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Autoimmunity Reviews xxx (xxxx) xxxx Contents lists available at ScienceDirect Autoimmunity Reviews journal homepage: www.elsevier.com/locate/autrev Covid-19 and autoimmunity Michael Ehrenfelda,⁎, Angela Tincanic,d, Laura Andreolid, Marco Cattalinie,j, Assaf Greenbaumf, Darja Kanducg, Jaume Alijotas-Reigh, Vsevolod Zinserlingi, Natalia Semenovai, Howard Amitala,b, Yehuda Shoenfelda,b,c a The Zabludowicz Center for autoimmune diseases, Sheba Medical Center, Israel b The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel c I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation, Sechenov University, Russia d U.O. Reumatologia e Immunologia Clinica, ASST-Spedali Civili di Brescia, Università degli Studi di Brescia, Italy e Pediatrics Clinic, ASST Spedali Civili di Brescia, Brescia, Italy f The Hebrew University, Hadassah Medical School, Jerusalem, Israel g Department of Biosciences, Biotechnologies, and Biopharmaceutics, University of Bari, Italy h Hospital Universitari Vall d'Hebron & Universitat Autònoma de Barcelona, Barcelona, Spain i V.A. Almazov Research Center and S.P. Botkin infectious Hospital, Saint-Petersburg, Russia j Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy 1. Introduction this is the third instance of the emergence of a novel coronavirus, after the severe acute respiratory syndrome (SARS) in 2003 and the Middle Though the exact etiology of autoimmune diseases still remains East respiratory syndrome coronavirus (MERS-CoV) in 2012 [17,18]. In unknown, there are various factors which are believed to contribute to December 2019 a novel outbreak of a new strain of coronavirus infec- the emergence of an autoimmune disease in a host including the genetic tion emerged in Wuhan, China the SARS-CoV-2 or the Covid-19. The predisposition, the environmental triggers such as bacterial infections, disease which was declared as a pandemic in early March 2020, is including the gut microbiota, viral fungal and parasitic infections, as characterized by fever, dry cough, myalgia and or extreme fatigue, may well as physical and environmental agents, hormonal factors and the be asymptomatic or with minimal flu-like constitutional symptoms hosts immune system dysregulation. All these factors interplay was leading to a favorable outcome in many instances. However, some of coined by Shoenfeld et al., many years ago “The Mosaic of the patients encounter a severe pneumonia with sepsis leading to an Autoimmunity” [1–4]. The most prominent pathogenic viruses which acute respiratory distress syndrome (ARDS) with respiratory failure have been proposed in the triggering and initiation of autoimmune requiring mechanical ventilation, and at times accompanied by hy- diseases include: Parvovirus B19, Epstein-Barr-virus (EBV), Cytomega- perferritinemia and multiple organ involvement including hematolo- lovirus (CMV), Herpes virus-6, HTLV-1, Hepatitis A and C virus, and gical, gastrointestinal, neurological and cardiovascular complications Rubella virus [5–11]. These viruses have been implicated in the in- leading to death [19–23]. The ARDS described in up to 20% of Covid-19 itiation of chronic inflammatory or autoimmune diseases such as cases, is reminiscent of the cytokine release syndrome-induced ARDS rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syn- and secondary hemophagocytic lymphohistiocytosis (sHLH) observed drome, primary billiary cholangitis, multiple sclerosis, polymoysitis, in patients with SARS-CoV and MERS-CoV as well as in leukemia pa- uveitis, Henoch Schonlein Puprpura, Systemic Juvenile Idiopathic ar- tients receiving engineered T cell therapy. These cases with Covid-19 thritis, systemic sclerosis, Hashimoto thyroiditis and autoimmune he- are those who develop through the excessive cytokine release and the patitis [12,13]. Suggested mechanisms of induction of the auto- uncontrolled immune activation, the multiorgan failure with a grave immunity include both molecular mimicry [14] as well as “bystander prognosis [24,25]. activation” whereby the infection may lead to activation of antigen presenting cells that may in turn activate pre-primed auto-reactive T- 2. Autoimmune diseases / syndromes potentially associated with cells, thus leading to the production of pro-inflammatory mediators, Covid-19 described so far which in turn may lead to tissue damage [15]. Alternative suggested mechanisms include epitope spreading as well as presentation of cryptic It has been suggested that the shared pathogenetic mechanisms and antigens [16]. clinical-radiological aspects between the hyper-inflammatory diseases Corona viruses represent a major group of viruses mostly affecting and Covid-19 may suggest that SARS-CoV-2 could act as a triggering human beings through zoonotic transmission. In the past two decades, factor for the development of a rapid autoimmune and/or ⁎ Corresponding author at: Rheumatic Disease Unit, The Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel Hashomer 5265601, Israel. E-mail address: ehrenfel@post.tau.ac.il (M. Ehrenfeld). https://doi.org/10.1016/j.autrev.2020.102597 Received 22 May 2020; Accepted 25 May 2020 1568-9972/ © 2020 Elsevier B.V. All rights reserved. Please cite this article as: Michael Ehrenfeld, et al., Autoimmunity Reviews, https://doi.org/10.1016/j.autrev.2020.102597 M. Ehrenfeld, et al. Autoimmunity Reviews xxx (xxxx) xxxx autoinflammatory dysregulation, leading to the severe interstitial autoimmune disorder in which the immune system attacks gangliosides pneumonia, in genetic predisposed individuals [26]. Furthermore, in an on the peripheral nervous system [34,35]. There are so far 2 reports of online pre-published study from Germany the authors studied pro- GBS associated with Covid-19 infection [36,37]. It is yet unclear whe- spectively a group of 22 patients for the possible role of autoimmunity ther Covid-19 induces the production of antibodies against these spe- in SARS-CoV-2 -associated respiratory failure. Based on serological, cific gangliosides. The first is a report of five out of 1200 patients radiological and histomorphological similarities between Covid-19-as- hospitalized between February 28th and March 21st, 2020 in Northern sociated ARDS and acute exacerbation of connective tissue disease in- Italy hospitals. The onset of neurological