justify why aPL, detected with different assays, can be found in patients affected by COVID-19, sometimes associated with thrombosis but not always.
T104 16226-16466 Sentence denotes To our knowledge, no increased rate of miscarriages or fetal loss have been reported during SARS-CoV-2 pandemic so far, although some severe pregnancy complication, like those linked to aPL, such as HELLP syndrome were occasionally seen (A.
T105 16467-16501 Sentence denotes Lojacono, personal communication).
T106 16502-16673 Sentence denotes Whether pregnant women with COVID-19 have an increased rate of positive aPL during pregnancy is not known yet nor it is defined their possible impact on pregnancy outcome.
T107 16674-16713 Sentence denotes COVID-19 is a novel infectious disease.
T108 16714-16799 Sentence denotes The true relationship between this infection and aPL need to be further investigated.
T109 16800-17007 Sentence denotes However, according to the “second hit hypothesis” [60], the thrombogenic potential of aPL is magnified in the presence of an infection or a severe inflammatory state, which is often associated with COVID-19.
T110 17008-17234 Sentence denotes Therefore, the search for aPL may be considered in the management of COVID-19 patients with vascular manifestations, as the detection of positive aPL would allow of the indication for an early adequate anticoagulant treatment.
T111 17235-17425 Sentence denotes In the case of aPL positivity, a follow-up testing after at least 12 weeks is warranted, in order to verify the persistence of aPL, which would suggest the post-infectious occurrence of APS.
T112 17426-17645 Sentence denotes In fact, APS is currently considered as a systemic autoimmune disease which is not limited to thrombosis and pregnancy morbidity and deserves specific long-term management including anticoagulation and immunomodulation.
T113 17647-17693 Sentence denotes 7 Kawasaki like disease secondary to COVID-19
T114 17694-17793 Sentence denotes Kawasaki disease (KD) is a systemic vasculitis that usually affects children less than 5 years old.
T115 17794-17990 Sentence denotes Soon after the first description by Tomisaku Kawasaki in 1967, it was clear that the disease, although self-limiting, might cause coronary artery aneurism (CAA) in a high percentage of cases [61].
T116 17991-18104 Sentence denotes KD is nowadays considered as the first cause of acquired heart disease in children from developed countries [62].
T117 18105-18220 Sentence denotes The disease is far more common in eastern countries, and in children of eastern origin living in western countries.
T118 18221-18357 Sentence denotes For example, the 2010 annual incidence for KD was 222.9 cases/100000 children <5 y/o in Japan, compared to 20/100000 in the USA [63,64].
T119 18358-18502 Sentence denotes Since no specific test is available, diagnosis relies on the recognition of the cardinal clinical features and the exclusion of other mimickers.
T120 18503-18708 Sentence denotes The mainstay of treatment is the administration of intravenous immunoglobulins (IVIG) at 2 g/kg of body weight, as soon as the diagnosis is established, and possibly within 10 days from the onset of fever.
T121 18709-18768 Sentence denotes IVIG have been demonstrated to reduce the risk of CAA [65].
T122 18769-18956 Sentence denotes A subgroup of patients, accounting for nearly 5% of those with KD, has been described to have a very severe disease onset with systolic hypotension or shock (Kawasaki Shock Syndrome-KSS).
T123 18957-19063 Sentence denotes The shock may be caused by a capillary leak syndrome or by poor perfusion due to inflammatory myocarditis.
T124 19064-19367 Sentence denotes KSS patients are more likely to be females and to have earlier onset, incomplete presentations, and more severe laboratory abnormalities (lower platelet counts, higher serum CRP levels, hyponatremia, increased transaminases, metabolic acidosis, consumptive coagulopathy, and lower serum albumin levels).
T125 19368-19546 Sentence denotes Patients with KSS are often resistant to IVIG treatment and have a higher incidence of coronary artery aneurysms, mitral regurgitation, and prolonged myocardial dysfunction [66].
T126 19547-19679 Sentence denotes Northern Italy was the first European region to be severely hit by the SARS-COV2 epidemic after the original outbreak in China [67].
T127 19680-19866 Sentence denotes Although the data on the clinical presentation of COVID-19 in children is still scarce, lower rates of infection and milder forms of disease seem to be typical of this age group [68,69].
T128 19867-20103 Sentence denotes Since the end of March 2020, we observed and treated or received information from all over Italy about an abnormally elevated number of critically ill patients with clinical characteristics consistent with Kawasaki Shock Syndrome (KSS).
T129 20104-20376 Sentence denotes The common features were: “middle-aged” children (6–9 y/o) with a history of persistent high spiking fever in the previous days, abdominal pain, diarrhea, skin rash, and rapidly deteriorating clinical conditions with the onset of shock, without clear signs of dehydration.
T130 20377-20481 Sentence denotes Other less common features were arthralgia, cough, meningism, conjunctivitis and reddened, cracked lips.
