Autoimmunity as the comet tail of COVID-19 pandemic

Table 1 Studies describing autoimmune disorders during coronavirus disease 2019

Ref.	Year	Number of subjects	Type of study	Comments
Harzallah et al[117]	2020	56	Retrospective cohort analysis	Positivity of LAC and anti-cardiolipin/anti-β2-glycoprotein IgG or IgM in 45% and 10% of COVID-19 patients, respectively
Zhou et al[123]	2020	21	Case series	Positivity of anti-52 kDa Ro-SSA, anti-60 kDa Ro-SSA antibodies and ANA in 20%, 25% and 50% of critically or severely ill COVID-19 patients, respectively. Anti-SCL70, ACA, anti-U1-RNP, anti-Jo1, anti-Sm-D1, anti-dsDNA antibodies and RF not detected
Gao et al[122]	2020	10	Case series	Positivity of ACPA in 20% of COVID-19 patients with ANA and RF negative
Helms et al[118]	2020	150	Retrospective cohort analysis	Thromboembolic events reported in 64 COVID-19 cases; positivity of LAC in 87.7% of the tested patient cohort (57 individuals)
Zhang et al[19]	2020	3	Case series	Ischemia of upper and lower limbs and cerebral infarcts in 3 COVID-19 patients with positivity of anti-cardiolipin and anti-β2-glycoprotein IgA and IgG
Pilotto et al[136]	2020	1	Case report	Immune-mediated encephalitis in a 60-year-old man recovering with i.v. pulses of methylprednisolone (1 g/d for five days)
Ottaviani et al[137]	2020	1	Case report	Guillain-Barré syndrome occurring in a 66-year-old woman 10 days after the recovery from cough, rash and fever; neurological symptoms worsening with the development of transient episodes of confusion and psychomotor agitation. Progressive worsening of gas exchanges ending in a multi-organ failure
Zhao et al[12]	2020	1	Case report	Guillain-Barré syndrome as the first COVID-19 manifestation in a 61-year-old woman; SARS occurring 8 days later. Neurologic symptoms disappearing at COVID-19 recovery
Lazarian et al[13]	2020	7	Case series	Autoimmune hemolytic anemia developing after a mean delay of 9 days since the first COVID-19 symptoms and sustained by either warm or cold IgG; association with pre-existent lympho-proliferative disorders, partial response to steroid and rituximab
Zagorski et al[141]	2020	1	Case report	Hemolytic anemia sustained by cold agglutinins in a 46-year-old woman, admitted to hospital with fever, jaundice and dyspnea; SARS-CoV-2 RT-PCR and direct Coombs test positive and detection of cold IgG and complement. Rapidly fatal course of COVID-19 due to cardiogenic shock
Capes et al[142]	2020	1	Case report	Hemolytic anemia sustained by cold agglutinins in a 62-year-old oncologic male patient with COVID-19 (asthenia, fever, dyspnea with bilateral lung infiltrates); SARS-CoV-2 RT-PCR, direct Coombs test and ANA positive; anti-ENA and APL antibodies negative
Zulfiqar et al[14]	2020	1	Case report	Immune thrombocytopenic purpura developing 8 days after the first COVID-19 symptoms managed with platelet transfusion, i.v. prednisolone, eltrombopag and IVIG; anti-platelet antibodies not detected
Li et al[143]	2020	1	Case report	Evans syndrome developing in a 39-year-old man complaining of classical symptoms of COVID-19; chronological distance between thrombocytopenia, present at admission, and hemolytic anemia, occurring after discharge
Beydon et al[15]	2020	1	Case report	Myositis of the proximal lower limb muscles as the exordium manifestation of COVID-19, confirmed by CK serum increase and MRI findings and followed by fever and respiratory symptoms. SARS-CoV-2 detected in bronchoalveolar lavage fluid but not in nasopharyngeal swab
Craver et al[16]	2020	1	Case report	Fatal eosinophilic myocarditis in a 17-year-old male patient
Coyle et al[154]	2020	1	Case report	Myocarditis and ARDS recovering with steroids, anti-IL-6R and aldose reductase inhibitor
Andina et al[17]	2020	22	Retrospective case series	Chilblains of the feet and fingers in a pediatric cohort (median age 12 years) following respiratory and gastrointestinal symptoms (median time delay 1-28 days); oropharyngeal swab positive for SARS-CoV-2 only in one case. Rapid recovery with symptomatic oral or topical drugs
Landa et al[156]	2020	6	Case series	Chilblain-like lesions of toe, fingers and heels in an asymptomatic 31-year median aged cohort of patients; respiratory symptoms and fever reported in few of them 3-4 weeks before; oropharyngeal swab positive for SARS-CoV-2 in 2 cases
Verdoni et al[164]	2020	29	Observational study	30-fold increase in Kawasaki vasculitis and MAS in SARS-CoV-2-infected compared to non-infected children (mean age 7.5 years); frequent cases of shock syndrome and cardiac involvement requiring high dose steroidal therapy in addition to IVIG
Toubiana et al[168]	2020	21	Prospective observational study	Kawasaki syndrome reported in 21 subjects (median age 7.9 years, 12 females, 12 of African descent, 90% being SARS-CoV-2 positive at nasopharyngeal swab or at blood test for anti-SARS-CoV-2 IgG); myocarditis found in 76% of patients; gastrointestinal involvement present in 100% of patients; coronary artery dilatation found in 24% of patients. Rapid recovery in all the cases with IVIG and steroids