symptoms began 7–10 days duced interstitial lung disease, the authors suggest that SARS-CoV-2 after the initial respiratory symptoms. Four out of the 5 patients had infection might trigger or simulate a form of organ specific auto- lower-limb weakness and paresthesia and one was with facial diplegia immunity in predisposed patients [27]. In a similar retrospective study followed by ataxia and paresthesia. Generalized, flaccid tetraparesis or from China of 21 patients with critical SARS-CoV-2 pneumonia, the tetraplegia evolved over a period of 36 h to 4 days in 4 of the patients. authors showed a prevalence of between 20 and 50% of autoimmune Three of them required mechanical ventilation. Anti-ganglioside anti- disease related autoantibodies, suggesting the rational for im- bodies were either negative or not done. All patients received IVIG (1 of munosupression in such cases of Covid-19 [28]. then required 2 cycles) and one had started plasma exchange. The second report from Iran describes a 65 year old male patient admitted 3. Immune thrombocytopenic purpura – ITP secondary to COVID- to hospital because of acute progressive symmetric ascending quad- 19 riparesis, two weeks after a history of cough, fever and dyspnea. Covid- 19 was diagnosed by RT-PCR. The patient was treated by hydroxy- Immune thrombocytopaenic purpura (ITP) is an autoimmune sys- chloroquine, Lopinavir/Ritonavir, and Azithromycin. GBS was con- temic disease manifested by the presence of low blood platelets count firmed by EMG. The patient was treated by IVIG for 5 days. Another (<10 [5]/μl) and the production of autoantibodies against glycopro- early report of a single GBS patient came from China during the SARS- teins expressed on the platelet surface. The clinical course is often CoV-2 epidemic, although there is some concern regarding the causality acute, and life-threatening events may occur especially in children, in this particular case [38]. with 52% of pediatric patients recovering either spontaneously or after treatment. A chronic ITP evolution is observed in 64% of adults, of 5. Miller Fisher syndrome (MFS) secondary to COVID-19 whom 12% will develop an overlapping autoimmune disease. Several microbial infections as well as viruses including CMV, EBV parvovirus, MFS is a rare, acquired disease that is considered to be a mild rubella, measles or HIV can potentially trigger ITP through molecular variant of Guillain-Barré syndrome, and is observed in about 5% of all mimicry [29,30].. The association between ITP and Covid-19 has been cases of GBS. It is characterized by a triad of ataxia, areflexia, and suggested in a single case report of a 65-year-old female patient with a ophthalmoplegia. Acute onset of external ophthalmoplegia is a cardinal background history of hypertension, autoimmune hypothyroidism, and feature. Ataxia tends to be out of proportion to the degree of sensory positive swab for Covid-19 who presented with fever, dry cough and loss. Patients may also have mild limb weakness, ptosis, facial palsy, or signs of pneumonia. Laboratory studies were within normal limits and bulbar palsy. Occasionally generalized muscle weakness and re- she was treated by intra-venous amoxicillin–clavulanic acid, low-mo- spiratory failure may develop. Patients have reduced or absent sensory lecular weight heparin and oxygen. The normal platelet count on ad- nerve action potentials and absent tibial H reflex. Like GBS, symptoms mission had gradually dropped to 66,000 and later to 8000 per cubic may be preceded by a viral illness. The majority of individuals with millimeter on day seven accompanied by classical lower-extremity MFS have unique antibodies that characterize the disorder, which are purpura and epistaxis. Both heparin and the antibiotics were dis- Anti-GQ1b and anti-GD1b antibodies. Dense concentrations of GQ1b continued. She was treated by two rounds of IVIG while the platelets ganglioside are found in the oculomotor, trochlear, and abducens had drooped even further to 1000 per cubic millimeter followed by the nerves, which may explain the relationship between anti-GQ1b anti- onset of right frontal headache, with a CT of the head demonstrating bodies and ophthalmoplegia. Treatment for MFS is identical to treat- subarachnoid microhemorrhage. A platelet transfusion was adminis- ment for GBS: intravenous immunoglobulin (IVIG) or plasmapheresis. A tered with concurrent starting of 100 mg of prednisolone. On day 10, group from Spain reported of two patients infected with SARS-CoV-2 the headache had resolved with no new neurologic findings, and the who acutely presented with MFS and polyneuritis cranialis respectively. platelet count had gradually increased to 139,000 on day 13 with a Both patients presented with the typical neurological symptoms. One of complete resolution of the purpura. The temporal sequence in this case the two patients was found to be positive for anti-GD1b-IgG antibodies suggests, but does not prove, that the ITP was triggered by the Covid-19 and was treated with IVIG and the second patient with acetaminophen. especially in view of the history of autoimmune hypothyroidism which Two weeks later, both patients made a complete neurological recovery, is often associated with ITP. There are however other potential causes except for residual anosmia and ageusia in the first case [39]. for the thrombocytopenia in this case such as the treatment with amoxicillin–clavulanic acid as well as the known heparin-induced- 6. Antiphospholipid antibodies and thrombosis secondary to thrombocytopenia (HIT) [31,32]. Another report by Tsao et al. cur- COVID-19 rently online, describes a case of SARS-CoV-2 positive pediatric patient with ITP and raises the awareness of ITP as a possible pediatric pre- Deep vein thrombosis, pulmonary embolism and stroke have been sentation of the virus [33]. observed in patients affected by severe forms of COVID-19 [40,41]. These vascular events, particularly strokes, were mostly recorded in 4. Guillian-Barrė syndrome (GBS) secondary to COVID-19 elderly patients [41]. However, 5 cases of stroke were recently reported in relatively young patients (age range: 33–49 years), in association GBS is a progressive, ascending, symmetrical flaccid limbs paralysis, with prolonged activated partial-thromboplastin time (aPTT) in 2 cases along with areflexia or hyporeflexia