T131 20482-20604 Sentence denotes Labworks usually showed high inflammatory markers, low lymphocyte count, low sodium, and high troponin and pro-BNP levels.
T132 20605-20733 Sentence denotes Echocardiography was consistent with myocarditis in the majority of patients instead of classical coronary artery abnormalities.
T133 20734-20852 Sentence denotes Patients were diagnosed as Kawasaki disease (typical or incomplete) and treated accordingly with IVIG and/or steroids.
T134 20853-20942 Sentence denotes One patient refractory to such treatments responded successfully to intravenous anakinra.
T135 20943-21128 Sentence denotes Althoug all the patients had family contacts consistent with COVID-19, serology and nasopharyngeal swabs were inconsistently positive both in the single patients and among all children.
T136 21129-21207 Sentence denotes To date we are aware of at least 10 cases of KSS possibly related to COVID-19.
T137 21208-21340 Sentence denotes Given the unprecedented cluster of patients we decided to launch a nationwide alert for pediatricians and start a national registry.
T138 21341-21552 Sentence denotes Few days after the diagnosis of our first cases, news from all over Europe first, and Eastern USA thereafter, reported on the identification of patients with remarkably the same characteristics we have observed.
T139 21553-21769 Sentence denotes Some children with a less severe picture, without shock at the onset, but with clinical characteristics of systemic inflammation and some features of KD have also been seen by us and others (personal communications).
T140 21770-21864 Sentence denotes These observations lead to a variety of nationwide alerts in the respective countries [70,71].
T141 21865-22014 Sentence denotes On May 7, 2020, Riphagen et al. published on 8 patients treated at the South Thames Retrieval Service for a severe acute illness similar to KSS [72].
T142 22015-22130 Sentence denotes Age at presentation was between 4 and 14 years, 6 out of 8 children were of Afro-Caribbean descent and 5 were boys.
T143 22131-22264 Sentence denotes All the children had a similar disease onset with persistent fever, skin rash, conjunctivitis, peripheral oedema, and extremity pain.
T144 22265-22387 Sentence denotes Gastrointestinal symptoms were frequent and severe, all children developed shock requiring ICU admission and vasopressors.
T145 22388-22545 Sentence denotes Another key feature described in those patients was the cardiac involvement, as testified by very elevated cardiac enzymes, and echo-bright coronary vessels.
T146 22546-22594 Sentence denotes One patient developed a giant coronary aneurism.
T147 22595-22700 Sentence denotes Lab works typically showed high C-reactive protein, procalcitonin, ferritin, triglycerides, and D-dimers.
T148 22701-22785 Sentence denotes All children were treated with IVIG (2 g/kg) and 6 also received aspirin (50 mg/kg).
T149 22786-22954 Sentence denotes Broncho-alveolar lavage or nasopharyngeal aspirates were negative for SARS-COV-2 in all children; some of the patients had histories of familial contact with the virus.
T150 22955-23095 Sentence denotes The authors stated that, at the time they were writing their report, another ICU in London managed 20 patients with similar characteristics.
T151 23096-23294 Sentence denotes As per the Royal College of Pediatrics and Child Health (RCPCH) alert, some of these patients resulted to be positive for SARS-CoV-2 infection, by either nasopharyngeal swab, serology, or both [69].
T152 23295-23380 Sentence denotes The New York State Department of Health reported sixty-four cases as of May 5th 2020.
T153 23381-23657 Sentence denotes For the purpose of this review we will refer to this clinical entity as Pediatric COVID-19 Hyperinflammatory Syndrome (PeCOHS), while the English authorities refers to it as Pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 infection (PIMS-TS).
T154 23658-23866 Sentence denotes Verdoni et al. published the first Italian experience on 10 patients admitted to their hospital for Kawasaki-like disease from February 18th to April 20th, 2020 (during the peak of COVID19 epidemic in Italy).
T155 23867-24014 Sentence denotes Very nicely, the authors compared these children (group 2) to the historical cohort of KD patients seen in the last 5 years (group 1, 19 patients).
T156 24015-24117 Sentence denotes Half of the children in group 2 presented with classic KD, while half were diagnosed as incomplete KD.
T157 24118-24276 Sentence denotes Half of the patients showed hypotension and signs of hypoperfusion at onset, and were interpreted as KSS, and half had signs of myocarditis at echocardiogram.
T158 24277-24329 Sentence denotes Pro-BNP was above normal values in all the patients.
T159 24330-24438 Sentence denotes Half of the patients satisfied the PRINTO laboratory criteria for Macrophage Activation Syndrome (MAS) [73].
T160 24439-24467 Sentence denotes Two patients developed CAAs.
T161 24468-24662 Sentence denotes Patients in group 2 displayed older age, a higher frequency of gastrointestinal and respiratory symptoms, meningeal signs, myocarditis, shock syndrome, and MAS criteria as compared with group 1.