Licciardi et al[18]	2020	2	Case series	Kawasaki-like syndrome developing in two SARS-CoV-2-infected male children (7-year-old and 12-year-old), characterized by fever, mucocutaneous manifestations, blood cytopenia, complement consumption, hypoalbuminemia, increased serum ferritin and inflammatory markers and cardiac injury recovering with i.v. methylprednisolone and IVIG. Nasopharyngeal swab negative for SARS-CoV-2; anti-SARS-CoV-2 antibodies present
Deza Leon et al[165]	2020	1	Case report	Kawasaki-like syndrome developing in a 6-year-old female, along with respiratory distress, hypotension and myocarditis, treated with antibiotics, IVIG, aspirin and extra corporeal membrane oxygenation. Nasopharyngeal swab for SARS-CoV-2 and Group A Streptococcus nasopharyngeal rapid test positive
Rivera-Figueroa et al[166]	2020	1	Case report	Incomplete Kawasaki disease in a 5-year-old male patient, characterized by mucocutaneous manifestations, cervical lymphadenopathy, pericardial effusion and hypotension. Resolution after supportive therapy, IVIG, i.v. steroids and aspirin. Nasopharyngeal swab for SARS-CoV-2 and Group A Streptococcus nasopharyngeal rapid test positive
Pouletty et al[167]	2020	16	Multicentre retrospective case-control analysis	Kawasaki and Kawasaki-like syndromes reported in a cohort of 16 patients (median age 10 years); complete form described in 10 cases and cardiogenic shock developing in 7 patients; SARS-CoV-2 detected in nasopharyngeal secretions and stool in 9 and 2 patients, respectively; serology positive in 7 out of 8 patients. Limited response to single IVIG infusion; additional lines of treatment (multiple infusions of IVIG, steroids, IL-1 or IL-6 inhibitors and ASA) required
Belhadjer et al[173]	2020	35	Case series	MIS-C (fever, cardiogenic shock, increased CRP serum value and acute left ventricle failure) described in pediatric patients (median age 10 years) admitted to French and Swiss hospitals from March to April 2020. Gastrointestinal symptoms reported in 80% of cases and SARS-CoV-2 positivity detected in 88.5% of cases (positive nasopharyngeal swab in 34% of patients and presence of anti-SARS-CoV-2 antibodies in 86% of individuals). Cardiogenic shock present in 80% of subjects at admission; Takotsubo syndrome, pericardial effusion and coronary artery dilatation without aneurysms also described. Rapid resolution with i.v. supportive therapy, IVIG, steroids. Anakinra required in 3 cases
Feldstein et al[177]	2020	186	Retrospective cohort analysis	MIS-C reported in 186 United States patients (median age 8.3 years, 115 males), 70% of whom testing positive for SARS-CoV-2 (RT-PCR and/or antibodies). Gastrointestinal symptoms most commonly reported (92% of cases), followed by cardiovascular (80% of cases), hematological (76% of cases), mucocutaneous (74% of cases) and respiratory (70% of cases) manifestations. Detection of coronary artery aneurysms in 8% of cases and death occurring in 4 patients. Treatment based on the administration of IVIG, steroids, IL-6- and IL-1-inhibitors beyond supportive therapy
Dufort et al[178]	2020	191	Retrospective cohort analysis	SARS-CoV-2-related MIS-C identified in 99 out of the 191 reported cases to the NYSDOH (53 males mostly aged 6-12 years; 40% black and 36% Hispanic); fever and increased systemic inflammatory markers described in all the patients; gastrointestinal symptoms occurring in 80% of patients, followed by cutaneous (60% of cases), ocular (56% of cases), and mucosal (27% of cases) manifestations; myocarditis detected in 53% of patients; 2 deaths recorded
Whittaker et al[175]	2020	58	Case series	MIS-C described in a United Kingdom cohort of pediatric/juvenile patients (median age 9 years; 33 females); COVID-19 symptoms reported in 78% of patients, with the gastrointestinal tract being the most commonly involved; anti-SARS-CoV-2 IgG found in 87% of patients. Complete Kawasaki syndrome ascertained in 13 patients and coronary artery dilatation found in 14% of cases. Cardiogenic shock developing in 29 subjects and requiring resuscitation procedures
Belot et al[174]	2020	156	Nationwide surveillance analysis	Confirmed association with SARS-CoV-2 infection in 79 out of 156 PIMS reported cases; Kawasaki-like syndrome, myocarditis and MAS described in 61%, 70%, and 23% of patients (median age 8 years), respectively, and requiring critical care intervention in 67% of cases

ACPA: Anti-citrullinated protein antibodies; ANA: Antinuclear antibodies; anti-dsDNA: Anti-double stranded DNA; anti-ENA: Anti-extractable nuclear antigen; APL: Anti-phospholipid; ARDS: Acute respiratory distress syndrome; ASA: Acetylsalicylic acid; CK: Creatine phosphokinase; CRP: C-reactive protein; COVID-19: Coronavirus disease 2019; i.v.: Intravenous; Ig: Immunoglobulin; IL-6R: Interleukin-6 receptor; IVIG: Intravenous immunoglobulins; LAC: Lupus anticoagulant; MAS: Macrophage activation syndrome; MIS-C: Multisystem inflammatory syndrome in children; MRI: Magnetic resonance imaging; NYSDOH: New York State Department of Health; PIMS: Pediatric inflammatory multisystem syndrome; RF: Rheumatoid factor; RNP: Ribonucleoprotein; RT-PCR: Real-time reverse transcription polymerase chain reaction; SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2.