with or without cranial nerve in- [42]. volvement which can progress over days to weeks. The disease may be Vascular manifestations of COVID-19 comprise either venous or triggered by respiratory or intestinal infections or vaccinations. The arterial thrombosis or stroke in subjects under the age of 50, sometimes known triggering infections include Influenza; Chlamydia; CMV; var- with a severe phenotype that can resemble the “catastrophic” clinical icella; mumps; rubella; HIV; Polio; Hepatitis E; Borrelia; Mycoplasma picture associated with antiphospholipid antibodies (aPL). In patients pneumonia as well as Campilobacter Jejuni. GBS is an immune-mediated with systemic autoimmune diseases such as Systemic Lupus disorder with molecular mimicry playing an important role in its Erythematosus (SLE), aPL represent the major cause of thrombosis 2 M. Ehrenfeld, et al. Autoimmunity Reviews xxx (xxxx) xxxx (either arterial or venous or microangiopathic) and pregnancy mor- sometimes associated with thrombosis but not always. To our knowl- bidity. aPL are pathogenic autoantibodies that can cause the same edge, no increased rate of miscarriages or fetal loss have been reported vascular and obstetric manifestations also in subjects without any other during SARS-CoV-2 pandemic so far, although some severe pregnancy autoimmune disease, suffering from the so called Primary complication, like those linked to aPL, such as HELLP syndrome were Antiphospholipid Syndrome (APS) [43]. The more severe form of APS occasionally seen (A. Lojacono, personal communication). Whether (the “catastrophic” APS, CAPS) is characterized by a rapidly occurring pregnant women with COVID-19 have an increased rate of positive aPL multiorgan thrombotic damage with histopathological evidence of mi- during pregnancy is not known yet nor it is defined their possible im- croangiopathy [44], recalling pictures described in patients with pact on pregnancy outcome. COVID-19 is a novel infectious disease. COVID-19. CAPS is usually preceded by a precipitating factor, which is The true relationship between this infection and aPL need to be further an infection in the majority of the cases [45]. The link between infec- investigated. However, according to the “second hit hypothesis” [60], tion and aPL was first observed when patients with different auto- the thrombogenic potential of aPL is magnified in the presence of an immune conditions were found to be positive for the serological test of infection or a severe inflammatory state, which is often associated with syphilis, whose antigen was described as a mixture of phospholipids, COVID-19. Therefore, the search for aPL may be considered in the including cardiolipin [46]. Nowadays, the detection of aPL is performed management of COVID-19 patients with vascular manifestations, as the by anticardiolipin (aCL) and anti-beta2glicoprotein I (anti-b2GPI) im- detection of positive aPL would allow of the indication for an early munoassays and by the functional coagulation test lupus anticoagulant adequate anticoagulant treatment. In the case of aPL positivity, a (LA), according to the international consensus APS classification cri- follow-up testing after at least 12 weeks is warranted, in order to verify teria [47]. the persistence of aPL, which would suggest the post-infectious occur- Three cases of COVID-19 patients with severe thrombotic events rence of APS. In fact, APS is currently considered as a systemic auto- associated with aCL and anti-b2GPI were recently reported [48]. Spe- immune disease which is not limited to thrombosis and pregnancy cifically, aCL of IgA isotype and anti-b2GPI of IgG and IgA isotype were morbidity and deserves specific long-term management including an- detected, raising the hypothesis that the mucosal damage induced by ticoagulation and immunomodulation. SARS-CoV-2 could preferentially stimulate the IgA immune response. LA was found to be negative in these 3 patients. 7. Kawasaki like disease secondary to COVID-19 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 Kawasaki disease (KD) is a systemic vasculitis that usually affects anti-b2GPI were positive only in 5 (8.9%). No specific relation with children less than 5 years old. Soon after the first description by thrombosis was mentioned in this cohort [49]. Tomisaku Kawasaki in 1967, it was clear that the disease, although self- In addition, LA was studied in patients with prolonged aPTT, a limiting, might cause coronary artery aneurism (CAA) in a high per- finding that has been frequently reported in COVID-19. More than 90% centage of cases [61]. KD is nowadays considered as the first cause of of patients with prolonged aPTT, with or without clinical evidence of acquired heart disease in children from developed countries [62]. The thrombosis, resulted positive for LA [50]. disease is far more common in eastern countries, and in children of Another study investigated patients with acute respiratory distress eastern origin living in western countries. For example, the 2010 annual syndrome and COVID-19 from intensive care units. In this study, 50 out incidence for KD was 222.9 cases/100000 children <5 y/o in Japan, of 59 (84.7%) tested patients had LA positive, strongly associated with compared to 20/100000 in the USA [63,64]. Since no specific test is high D-dimers and thrombosis, particularly if the test was performed available, diagnosis relies on the recognition of the cardinal clinical early in the disease course. In this series only one patient had positive features and the exclusion of other mimickers. The mainstay of treat- aCL of IgM isotype [51]. ment is the administration of intravenous immunoglobulins (IVIG) at Therefore, we can assume that aPL can be frequently detected in 2 g/kg of body weight, as soon as the diagnosis is established, and patients with SARS-CoV-2 infection. Certainly, this finding is not sur- possibly within 10 days from the onset of fever. IVIG have been de- prising [52]. In fact, the occurrence of transient aPL was described in monstrated to reduce the risk of CAA [65]. A subgroup of patients, patients affected by several viral infections such as human im- accounting for nearly 5% of those with KD, has been described to have a munodeficiency virus (HIV), varicella zoster, hepatitis C virus, cyto- very severe disease onset with systolic hypotension