T162 24663-24849 Sentence denotes Nasopharyngeal swab for SARS-CoV-2 was positive in 2 patients only, 8 patients had positive IgG while 3 patients had positive IgM (all of whom were positive also for IgG) for SARS-CoV-2.
T163 24850-24945 Sentence denotes All patients from group 2 were treated with IVIG and steroids, with good clinical outcome [74].
T164 24946-25138 Sentence denotes The occurrence of such cases with a stereotyped clinical picture, which is rarely seen in children, during the peak of SARS-CoV2 infection in highly epidemic areas, points to a causative link.
T165 25139-25241 Sentence denotes One hypothesis is that these children were suffering from actual KD triggered by the SARS-CoV-2 virus.
T166 25242-25322 Sentence denotes Indeed, a microbial etiology has been long advocated as a possible cause for KD.
T167 25323-25554 Sentence denotes Many viruses (HHV-6, Epstein Barr virus, Cytomegalovirus, Coronavirus other than SARS-CoV-2, Parvovirus B19 etc.) but also bacterial infections (such as staphylococci, streptococci, Bartonella, and Yersinia) have been linked to KD.
T168 25555-25731 Sentence denotes Interestingly enough, a case of classic KD has been recently reported in a 6 months-old child who tested positive for SARS-CoV-2, although this could be just coincidental [75].
T169 25732-25969 Sentence denotes The clinical and laboratory characteristics of the patients recently described are strikingly similar to the KSS typical picture, except for the older age, male predominance and relatively low frequency of coronary artery aneurysms [65].
T170 25970-26159 Sentence denotes Given these differences, it can be speculated that this COVID-19 Hyperinflammatory Syndrome is indeed a systemic vasculitis peculiar of the pediatric age and caused by SARS-CoV-2 infection.
T171 26160-26224 Sentence denotes How SARS-CoV-2 infection may cause a hyperinflammatory syndrome?
T172 26225-26439 Sentence denotes At this point we can only formulate hypotheses, based on the clinical picture of the observed patients and using other diseases with overlapping manifestations, such as KD and Toxic Shock Syndrome (TSS), as models.
T173 26440-26652 Sentence denotes The delay between the pandemic peak of COVID-19 and the occurrence of this hyperinflammatory syndrome in children does not point to a direct effect of the infection, but rather towards an immune-mediated disease.
T174 26653-26814 Sentence denotes This seems to be confirmed also by the observation of Verdoni et al. that the majority of their patients had positive SARS-CoV-2 IgG, but negative IgM and swabs.
T175 26815-26993 Sentence denotes Staphylococcal or Streptococcal TSS are the result of T cells induction by superantigens TSST-1, enterotoxins B or C (staphylococci), or pyrogenic exotoxin A or B (streptococci).
T176 26994-27193 Sentence denotes Superantigens can stimulate clonal T cell proliferation and this leads to the production of massive amounts of pro-inflammatory cytokines, as IL-1, IL-6, and IFN-γ in a so-called cytokine storm [76].
T177 27194-27455 Sentence denotes There is a body of evidence suggesting that KD may be caused by a superantigen response, and recent data demonstrated that KSS is characterized by a massive pro-inflammatory cytokine release that differentiate those patients from the “regular” KD patients [77].
T178 27456-27582 Sentence denotes This cytokine storm could be the underlying mechanism leading to the clinical picture similar of that of TSS, KSS, and PeCOHS.
T179 27583-28061 Sentence denotes Other possible mechanisms by which SARS-CoV-2 could induce a hyperinflammatory syndrome are: i) the autoantibodies formation through “molecular mimicry”, as in Acute Rheumatic Fever (although this mechanism would not justify the occurrence of shock); ii) a vascular damage secondary to the deposition of immune-complexes as in acute serum sickness; iii) an antibody-dependent enhancement (ADE) with IgG immune complexes that enhance virus infection in Fc-receptor-bearing cells.
T180 28062-28203 Sentence denotes Intriguingly, this phenomenon is the cause of Dengue vascular permeability syndrome, which, again, shares some similarities with PeCOHS [78].
T181 28204-28327 Sentence denotes ADE were demonstrated in SARS-CoV infection years ago, mediated by antibodies directed to the envelope spike proteins [79].
T182 28328-28397 Sentence denotes Children with SARS-CoV-2 infection usually have a benign course [67].
T183 28398-28687 Sentence denotes Differently from what we usually see in Kawasaki Disease, which has a predilection for asian countries, PeCOHS has not been described so far in those countries, suggesting that both the genetic predisposition of the host and differences in the viral genome may play a role in this disease.
T184 28688-28798 Sentence denotes To our knowledge, the majority of patients with PeCOHS respond to a variable combination of steroids and IVIG.
T185 28799-29028 Sentence denotes The discussion about the immunomodulatory effects of both steroids and IVIG is beyond the scope of this review, but it is interesting to highlight that one of the many effects of IVIG is the down modulation of superantigens [80].
T186 29029-29155 Sentence denotes Of note, IVIG is the therapy of choice in the capillary leak syndrome, whose main features are similar to KSS and PeCOHS [81].
T187 29156-29430 Sentence denotes Finally, the efficacy of anti-IL-1 treatment as “rescue therapy” for cases resistant to IVIG+steroids points out the relevance of this pro-inflammatory cytokine in the hyperinflammatory state, similar to what already shown in adults with COVID-19 and hyperinflammation [82].
T188 29431-29681 Sentence denotes In conclusion, although SARS-CoV-2 infection appears to occur as a oligo-symptomatic form in the majority of children, there is mounting evidence that it can cause a systemic hyperinflammatory syndrome that mimics KSS, but has some peculiar features.
T189 29682-29890 Sentence denotes The role of host and virus genetics and the exact immune mechanisms leading to the disease are far from been understood, and case collection would help us in better characterization of the clinical phenotype.
T190 29891-30097 Sentence denotes As light has been shed on the interaction between SARS-CoV-2 and the immune system, we will gain hints also at Kawasaki Disease pathogenesis, almost 50 years from its first description by Tomisaku Kawasaki.
T191 30099-30166 Sentence denotes 8 Preexisting autoimmune rheumatic diseases and COVID-19 infection
T192 30167-30523 Sentence denotes Since the breakout of the Covid-19 in late 2019 in China, many unresolved issues regarding both dealing with the fate of the preexisting autoimmune rheumatic diseases in patients who are affected by the virus including those under immunosuppressive and biologic therapy, as well as the impact of these therapies on the severity of the viral disease itself.
T193 30524-30844 Sentence denotes Early reports in the course of the pandemia suggested that based on the data recovered from other and previous viral infections, there would be an increased probability for patients with rheumatic diseases to acquire the Covid-19 disease or are they prone to an increased severity of the infection if they do acquire it.
T194 30845-31023 Sentence denotes On the contrary, however, early on, there was some evidence regarding the potential benefit of some of the drugs which have been used in the therapy of rheumatic disease [83,84].
T195 31024-31099 Sentence denotes Patients with SLE had posed a serious concern during the Covid-19 pandemia.
T196 31100-31317 Sentence denotes This group of patients is well known to bear an increased risk of severe infections, due to both their immune system and the related organ damage as well as due to the therapies used including immunosuppressive drugs.
T197 31318-31669 Sentence denotes In a report of 19 SLE patients from France who were clinically quiescent on a long-term treatment with Hydroxychloroquine (HCQ) and were infected by the Covid-19 virus, the authors were able to conclude that the clinical course of these lupus patients did not show any signs of the disease exacerbation, except for a single case of tenosynovitis [85].
T198 31670-31920 Sentence denotes A preliminary analysis of patients included in the COVID-19 Global Rheumatology Alliance registry, showed that 17% of 110 patients with rheumatic diseases who have been diagnosed with COVID-19 as of April the 1st, 2020- were patients with lupus [86].
T199 31921-32144 Sentence denotes Thus the frequency of patients with lupus who have been diagnosed with COVID-19 was over-represented, at about twice as compared to rheumatoid arthritis which is a much commoner rheumatic disease among the adult population.
T200 32145-32604 Sentence denotes In a recent small report from northern Italy of SLE patients with either swab confirmed Covid-19 infection (n = 4) or a clinical diagnosis, based on 3 out of 4 symptoms of the viral infection (n = 8), the authors stated that the disease course was generally mild and self-resolving although one of the four patients who was on haemodialysis due to end-stage renal disease, needed intensive care for the development of acute respiratory distress syndrome [87].
T201 32605-32871 Sentence denotes Based on the clinical information published to date from the new and previous outbreaks caused by the coronaviruses, there is no overwhelming evidence that patients with rheumatic disease are at an increased risk compared with other comorbidities [[88], [89], [90]].
T202 32872-33249 Sentence denotes In a rather larger prospective report from New York, the authors reviewed a group of 86 patients with immune-mediated inflammatory disease including 59 cases of inflammatory arthritides (rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, psoriasis and inflammatory bowel disease) with confirmed Covid-19, and 27 additional patients with suspected Covid-19 [91].
T203 33250-33327 Sentence denotes Two-thirds of the patients were on biologics or other immunomodulatory drugs.
T204 33328-33462 Sentence denotes Hospitalized patients, as compared to those who were only followed on an out-patient basis, had more classical Covid-19 comorbidities.
T205 33463-33623 Sentence denotes Conventional DMARDs were used more frequently in the hospitalized group of patients, whereas biologics were more often used in the ambulatory group of patients.