or shock (Kawasaki megalovirus (CMV), Epstein–Barr virus (EBV), adenovirus, parvovirus Shock Syndrome-KSS). The shock may be caused by a capillary leak B19 [53]. In addition, aPL were also detected in patients with infections syndrome or by poor perfusion due to inflammatory myocarditis. KSS of different origin (bacterial, parasitic, etc) and an infection was often patients are more likely to be females and to have earlier onset, in- reported just before the clinical onset of APS [54]. These observations complete presentations, and more severe laboratory abnormalities suggest the possible existence of molecular mimicry due to similarity (lower platelet counts, higher serum CRP levels, hyponatremia, in- between the peptide regions identified in the b2GPI molecule (and re- creased transaminases, metabolic acidosis, consumptive coagulopathy, cognized by anti-b2GPI) and membrane proteins of several virus and and lower serum albumin levels). Patients with KSS are often resistant bacteria [55]. Animals immunized with different viruses or bacteria (or to IVIG treatment and have a higher incidence of coronary artery an- proteins derived from them) developed anti-b2GPI antibodies that in eurysms, mitral regurgitation, and prolonged myocardial dysfunction some cases were associated with the occurrence of thrombosis [56]. The [66]. different pathogenic potential of antibodies can be attributed to the fine Northern Italy was the first European region to be severely hit by specificity that they acquire after immunization with different antigens. the SARS-COV2 epidemic after the original outbreak in China [67]. It is in fact known that antibodies directed to domain 1 of the b2GPI Although the data on the clinical presentation of COVID-19 in children molecule are associated with an increased risk of thrombosis (in sys- is still scarce, lower rates of infection and milder forms of disease seem temic autoimmune diseases and APS) [57] while antibodies directed to to be typical of this age group [68,69]. Since the end of March 2020, we other parts of the molecule, such as domain 4/5, can be regarded as observed and treated or received information from all over Italy about “innocent” [58]. On the other hand, the features of the host can also be an abnormally elevated number of critically ill patients with clinical important, since genetic background is recognized as one of the de- characteristics consistent with Kawasaki Shock Syndrome (KSS). The terminant factors in the induction of autoimmunity and can be the common features were: “middle-aged” children (6–9 y/o) with a history driver which turns aPL from being transient to persistent and patho- of persistent high spiking fever in the previous days, abdominal pain, genic [59]. diarrhea, skin rash, and rapidly deteriorating clinical conditions with The above considerations widely justify why aPL, detected with the onset of shock, without clear signs of dehydration. Other less different assays, can be found in patients affected by COVID-19, common features were arthralgia, cough, meningism, conjunctivitis and 3 M. Ehrenfeld, et al. Autoimmunity Reviews xxx (xxxx) xxxx reddened, cracked lips. Labworks usually showed high inflammatory Table 1 markers, low lymphocyte count, low sodium, and high troponin and Heptapeptide sharing between SARS-CoV-2 spike glycoprotein and the human pro-BNP levels. Echocardiography was consistent with myocarditis in proteins. the majority of patients instead of classical coronary artery abnormal- Peptide Human Protein Name ities. Patients were diagnosed as Kawasaki disease (typical or in- complete) and treated accordingly with IVIG and/or steroids. One pa- SSTASAL 40S ribosomal protein S13 KLNDLCF Interleukin-7 tient refractory to such treatments responded successfully to FLPFFSN OTU domain-containing protein 6A intravenous anakinra. Althoug all the patients had family contacts EIDRLNE Protein SET consistent with COVID-19, serology and nasopharyngeal swabs were IGAGICA Hepatitis A virus cellular receptor 2 inconsistently positive both in the single patients and among all chil- EIDRLNE Protein SETSIP LDKYFKN Follistatin-related protein 1 dren. To date we are aware of at least 10 cases of KSS possibly related to VSGTNGT Lysosome-associated membrane glycoprotein 1 COVID-19. Given the unprecedented cluster of patients we decided to FKNLREF Isovaleryl-CoA dehydrogenase, mitochondrial launch a nationwide alert for pediatricians and start a national registry. LPPLLTD Maestro heat-like repeat-containing protein family member 9 Few days after the diagnosis of our first cases, news from all over DKVFRSS Zinc finger protein 528 Europe first, and Eastern USA thereafter, reported on the identification LVKQLSS E3 SUMO-protein ligase PIAS1 VTLADAG Non-receptor tyrosine-protein kinase TNK1 of patients with remarkably the same characteristics we have observed. RRARSVAS Amiloride-sensitive sodium channel subunit alpha Some children with a less severe picture, without shock at the onset, but SPRRARS Hermansky-Pudlak syndrome 1 protein with clinical characteristics of systemic inflammation and some features KVEAEVQ EMILIN-3 of KD have also been seen by us and others (personal communications). TRFQTLL Disheveled-associated activator of morphogenesis 2 VYSTGSN Neural cell adhesion molecule L1-like protein These observations lead to a variety of nationwide alerts in the re- GLTVLPP FH1/FH2 domain-containing protein 3 spective countries [70,71]. On May 7, 2020, Riphagen et al. published SLLIVNN ATP-binding cassette sub-family A member 10 on 8 patients treated at the South Thames Retrieval Service for a severe DEDDSEPV Unconventional myosin-XVI acute illness similar to KSS [72]. Age at presentation was between 4 and NASVVNI Thyroid adenoma-associated protein 14 years, 6 out of 8 children were of Afro-Caribbean descent and 5 were LIRAAEI Unconventional myosin-XVIIIa TGRLQSL Neuron navigator 3 boys. All the children had a similar disease onset with persistent fever, DEVRQIA Histone-lysine N-methyltransferase 2C skin rash, conjunctivitis, peripheral oedema, and extremity pain. Gas- SSSGWTA Transmembrane protein KIAA1109 trointestinal symptoms were frequent and severe, all children devel- oped shock requiring ICU admission and vasopressors. Another key Data on protein function/disease from Uniprot (https://www.uniprot.org/). feature