T206 33624-33751 Sentence denotes The authors suggest that based on their findings the baseline use of biologics was not associated with worse Covid-19 outcomes.
T207 33752-33856 Sentence denotes In another small report from China five patients with rheumatic disease and Covid-19 are described [92].
T208 33857-33919 Sentence denotes Four had rheumatoid arthritis and one with systemic sclerosis.
T209 33920-33999 Sentence denotes All 5 patients had chest CT showing patchy ground glass opacities in the lungs.
T210 34000-34123 Sentence denotes All 5 patients were treated with antiviral agents, antibiotics and the immunomodulatory agents for their rheumatic disease.
T211 34124-34337 Sentence denotes Two of the 5 patients remained in stable condition in the course of the hospitalization, 2 progressed to severe Covid-19 and one was critically ill, though all patients recovered and were discharged from hospital.
T212 34338-34611 Sentence denotes Similarly, a report by Monti et al. [93] suggested that patients with rheumatoid arthritis treated with biological DMARDs or targeted synthetic DMARDs did not seem to be at increased risk of life-threatening complications from Covid-19 compared with the general population.
T213 34612-34913 Sentence denotes Another recent study from Italy supports the approach of encouraging connective tissue disease patients to maintain the ongoing rheumatologic therapy as well as adhere to the measures of infection prevention, thus avoiding relapse of the rheumatic disease without increasing the risk of Covid-19 [94].
T214 34914-35133 Sentence denotes Their study population included 123 adult patients (110 females) with systemic lupus erythematosus (n = 61), systemic sclerosis (n = 43), undifferentiated connective tissue disease (n = 9) and Sjogren syndrome (n = 10).
T215 35134-35268 Sentence denotes About 60% of the patients were treated with conventional DMARDs, with a similar percentage of patients taking corticosteroids as well.
T216 35269-35320 Sentence denotes Twenty five of the 110 patients received biologics.
T217 35321-35552 Sentence denotes Only one rather young female patient with systemic sclerosis was found to be positive for Covid-19 and developed a critical course with interstitial pneumonia leading to her death despite intubation and an attempt with tocilizumab.
T218 35553-35729 Sentence denotes A further 14 patients reported mild respiratory symptoms compatible with a viral infection but did not have access to a swab test and showed a rapid recovery of their symptoms.
T219 35730-35921 Sentence denotes The authors concluded that only 5 out of their 123 patients had discontinued their current rheumatological therapy, with none of the rest 115 patients experiencing flare-ups of their disease.
T220 35922-36131 Sentence denotes Similarly, Conticini et al recently reported of a large cohort of 859 patients from Italy affected by different rheumatic diseases, which were treated by biological DMARDs or by targeted synthetic DMARDs [95].
T221 36132-36297 Sentence denotes Only 2 patients who were both on biologics (rituximab or tocilizumab), were diagnosed with COVID-19, one of which even with bilateral diffuse interstitial pneumonia.
T222 36298-36385 Sentence denotes Both patients had a complete recovery without interruption of the biological treatment.
T223 36386-36553 Sentence denotes Similar favorable outcome has been reported for few cases with large-vessel vasculitis and granulomatosis with polyangiitis associated with Covid-19 infection [96,97].
T224 36554-36646 Sentence denotes Thus it seems that baseline use of biologics is not associated with worse Covid-19 outcomes.
T225 36647-36863 Sentence denotes The situation might be different with patients suffering from systemic sclerosis, where the typical interstitial lung disease (ILD) could share some CT features with Covid-19 associated pneumonia [[98], [99], [100]].
T226 36864-37012 Sentence denotes Currently the impact of pre-existing systemic sclerosis associated with pulmonary and cardiac involvement, on the course of Covid-19 is yet unknown.
T227 37013-37225 Sentence denotes Such a single case with scleroderma associated ILD and polyarthritis, who had been previously treated with anti-interleukin-6 receptor blocker (Tocilizumab) with a favorable response, was recently reported [101].
T228 37226-37407 Sentence denotes In the course of this therapy, 4 weeks after the last tocilizumab infusion, she reported a contact with Covid-19 and was found to be positive for the virus by a nasopharyngeal swab.
T229 37408-37575 Sentence denotes Her condition remained stable during the course of the acute disease and following a negative swab and cure, she had received the next scheduled tocilizumab injection.
T230 37576-37810 Sentence denotes It should be noted that early reports from China during the outbreak of the SARS-Cov2 were able to demonstrate increased levels of IL-6 and CRP, suggesting that this subgroup of patients may develop the Covid19 related cytokine storm.
T231 37811-37896 Sentence denotes Randomized trials using anti-IL-6 receptor monoclonal antibody are currently ongoing.
T232 37897-38078 Sentence denotes Recently many countries and organizations have set up registries incorporating patients with pre-existing rheumatic and autoimmune diseases who had encountered a Covid-19 infection.
T233 38079-38201 Sentence denotes The largest international registries include The Global Rheumatology Alliance of Covid-19 and the Eular Covid-19 database.
T234 38203-38263 Sentence denotes 9 Therapy - using rheumatologic drugs in COVID-19 infection
T235 38264-38362 Sentence denotes Many countries and organizations have published guidelines for treatment of the COVID-19 pandemic.
T236 38363-38586 Sentence denotes Of note are the Treatment Guidelines of the National Institutes of Health and the American College of Rheumatology guidance for the management of adult patients with rheumatic disease during the COVID-19 pandemic [102,103].
T237 38587-38756 Sentence denotes Chloroquine and Hydroxychloroquine, are anti malarial drugs, used to treat autoimmune diseases, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA).
T238 38757-38833 Sentence denotes Both chloroquine and hydroxychloroquine (HCQ) have immunomodulatory effects.
T239 38834-38996 Sentence denotes In general, HCQ has fewer and less severe toxicities (including fewer propensities to prolong the QTc interval) and fewer drug-drug interactions than chloroquine.
T240 38997-39244 Sentence denotes The proposed mechanisms of action and rationale for use for COVID-19 of both drugs have to do with the increase of the endosomal pH, inhibiting fusion of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the host cell membranes.
T241 39245-39417 Sentence denotes Furthermore, Chloroquine inhibits glycosylation of the cellular angiotensin-converting enzyme 2 receptor, which may interfere with binding of SARS-CoV to the cell receptor.
T242 39418-39683 Sentence denotes In vitro, both chloroquine and HCQ may block the transport of SARS-CoV-2 from early endosomes to endolysosomes, which may be required for release of the viral genome, and several studies have demonstrated in vitro activity of chloroquine against SARS-CoV [104,105].
T243 39684-39799 Sentence denotes Though HCQ has been administered to patients with Covid-19 there are to date no robust evidence supporting its use.
T244 39800-40071 Sentence denotes In a retrospective computerized database of 1317 positive subjects for Covid-19 out of a sample size of 14,520, a comparison was conducted between those who tested positive versus those who were found negative, in terms of the rate of administration of HCQ or colchicine.
T245 40072-40328 Sentence denotes The authors did not find any significant difference in terms of the rates of usage of either drug, thus they concluded that their findings raise doubts regarding the protective role of both these medication in the battle against SARS-CoV-2 infection [106].
T246 40329-40407 Sentence denotes Similar results were drawn by a study from a large medical center in New York.
T247 40408-40528 Sentence denotes The authors examined the association between HCQ use and intubation or death among a group of 1446 consecutive patients.
T248 40529-40647 Sentence denotes HCQ administration was not associated with either a greatly lowered or an increased risk of intubation or death [107].
T249 40648-40898 Sentence denotes Many similar reports came to the same conclusions [[108], [109], [110]], to the extent that the FDA has issued a safety alert and the American College of Physicians has as well recommended against the use of chloroquine or HCQ for COVID-19 [111,112].
T250 40899-41228 Sentence denotes Furthermore, an attempt to evaluate HCQ serum or plasma levels from various rheumatic disease patients receiving this treatment, found that these plasma or serum levels were unlikely to achieve the concentration shown to inhibit SARS-CoV-2 in vitro (average target 0.48 mg/L as opposed to the antiviral target of 4/1 mg/L) [113].
T251 41230-41291 Sentence denotes 10 Anti-IL-6 receptor antibodies – Tocilizumab and Sarilumab
T252 41292-41428 Sentence denotes IL-6 is a pleiotropic, pro-inflammatory cytokine produced by a variety of cell types, including lymphocytes, monocytes, and fibroblasts.
T253 41429-41539 Sentence denotes Infection by the related SARS-CoV induces a dose-dependent production of IL-6 from bronchial epithelial cells.
T254 41540-41683 Sentence denotes Elevations in IL-6 levels may be an important mediator when severe systemic inflammatory responses occur in patients with SARS-CoV-2 infection.
T255 41684-41921 Sentence denotes COVID-19-associated systemic inflammation and hypoxic respiratory failure is associated with an acute cytokine release, as indicated by elevated blood levels of IL-6, C-reactive protein (CRP), D-dimer, and ferritin [[114], [115], [116]].
T256 41922-42032 Sentence denotes Few clinical studies aiming to evaluate the efficacy of anti-IL-6 receptor blocker have been published so far.
T257 42033-42226 Sentence denotes In a report from China by Xu et al. the authors were able to show that tocilizumab effectively improved clinical symptoms as well as reversed the deterioration of sever Covid-19 patients [117].
T258 42227-42477 Sentence denotes Within 5 days after tocilizumab, 15 of the 20 patients had lowered their oxygen intake and 19 of the 20 showed a noticeable improvement in the CT of the lungs, as well as a significant reduction in CRP levels which was noted in 16 of the 19 patients.