described in those patients was the cardiac involvement, as Sequential overlapping heptapeptides are given bold. testified by very elevated cardiac enzymes, and echo-bright coronary vessels. One patient developed a giant coronary aneurism. Lab works which is rarely seen in children, during the peak of SARS-CoV2 infec- typically showed high C-reactive protein, procalcitonin, ferritin, tri- tion in highly epidemic areas, points to a causative link. One hypothesis glycerides, and D-dimers. All children were treated with IVIG (2 g/kg) is that these children were suffering from actual KD triggered by the and 6 also received aspirin (50 mg/kg). Broncho-alveolar lavage or SARS-CoV-2 virus. Indeed, a microbial etiology has been long ad- nasopharyngeal aspirates were negative for SARS-COV-2 in all children; vocated as a possible cause for KD. Many viruses (HHV-6, Epstein Barr some of the patients had histories of familial contact with the virus. The virus, Cytomegalovirus, Coronavirus other than SARS-CoV-2, authors stated that, at the time they were writing their report, another Parvovirus B19 etc.) but also bacterial infections (such as staphylococci, ICU in London managed 20 patients with similar characteristics. As per streptococci, Bartonella, and Yersinia) have been linked to KD. the Royal College of Pediatrics and Child Health (RCPCH) alert, some of Interestingly enough, a case of classic KD has been recently reported in these patients resulted to be positive for SARS-CoV-2 infection, by ei- a 6 months-old child who tested positive for SARS-CoV-2, although this ther nasopharyngeal swab, serology, or both [69]. The New York State could be just coincidental [75]. The clinical and laboratory character- Department of Health reported sixty-four cases as of May 5th 2020. For istics of the patients recently described are strikingly similar to the KSS the purpose of this review we will refer to this clinical entity as Pe- typical picture, except for the older age, male predominance and rela- diatric COVID-19 Hyperinflammatory Syndrome (PeCOHS), while the tively low frequency of coronary artery aneurysms [65]. Given these English authorities refers to it as Pediatric inflammatory multisystem differences, it can be speculated that this COVID-19 Hyperinflammatory syndrome temporally associated with SARS-CoV-2 infection (PIMS-TS). Syndrome is indeed a systemic vasculitis peculiar of the pediatric age Verdoni et al. published the first Italian experience on 10 patients and caused by SARS-CoV-2 infection. admitted to their hospital for Kawasaki-like disease from February 18th How SARS-CoV-2 infection may cause a hyperinflammatory syn- to April 20th, 2020 (during the peak of COVID19 epidemic in Italy). drome? At this point we can only formulate hypotheses, based on the Very nicely, the authors compared these children (group 2) to the clinical picture of the observed patients and using other diseases with historical cohort of KD patients seen in the last 5 years (group 1, 19 overlapping manifestations, such as KD and Toxic Shock Syndrome patients). Half of the children in group 2 presented with classic KD, (TSS), as models. The delay between the pandemic peak of COVID-19 while half were diagnosed as incomplete KD. Half of the patients and the occurrence of this hyperinflammatory syndrome in children showed hypotension and signs of hypoperfusion at onset, and were does not point to a direct effect of the infection, but rather towards an interpreted as KSS, and half had signs of myocarditis at echocardio- immune-mediated disease. This seems to be confirmed also by the ob- gram. Pro-BNP was above normal values in all the patients. Half of the servation of Verdoni et al. that the majority of their patients had po- patients satisfied the PRINTO laboratory criteria for Macrophage sitive SARS-CoV-2 IgG, but negative IgM and swabs. Staphylococcal or Activation Syndrome (MAS) [73]. Two patients developed CAAs. Pa- Streptococcal TSS are the result of T cells induction by superantigens tients in group 2 displayed older age, a higher frequency of gastro- TSST-1, enterotoxins B or C (staphylococci), or pyrogenic exotoxin A or intestinal and respiratory symptoms, meningeal signs, myocarditis, B (streptococci). Superantigens can stimulate clonal T cell proliferation shock syndrome, and MAS criteria as compared with group 1. Naso- and this leads to the production of massive amounts of pro-in- pharyngeal swab for SARS-CoV-2 was positive in 2 patients only, 8 flammatory cytokines, as IL-1, IL-6, and IFN-γ in a so-called cytokine patients had positive IgG while 3 patients had positive IgM (all of whom storm [76]. There is a body of evidence suggesting that KD may be were positive also for IgG) for SARS-CoV-2. All patients from group 2 caused by a superantigen response, and recent data demonstrated that were treated with IVIG and steroids, with good clinical outcome [74]. KSS is characterized by a massive pro-inflammatory cytokine release The occurrence of such cases with a stereotyped clinical picture, that differentiate those patients from the “regular” KD patients [77]. 4 M. Ehrenfeld, et al. Autoimmunity Reviews xxx (xxxx) xxxx Fig. 1. Infiltration by CD8+ suppressor T-cells of different organs. IHC. Magnification 100. A-Lungs, B -Adrenal gland, C-liver, D- intestine. This cytokine storm could be the underlying mechanism leading to the adults with COVID-19 and hyperinflammation [82]. clinical picture similar of that of TSS, KSS, and PeCOHS. In conclusion, although SARS-CoV-2 infection appears to occur as a Other possible mechanisms by which SARS-CoV-2 could induce a oligo-symptomatic form in the majority of children, there is mounting hyperinflammatory syndrome are: i) the autoantibodies formation evidence that it can cause a systemic hyperinflammatory syndrome that through “molecular mimicry”, as in Acute Rheumatic Fever (although mimics KSS, but has some peculiar features. The role of host and virus this mechanism would not justify the occurrence of shock); ii) a vas- genetics and the exact immune mechanisms leading to the disease are cular damage secondary to the deposition of immune-complexes as in far from been understood, and case collection would help us in better acute serum sickness; iii) an antibody-dependent enhancement (ADE) characterization of the clinical phenotype. As