T259 42478-42566 Sentence denotes All patients have been discharged on an average of 15 days after the tocilizumab dosing.
T260 42567-42653 Sentence denotes Even though this is a small and uncontrolled study, the results seem to be impressive.
T261 42654-42777 Sentence denotes Over 20 randomized controlled trials with tocilizumab, or sarilumab as well as JAK-inhibitors as baricitinib, are underway.
T262 42779-42825 Sentence denotes 11 Interleukin-1 (IL-1) inhibitors – Anakinra
T263 42826-42883 Sentence denotes Anakinra is a recombinant human IL-1 receptor antagonist.
T264 42884-43224 Sentence denotes It is approved to treat rheumatoid arthritis and cryopyrin-associated periodic syndromes, and it is also used off-label for a variety of inflammatory conditions and severe chimeric antigen receptor T cell (CAR-T)-mediated cytokine release syndrome (CRS) and macrophage activation syndrome (MAS)/secondary hemophagocytic lymphohistiocytosis.
T265 43225-43330 Sentence denotes A case series of anakinra use in moderate to severe COVID-19 pneumonia has recently been published [118].
T266 43331-43555 Sentence denotes This small study of 9 patients with moderate to severe Covid-19 pneumonia, who did not reach respiratory failure and were given anakinra (Anti-IL-1), serves as a proof of concept since all 9 patients had dropped their fever,
T267 43556-43627 Sentence denotes CRP levels had dropped and normalized in 5 out of 8 patients at day 11.
T268 43628-43698 Sentence denotes CT scans did not deteriorate and all were alive at the last follow up.
T269 43699-43899 Sentence denotes Similar results were reached in a retrospective study from Italy of 16 patients with Covid-19 and adult respiratory distress syndrome who were managed with non-invasive ventilation outside of the ICU.
T270 43900-44025 Sentence denotes Treatment with high-dose anakinra was found to be safe and associated with clinical improvement in 72% of the patients [119].
T271 44027-44057 Sentence denotes 12 Covid-19 and autoimmunity:
T272 44058-44087 Sentence denotes The role of molecular mimicry
T273 44088-44270 Sentence denotes Notwithstanding the current wave of intensive worldwide research, the ethiopathology of the diseases induced by the SARS-CoV-2 infection is the central question that remains obscure.
T274 44271-44460 Sentence denotes One likely explanation is that the heterogeneity and multitude of the disorders induced by the current pandemic derive from molecular mimicry phenomena between the virus and human proteins.
T275 44461-44708 Sentence denotes The scientific rationale is that, following the infection, the immune responses raised against SARS-CoV-2 may cross-react with human proteins that share peptide sequences with the virus, in this way leading to autoimmune pathologic sequelae [120].
T276 44709-44928 Sentence denotes Actually, a recent report [121] militates in this direction and likely explains lungs and airways dysfunctions through the sharing of peptides between SARS-CoV-2 glycoprotein and alveolar lung surfactant proteins [121].
T277 44929-45276 Sentence denotes Moreover, in the clinical context exposed above, it is of note to report that Sars.CoV-2 shares 6 minimal immune determinants (KTVLK, TPEEH, RETMS, PFVVS, GLEAP, ICLLQ) with the Kawasaki antigen Inositol-trisphosphate 3-kinase C [122], thus highlighting as likely cross-reactions and consequent autoimmune Kawasaki disease in predisposed subjects.
T278 45277-45412 Sentence denotes Even more impressing it appears the heptapeptide sharing between the human proteome and the viral spike glycoprotein shown in Table 1 .
T279 45413-45461 Sentence denotes The clinical scenario that emerges is upsetting.
T280 45462-45622 Sentence denotes Indeed, the list of proteins reported in the table – when altered – configurate almost all the diseases that have been described in association with SARS-CoV-2.
T281 45623-45949 Sentence denotes Two examples from the table are 1) Histone-lysine N-methyltransferase 2C that may associate with neurodevelopmental disorders., seizures, behavioral abnormalities [123], and 2) Interleukin-7 that plays a central, critical role in the regulation of the immune system and associates with severe lymphopenia when deficient [124].
T282 45950-46040 Sentence denotes Table 1 Heptapeptide sharing between SARS-CoV-2 spike glycoprotein and the human proteins.
T283 46041-46067 Sentence denotes Peptide Human Protein Name
T284 46068-46101 Sentence denotes SSTASAL 40S ribosomal protein S13
T285 46102-46123 Sentence denotes KLNDLCF Interleukin-7
T286 46124-46164 Sentence denotes FLPFFSN OTU domain-containing protein 6A
T287 46165-46184 Sentence denotes EIDRLNE Protein SET
T288 46185-46230 Sentence denotes IGAGICA Hepatitis A virus cellular receptor 2
T289 46231-46253 Sentence denotes EIDRLNE Protein SETSIP
T290 46254-46291 Sentence denotes LDKYFKN Follistatin-related protein 1
T291 46292-46343 Sentence denotes VSGTNGT Lysosome-associated membrane glycoprotein 1
T292 46344-46395 Sentence denotes FKNLREF Isovaleryl-CoA dehydrogenase, mitochondrial
T293 46396-46463 Sentence denotes LPPLLTD Maestro heat-like repeat-containing protein family member 9
T294 46464-46495 Sentence denotes DKVFRSS Zinc finger protein 528
T295 46496-46532 Sentence denotes LVKQLSS E3 SUMO-protein ligase PIAS1
T296 46533-46582 Sentence denotes VTLADAG Non-receptor tyrosine-protein kinase TNK1
T297 46583-46640 Sentence denotes RRARSVAS Amiloride-sensitive sodium channel subunit alpha
T298 46641-46684 Sentence denotes SPRRARS Hermansky-Pudlak syndrome 1 protein
T299 46685-46701 Sentence denotes KVEAEVQ EMILIN-3
T300 46702-46760 Sentence denotes TRFQTLL Disheveled-associated activator of morphogenesis 2
T301 46761-46814 Sentence denotes VYSTGSN Neural cell adhesion molecule L1-like protein
T302 46815-46858 Sentence denotes GLTVLPP FH1/FH2 domain-containing protein 3
T303 46859-46910 Sentence denotes SLLIVNN ATP-binding cassette sub-family A member 10
T304 46911-46945 Sentence denotes DEDDSEPV Unconventional myosin-XVI
T305 46946-46988 Sentence denotes NASVVNI Thyroid adenoma-associated protein
T306 46989-47025 Sentence denotes LIRAAEI Unconventional myosin-XVIIIa
T307 47026-47052 Sentence denotes TGRLQSL Neuron navigator 3
T308 47053-47098 Sentence denotes DEVRQIA Histone-lysine N-methyltransferase 2C
T309 47099-47137 Sentence denotes SSSGWTA Transmembrane protein KIAA1109
T310 47138-47211 Sentence denotes Data on protein function/disease from Uniprot (https://www.uniprot.org/).
T311 47212-47264 Sentence denotes Sequential overlapping heptapeptides are given bold.
T312 47266-47330 Sentence denotes 13 The Covid-19 vaccine and the constraint of molecular mimicry
T313 47331-47743 Sentence denotes The extent of the molecular mimicry between SARS-CoV-2 and the human proteome should be carefully analyzed as a mandatory step preliminarily to any vaccine formulation As a matter of fact, because of the pathogen–host peptide commonality, a potential consequence of vaccination might consist of a specific autoimmune reactions hitting self-antigens such as the already analyzed alveolar surfactant protein [121].
T314 47744-47890 Sentence denotes Only peptide sequences uniquely belonging to the virus can represent the basis for safe and specific vaccinations protocols [[125], [126], [127]].
T315 47892-47964 Sentence denotes 14 Probable histopathological signs of autoimmune reactions in COVID-19
T316 47965-48110 Sentence denotes Based upon the possibility to detect autoimmune reactions by morphological methods we analyzed autopsies from 18 deceased patients from COVID-19.
T317 48111-48233 Sentence denotes The pathological investigation was done by using bright lineage of immunohistochemistry (CD2, 3, 5, 7, 8, 20, 31, 34, 69).
T318 48234-48318 Sentence denotes Our study allowed us to demonstrate the role of different mechanisms of death [128].
T319 48319-48545 Sentence denotes Of special interest was the diffuse infiltration of the lungs, along with focal infiltration of the kidney, liver, intestine, adrenals, pancreas and pericard by lymphocytes, which were seen in different grade in all our cases.
T320 48546-48858 Sentence denotes In order to understand its nature we were able to prove that the infiltrate was dominated by T lymphocytes (CD3+), and the most numerous of them were CD8+ suppressors, observed in the lungs (Fig. 1a), adrenals (Fig. 1b), liver (Fig. 1c), intestine (Fig. 1d) and other organs partly accompanied by tissue lesions.
T321 48859-49049 Sentence denotes Taking in to consideration that one of the most important mechanisms of autoimmune reactions is CD8+ T Cell mediated cytotoxicity, we assumed that the findings confirm an autoimmune process.
T322 49050-49144 Sentence denotes Further complex studies will hopefully allow us to optimize the strategy of treatment as well.
T323 49145-49212 Sentence denotes Fig. 1 Infiltration by CD8+ suppressor T-cells of different organs.
T324 49213-49217 Sentence denotes IHC.
T325 49218-49236 Sentence denotes Magnification 100.
T326 49237-49286 Sentence denotes A-Lungs, B -Adrenal gland, C-liver, D- intestine.