light has been shed on the with IgG immune complexes that enhance virus infection in Fc-re- interaction between SARS-CoV-2 and the immune system, we will gain ceptor-bearing cells. Intriguingly, this phenomenon is the cause of hints also at Kawasaki Disease pathogenesis, almost 50 years from its Dengue vascular permeability syndrome, which, again, shares some first description by Tomisaku Kawasaki. similarities with PeCOHS [78]. ADE were demonstrated in SARS-CoV infection years ago, mediated by antibodies directed to the envelope 8. Preexisting autoimmune rheumatic diseases and COVID-19 spike proteins [79]. infection Children with SARS-CoV-2 infection usually have a benign course [67]. Differently from what we usually see in Kawasaki Disease, which Since the breakout of the Covid-19 in late 2019 in China, many has a predilection for asian countries, PeCOHS has not been described unresolved issues regarding both dealing with the fate of the preexisting so far in those countries, suggesting that both the genetic predisposition autoimmune rheumatic diseases in patients who are affected by the of the host and differences in the viral genome may play a role in this virus including those under immunosuppressive and biologic therapy, disease. as well as the impact of these therapies on the severity of the viral To our knowledge, the majority of patients with PeCOHS respond to disease itself. Early reports in the course of the pandemia suggested that a variable combination of steroids and IVIG. The discussion about the based on the data recovered from other and previous viral infections, immunomodulatory effects of both steroids and IVIG is beyond the there would be an increased probability for patients with rheumatic scope of this review, but it is interesting to highlight that one of the diseases to acquire the Covid-19 disease or are they prone to an in- many effects of IVIG is the down modulation of superantigens [80]. Of creased severity of the infection if they do acquire it. On the contrary, note, IVIG is the therapy of choice in the capillary leak syndrome, however, early on, there was some evidence regarding the potential whose main features are similar to KSS and PeCOHS [81]. Finally, the benefit of some of the drugs which have been used in the therapy of efficacy of anti-IL-1 treatment as “rescue therapy” for cases resistant to rheumatic disease [83,84]. IVIG+steroids points out the relevance of this pro-inflammatory cyto- Patients with SLE had posed a serious concern during the Covid-19 kine in the hyperinflammatory state, similar to what already shown in pandemia. This group of patients is well known to bear an increased 5 M. Ehrenfeld, et al. Autoimmunity Reviews xxx (xxxx) xxxx risk of severe infections, due to both their immune system and the re- recovery of their symptoms. The authors concluded that only 5 out of lated organ damage as well as due to the therapies used including im- their 123 patients had discontinued their current rheumatological munosuppressive drugs. In a report of 19 SLE patients from France who therapy, with none of the rest 115 patients experiencing flare-ups of were clinically quiescent on a long-term treatment with their disease. Similarly, Conticini et al recently reported of a large co- Hydroxychloroquine (HCQ) and were infected by the Covid-19 virus, hort of 859 patients from Italy affected by different rheumatic diseases, the authors were able to conclude that the clinical course of these lupus which were treated by biological DMARDs or by targeted synthetic patients did not show any signs of the disease exacerbation, except for a DMARDs [95]. Only 2 patients who were both on biologics (rituximab single case of tenosynovitis [85]. A preliminary analysis of patients or tocilizumab), were diagnosed with COVID-19, one of which even included in the COVID-19 Global Rheumatology Alliance registry, with bilateral diffuse interstitial pneumonia. Both patients had a com- showed that 17% of 110 patients with rheumatic diseases who have plete recovery without interruption of the biological treatment. Similar been diagnosed with COVID-19 as of April the 1st, 2020- were patients favorable outcome has been reported for few cases with large-vessel with lupus [86]. Thus the frequency of patients with lupus who have vasculitis and granulomatosis with polyangiitis associated with Covid- been diagnosed with COVID-19 was over-represented, at about twice as 19 infection [96,97]. Thus it seems that baseline use of biologics is not compared to rheumatoid arthritis which is a much commoner rheu- associated with worse Covid-19 outcomes. The situation might be dif- matic disease among the adult population. In a recent small report from ferent with patients suffering from systemic sclerosis, where the typical northern Italy of SLE patients with either swab confirmed Covid-19 interstitial lung disease (ILD) could share some CT features with Covid- infection (n = 4) or a clinical diagnosis, based on 3 out of 4 symptoms 19 associated pneumonia [98–100]. Currently the impact of pre-ex- of the viral infection (n = 8), the authors stated that the disease course isting systemic sclerosis associated with pulmonary and cardiac in- was generally mild and self-resolving although one of the four patients volvement, on the course of Covid-19 is yet unknown. Such a single who was on haemodialysis due to end-stage renal disease, needed in- case with scleroderma associated ILD and polyarthritis, who had been tensive care for the development of acute respiratory distress syndrome previously treated with anti-interleukin-6 receptor blocker (Tocili- [87]. Based on the clinical information published to date from the new zumab) with a favorable response, was recently reported [101]. In the and previous outbreaks caused by the coronaviruses, there is no over- course of this therapy, 4 weeks after the last tocilizumab infusion, she whelming evidence that patients with rheumatic disease are at an in- reported a contact with Covid-19 and was found to be positive for the creased risk compared with other comorbidities [88–90]. In a rather virus by a nasopharyngeal swab. Her condition remained stable during larger prospective report from New York, the authors reviewed a group the course of the acute disease and following a negative swab and cure, of 86 patients with immune-mediated inflammatory disease including she had received the next scheduled tocilizumab injection. It should be 59 cases of inflammatory arthritides (rheumatoid arthritis, psoriatic noted that early reports from China during the outbreak of the SARS- arthritis, ankylosing spondylitis, psoriasis and inflammatory bowel Cov2 were able to demonstrate increased levels of IL-6 and CRP, sug- disease) with confirmed Covid-19, and 27 additional patients with gesting that this subgroup of patients may develop the Covid19 related suspected Covid-19 [91]. Two-thirds of the patients were on biologics cytokine storm. Randomized trials using anti-IL-6 receptor monoclonal or other immunomodulatory drugs. Hospitalized patients, as compared antibody are currently ongoing. Recently many countries and organi- to those who were only followed on an out-patient basis, had more zations have set up registries incorporating patients with pre-existing classical Covid-19 comorbidities. Conventional DMARDs were used rheumatic and autoimmune diseases who had encountered a Covid-19 more frequently in the hospitalized group of patients, whereas biologics infection. The largest international registries include The Global were more often used in the ambulatory group of patients. The authors Rheumatology Alliance of Covid-19 and the Eular Covid-19 database. suggest that based on their findings the baseline use of biologics was not associated with worse Covid-19 outcomes. In another small report 9. Therapy - using rheumatologic drugs in COVID-19 infection from China five patients with rheumatic disease and Covid-19 are de- scribed [92]. Four had rheumatoid arthritis and one with systemic Many countries and organizations have published guidelines for sclerosis. All 5 patients had chest CT showing patchy ground glass treatment of the COVID-19 pandemic. Of note are the Treatment opacities in the lungs. All 5 patients were treated with antiviral agents, Guidelines of the National Institutes of Health and the American antibiotics and the immunomodulatory agents for their rheumatic dis- College of Rheumatology guidance for the management of adult pa- ease. Two of the 5 patients remained in stable condition in the course of tients with rheumatic disease during the COVID-19 pandemic the hospitalization, 2 progressed to severe Covid-19 and one was cri- [102,103]. tically ill, though all patients recovered and were discharged from Chloroquine and Hydroxychloroquine, are anti malarial drugs, hospital. Similarly, a report by Monti et al. [93] suggested that patients used to treat autoimmune diseases, such as systemic lupus er- with rheumatoid arthritis treated with biological DMARDs or targeted ythematosus (SLE) and rheumatoid arthritis (RA). Both chloroquine and synthetic DMARDs did not seem to be at increased risk of life-threa- hydroxychloroquine (HCQ) have immunomodulatory effects. In gen- tening complications from Covid-19 compared with the general popu- eral, HCQ has fewer and less severe toxicities (including fewer pro- lation. Another recent study from Italy supports the approach of en- pensities to prolong the QTc interval) and fewer drug-drug interactions couraging connective tissue disease patients to maintain the ongoing than chloroquine. The proposed mechanisms of action and rationale for rheumatologic therapy as well as adhere to the measures of infection use for COVID-19 of both drugs have to do with the increase of the prevention, thus avoiding relapse of the rheumatic disease without in- endosomal pH, inhibiting fusion of the severe acute respiratory syn- creasing the risk of Covid-19 [94]. Their study population included 123 drome coronavirus 2 (SARS-CoV-2) and the host cell membranes. adult patients (110 females) with systemic lupus erythematosus Furthermore, Chloroquine inhibits glycosylation of the cellular angio- (n = 61), systemic sclerosis (n = 43), undifferentiated connective tensin-converting enzyme 2 receptor, which may interfere with binding tissue disease (n = 9) and Sjogren syndrome (n = 10). About 60% of of SARS-CoV to the cell receptor. In vitro, both chloroquine and HCQ the patients were treated with conventional DMARDs, with a similar may block the transport of SARS-CoV-2 from early endosomes to en- percentage of patients taking corticosteroids as well. Twenty five of the dolysosomes, which may be required for release of the viral genome, 110 patients received biologics. Only one rather young female patient and several studies have demonstrated in vitro activity of chloroquine with systemic sclerosis was found to be positive for Covid-19 and de- against SARS-CoV [104,105]. Though HCQ has been administered to veloped a critical course with interstitial pneumonia leading to her patients with Covid-19 there are to date no robust evidence supporting death despite intubation and an attempt with tocilizumab. A further 14 its use. In a retrospective computerized database of 1317 positive patients reported mild respiratory symptoms compatible with a viral subjects for Covid-19 out of a sample size of 14,520, a comparison was infection but did not have access to a swab test and showed a rapid conducted between those who tested positive versus those who were 6 M. Ehrenfeld, et al. Autoimmunity Reviews xxx (xxxx) xxxx found negative, in terms of the rate of administration of HCQ or col- 12. Covid-19 and autoimmunity: The role of molecular mimicry chicine. The authors did not find any significant difference in terms of the rates of usage of either drug, thus they concluded that their findings Notwithstanding the current wave of intensive worldwide research, raise doubts regarding the protective role of both these medication in the ethiopathology of the diseases induced by the SARS-CoV-2 infection the battle against SARS-CoV-2 infection [106]. Similar results were is the central question that remains obscure. One likely explanation is drawn by a study from a large medical center in New York. The authors that the heterogeneity and multitude of the disorders induced by the examined the association between HCQ use and intubation or death current pandemic derive from molecular mimicry phenomena between among a group of 1446 consecutive patients. HCQ administration was the virus and human proteins. The scientific rationale is that, following not associated with either a greatly lowered or an increased risk of the infection, the immune responses raised against SARS-CoV-2 may intubation or death [107]. Many similar reports came to the same cross-react with human proteins that share peptide sequences with the conclusions [108–110], to the extent that the FDA has issued a safety virus, in this way leading to autoimmune pathologic sequelae [120]. alert and the American College of Physicians has as well recommended Actually, a recent report [121] militates in this direction and likely against the use of chloroquine or HCQ for COVID-19 [111,112]. Fur- explains lungs and airways dysfunctions through the sharing of peptides thermore, an attempt to evaluate HCQ serum or plasma levels from between SARS-CoV-2 glycoprotein and alveolar lung surfactant proteins various rheumatic disease patients receiving this treatment, found that [121]. Moreover, in the clinical context exposed above, it is of note to these plasma or serum levels were unlikely to achieve the concentration report that Sars.CoV-2 shares 6 minimal immune determinants (KTVLK, shown to inhibit SARS-CoV-2 in vitro (average target 0.48 mg/L as TPEEH, RETMS, PFVVS, GLEAP, ICLLQ) with the Kawasaki antigen opposed to the antiviral target of 4/1 mg/L) [113]. Inositol-trisphosphate 3-kinase C [122], thus highlighting as likely cross-reactions and consequent autoimmune Kawasaki disease in pre- disposed subjects. Even more impressing it appears the heptapeptide 10. Anti-IL-6 receptor antibodies – Tocilizumab and Sarilumab sharing between the human proteome and the viral spike glycoprotein shown in Table 1. The clinical scenario that emerges is upsetting. In- IL-6 is a pleiotropic, pro-inflammatory cytokine produced by a deed, the list of proteins reported in the table – when altered – con- variety of cell types, including lymphocytes, monocytes, and fibro- figurate almost all the diseases that have been described in association blasts. Infection by the related SARS-CoV induces a dose-dependent with SARS-CoV-2. Two examples from the table are 1) Histone-lysine N- production of IL-6 from bronchial epithelial cells. Elevations in IL-6 methyltransferase 2C that may associate with neurodevelopmental levels may be an important mediator when severe systemic in- disorders., seizures, behavioral abnormalities [123], and 2) Interleukin- flammatory responses occur in patients with SARS-CoV-2 infection. 7 that plays a central, critical role in the regulation of the immune COVID-19-associated systemic inflammation and hypoxic respiratory system and associates with severe lymphopenia when deficient [124]. failure is associated with an acute cytokine release, as indicated by elevated blood levels of IL-6, C-reactive protein (CRP), D-dimer, and 13. The Covid-19 vaccine and the constraint of molecular mimicry ferritin [114–116]. Few clinical studies aiming to evaluate the efficacy of anti-IL-6 receptor blocker have been published so far. In a report The extent of the molecular mimicry between SARS-CoV-2 and the from China by Xu et al. the authors were able to show that tocilizumab human proteome should be carefully analyzed as a mandatory step effectively improved clinical symptoms as well as reversed the dete- preliminarily to any vaccine formulation As a matter of fact, because of rioration of sever Covid-19 patients [117]. Within 5 days after tocili- the pathogen–host peptide commonality, a potential consequence of zumab, 15 of the 20 patients had lowered their oxygen intake and 19 of vaccination might consist of a specific autoimmune reactions hitting the 20 showed a noticeable improvement in the CT of the lungs, as well self-antigens such as the already analyzed alveolar surfactant protein as a significant reduction in CRP levels which was noted in 16 of the 19 [121]. Only peptide sequences uniquely belonging to the virus can re- patients. All patients have been discharged on an average of 15 days present the basis for safe and specific vaccinations protocols [125–127]. after the tocilizumab dosing. Even though this is a small and un- controlled study, the results seem to be impressive. Over 20 randomized 14. Probable histopathological signs of autoimmune reactions in controlled trials with tocilizumab, or sarilumab as well as JAK-in- COVID-19 hibitors as baricitinib, are underway. Based upon the possibility to detect autoimmune reactions by morphological methods we analyzed autopsies from 18 deceased pa- 11. Interleukin-1 (IL-1) inhibitors – Anakinra tients from COVID-19. The pathological investigation was done by using bright lineage of immunohistochemistry (CD2, 3, 5, 7, 8, 20, 31, Anakinra is a recombinant human IL-1 receptor antagonist. It is 34, 69). Our study allowed us to demonstrate the role of different approved to treat rheumatoid arthritis and cryopyrin-associated peri- mechanisms of death [128]. Of special interest was the diffuse in- odic syndromes, and it is also used off-label for a variety of in- filtration of the lungs, along with focal infiltration of the kidney, liver, flammatory conditions and severe chimeric antigen receptor T cell intestine, adrenals, pancreas and pericard by lymphocytes, which were (CAR-T)-mediated cytokine release syndrome (CRS) and macrophage seen in different grade in all our cases. In order to understand its nature activation syndrome (MAS)/secondary hemophagocytic lymphohistio- we were able to prove that the infiltrate was dominated by T lympho- cytosis. A case series of anakinra use in moderate to severe COVID-19 cytes (CD3+), and the most numerous of them were CD8+ sup- pneumonia has recently been published [118]. This small study of 9 pressors, observed in the lungs (Fig. 1a), adrenals (Fig. 1b), liver patients with moderate to severe Covid-19 pneumonia, who did not (Fig. 1c), intestine (Fig. 1d) and other organs partly accompanied by reach respiratory failure and were given anakinra (Anti-IL-1), serves as tissue lesions. Taking in to consideration that one of the most important a proof of concept since all 9 patients had dropped their fever, mechanisms of autoimmune reactions is CD8+ T Cell mediated cyto- CRP levels had dropped and normalized in 5 out of 8 patients at day toxicity, we assumed that the findings confirm an autoimmune process. 11. CT scans did not deteriorate and all were alive at the last follow up. 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